Synthesis of insecticidally active halofenozide-[(acyloxy)alkoxy]carbonyl and (acyloxy)alkyl derivatives

Article abstract of DOI:10.1055/s-2002-19296

The synthesis of a diverse series of novel insecticidally active carboxylic acid N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazinocarbonyloxy methyl and ethyl esters as well as carboxylic acid N'-benzoyl-N'-tert-butyl-N-(4-chlorobenzoyl)hydrazino methyl esters are reported.

Full text of DOI:10.1055/s-2002-19296

PAPER
53
Synthesis of Insecticidally Active Halofenozide-[(Acyloxy)alkoxy]carbonyl
and (Acyloxy)alkyl Derivatives
S
ynthesisof
H
alofenoz
a
ide-[(Acyl
r
oxy)alko
k
xy]carbonyl
a
nd(A
J
cyloxy)a
.
D
erivati
M
ves ulvihill,* Steven H. Shaber, Brian S. MacDougall, Chris Ajello, Blanca Martinez-Teipel, Rhoda Joseph,
Duyan V. Nguyen, Damian G. Weaver, KiHo Chung, Arkady Gusev, Joel M. Wierenga, William D. Mathis
Rohm and Haas Company, 727 Norristown Road, Spring House, Pennsylvania, 19477, USA
Fax +1(215)6191617; E-mail: mark.mulvihill@osip.com
Received 9 June 2001; revised 28 September 2001
ylic acids (R2CO2H) via a parallel synthesis approach to
afford various halofenozide-N-[(acyloxy)alkoxy]carbon-
yl derivatives (7 and 8, Scheme 1, Table 1). To our knowl-
edge, this is the first attempt to apply the
[(acyloxy)alkoxy]carbonyl moiety to diacyl hydrazines.6
In the case of halofenozide-(acyloxy)alkyl derivatives,
various methods exist which allow for the conversion of
amines to (acyloxy)alkylamino derivatives.7 Such meth-
ods include the reaction of nitrogen derivatives (tertiary
amines, triazoles, amides, etc.) with commercially avail-
able halomethyl acetates.8 However, the limited number
of commercially available halomethyl acetates, as well as
a synthesis of them which involves the reaction of a car-
boxylic acid with formaldehyde in the presence of a Lewis
acid such as ZnCl2 (procedure known to produce chlorom-
ethyl methyl ether [CME] and bis-CME), does not allow
for an efficient or safe route to the production of a thor-
ough library of N-(acyloxy)alkyl derivatives.7 In attempts
to by-pass such difficulties, this paper will report our nov-
el approach to the synthesis of N-(acyloxy)alkyl deriva-
tives via reaction of halofenozide 1a with thiocarbonic
acid S-ethyl ester O-iodomethyl ester 9 followed by treat-
ment with sulfuryl chloride to afford chloromethyl inter-
mediate 11, which then can be further reacted with various
carboxylic acids (R3CO2H) in the final step via a parallel
synthesis approach to afford various halofenozide-N-
(acyloxy)alkyl derivatives (12) (Scheme 2, Table 2) in an
efficient high throughput fashion. To our knowledge, this
is the first approach to substituted-N-(acyloxy)alkyl de-
rivatives via a thiocarbonate approach.
Abstract: The synthesis of a diverse series of novel insecticidally
active carboxylic acid N’-benzoyl-N’-tert-butyl-N-(4-chlorobenzo-
yl)hydrazinocarbonyloxy methyl and ethyl esters as well as carbox-
ylic acid N’-benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)hydrazino
methyl esters are reported.
Key words: carboxylic acids, drugs, esters, diacyl hydrazines, par-
allel synthesis
N-tert-Butyl diacyl hydrazines are an important class of
environmentally safe and selective insecticidal com-
pounds.1 One such example, halofenozide (1a) (N’-ben-
zoyl-N’-tert-butyl-N-(4-chlorobenzoyl)hydrazide)
(Scheme 1), won the Presidential Green Chemistry
Award for its environmental friendliness and is commer-
cially used as an ecdysone agonist to selectively control
Coleoptera and Lepidoptera in turf and ornamentals.2,3
Halofenozide, due to its highly crystalline nature and low
water solubility (12.3 ppm), tends to have a non-optimal
use rate and formulation difficulties.4 With this in mind,
we set out to change the physical properties associated
with halofenozide while attempting to retain or increase
its biological efficacy through functionalization of the NH
moiety with [(acyloxy)alkoxy]carbonyl and (acy-
loxy)alkyl moieties, commonly utilized in the pharmaceu-
tical industry to enhance the properties of drugs.5 In the
case of halofenozide [(acyloxy)alkoxy]carbonyl deriva-
tives, this paper will report the reaction of halofenozide
with commercially available chloromethyl and 1-chloro-
ethyl chloroformate and the further reaction with carbox-
O
O
O
O
N
ClCO2CHR1X
N
R2CO2H
N
N
N
N
2 (R1 = H, X = Cl)
3 (R1 = CH3, X = Cl)
O
O
DIEA, THF or
Cs2CO3, DMF
Cl
O
O
M
O
O
X
Cl
Cl
O
R1
R1
1a (M = H)
1b (M = K)
KOt-Bu
THF
O
R2
4 (R1 = H, X = Cl)
5 (R1 = CH3, X = Cl)
6 (R1 = H, X = I)
NaI,
acetone
7 (R1 = H)
8 (R1 = CH3)
Scheme 1 Synthesis of halofenozide-N-[(acyloxy)alkoxy]carbonyl derivatives 7 and 8
Synthesis 2002, No. 1, 28 12 2001. Article Identifier:
1437-210X,E;2002,0,01,0053,0058,ftx,en;M02901SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

54
M. J. Mulvihill et al.
PAPER
Table 1 Halofenozide-N-[(acyloxy)alkoxy]carbonyl Derivatives 7
and 8
We began our efforts with the synthesis of halofenozide-
N-[(acyloxy)alkoxy]carbonyl derivatives by treating ha-
lofenozide 1a with potassium tert-butoxide followed by
reaction with commercially available chloromethyl chlo-
roformate 2 or 1-chloroethyl chloroformate 3 to afford
chloromethyl analog 4 and chloroethyl analog 5, respec-
tively. Chloromethyl derivative 4 was reacted with NaI in
acetone under typical Finkelstein reaction conditions9 to
afford iodo analog 6, which then was reacted with various
carboxylic acids (R2CO2H) in the presence of diisopropyl-
ethylamine (DIEA) in THF in a parallel synthesis fashion,
to afford various halofenozide-N-[(acyloxy)-methoxy]-
carbonyl derivatives (7a–7z) (Scheme 1, Table 1). In a
Com- R1 R2
pound #
Mass % UV
Found purity
7a
7b
H
H
Me
Ph
446
508
100
100
7c
7d
7e
7f
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
t-Bu
488
472
582
520
526
502
528
498
552
528
543
516
492
489
515
614
536
569
540
504
567
559
575
579
460
550
100
100
86
cyclopropyl
diethoxyphosphorylmethyl
2-methoxyethoxymethyl
hept-1-ynyl
92
7g
7h
7i
100
100
100
100
100
95
Table 2 Halofenozide-N-(acyloxy)alkyl Derivatives 12
tetrahydrofur-3-yl
Com- R3
pound #
Mass % UV
Found purity
3,3,3-trifluoropropyl
1-cyclopentenyl
7j
12a
12b
12c
12d
12e
12f
12g
12h
12i
Me
402
430
464
414
531
557
571
533
444
538
573
100
92
7k
7l
2-(3-fluorophenyl)ethenyl
5-methylthien-2-yl
5-nitro-2-furyl
2-propyl
Ph
100
86
7m
7n
7o
7p
7q
7r
7s
7t
100
100
100
86
vinyl
hexyl
1-(tert-butoxycarbonylamino)ethyl
1-(tert-butoxycarbonyl)pyrrolidin-2-yl
1-(tert-butoxycarbonyl)piperidin-4-yl
3,6-dichloro-2-pyridyl
t-Bu
100
100
96
methylthiomethyl
1-formylaminomethyl
1-acetylaminovinyl
3,5-dinitro-4-hydroxyphenyl
4-formylphenyl
100
100
95
100
84
12j
12k
diethoxyphosphorylmethyl
93
2,6-dimethoxy-3-pyridyl
2-(thien-2-yl)ethenyl
acetoxymethyl
100
100
88
1-tert-butoxycarbonyl-4-hydroxypyr-
95
7u
7v
7w
7x
7y
7z
8a
8b
8c
8d
8e
8f
rolidin-2-yl
12l
1-(tert-butoxycarbonylamino)methyl
1-(formylamino)methyl
1-acyl-4-hydroxypyrrolidin-2-yl
3-amino-4-methylphenyl
3,5,6-trichloro-4-amino-2-pyridyl
hydroxyethyl
517
445
515
493
582
432
479
479
494
509
481
388
508
481
88
100
100
89
5-(methoxycarbonyl)pyridin-2-yl
1-acetylaminopentyl
1-(tert-butoxycarbonylamino)ethyl
1-formylamino-2-phenylethyl
100
95
12m
12n
12o
12p
12q
12r
12s
12t
91
95
96
Me Me
100
100
96
100
100
100
100
100
100
100
100
91
Me 4-formylphenyl
2-aminophenyl
Me 1-(tert-butoxycarbonyl)piperidin-4-yl 629
4-aminophenyl
Me N-methyl-2-pyrrolidinyl
Me 2,6-dimethoxy-3-pyridyl
Me 5-methylthien-2-yl
Me 2-(2-fluorophenyl)ethenyl
Me vinyl
525
583
542
566
472
542
528
100
100
100
100
100
96
3,4-diaminophenyl
12u
12v
12w
12x
12y
3-amino-4-methoxyphenyl
2-hydroxy-3-pyridyl
H
8g
8h
8i
benzyloxymethyl
Me 3-methylthien-2-yl
Me thien-3-yl
3-amino-2-pyrazinyl
8j
100
Synthesis 2002, No. 1, 53–58 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Halofenozide-[(Acyloxy)alkoxy]carbonyl and (Acyloxy)alkyl Derivatives
55
O
O
O
O
EtS
O
9
I
R3CO2H,
DIEA, THF
N
SO2Cl2
N
O
N
N
O
N
O
N
1b
O
O
O
Cl
O
Cl
Cl
Cl
R3
11
SEt
12
10
Scheme 2 Synthesis of halofenozide-N-(acyloxy)methyl derivatives 12
further reaction of chloroethyl derivative 5, we discovered loxy)alkoxy]carbonyl derivatives (7 and 8) displayed
that chloroethyl analog 5 did not undergo halogen inter- higher insecticidal activity than their (acyloxy)alkyl coun-
conversion under Finkelstein conditions. Direct reaction terparts (12). The physical properties ranged from oils to
of chloroethyl analog 5 with carboxylic acids (R2CO2H) solids and the water solubility ranged from 1 ppb to 100
in the presence of DIEA in THF was very sluggish and ppm. Hydrolytic stability was measured as a function of
many times afforded no reaction. However, reaction in the pH (4.5, 6.5, and 8.5) to determine the chemical stability
presence of cesium carbonate in DMF smoothly afforded of this class of compounds. In most cases, the (acy-
various
halofenozide-N-[(acyloxy)-1-ethoxy]carbonyl loxy)alkyl derivatives were more hydrolytically stable
derivatives 8a–j (Scheme 1, Table 1). Compounds 7a, 7b, than their [(acyloxy)alkoxy]carbonyl counterparts. The
7c, 8a and 8b were fully characterized as representative hydrolytic stability and biological results in accordance
examples of this class of chemistry. The chemistry was with the entire library of compounds synthesized will be
then scaled down from 500 mg to 50 mg and a parallel reported at a later date.
synthesis approach (utilizing a 96 well reaction block [496
MBS, Advanced Chemtech] and a Genevac HT-12) was
Reagents and solvents were used as received from commercial ven-
applied to the synthesis of compounds 7d–z and 8b–j,
which were characterized by LC/UV/MS and are shown
in Table 1.
dors and no further attempts were made to purify or dry these items.
TLC with UV detection was performed on 4 8 cm, SIL 6UV/254
silica gel plates with fluorescent indicator (Alltech Associates,
Inc.). Column chromatography was performed on silica gel (Merck,
70–230 mesh). 1H and 13C NMR spectra were obtained in CDCl3 on
a Bruker 300 MHz spectrometer. All 1H NMR spectra are reported
in ppm relative to TMS. All 13C NMR spectra are reported in ppm
Our efforts toward the synthesis of halofenozide-N-(acy-
loxy)alkyl derivatives began with the reaction of the po-
tassium salt of halofenozide 1b with thiocarbonic acid S-
ethyl ester O-iodomethyl ester 95e to afford thiocarbonate relative to the central line of the triplet for CDCl3 at 77.00 ppm.
Melting points were obtained on a Thomas Hoover capillary
10. Thiocarbonate 10 was treated with sulfuryl chloride,
to afford chloromethyl derivative 11,10 which was reacted
melting point apparatus and are uncorrected. IR spectra (reported
in cm–1) were obtained on a Mattson Genesis II FT-IR spectropho-
with various carboxylic acids (R3CO2H) in the presence of
tometer after dissolving the compound in chloroform and then ap-
plying the solution to a polyethylene film. Elemental analyses were
diisopropylethylamine (DIEA) in THF in a parallel syn-
thesis fashion to afford various halofenozide-N-(acy-
loxy)methyl derivatives (12) (Scheme 2, Table 2).
Halofenozide-N-(acyloxy)methyl derivatives 12a, 12b
were prepared and fully characterized as representative
examples of this class of chemistry. The chemistry was
then scaled down from 500 mg to 50 mg and a parallel
synthesis approach (utilizing a 96 well reaction block [496
MBS, Advanced Chemtech] and a Genevac HT-12) was
applied to the synthesis of compounds 12b–y, which were
characterized by LC/UV/MS as shown in Table 2.
performed by Robertson Microlit Laboratories, Inc., 29 Samson
Avenue, P.O. Box 927, Madison, New Jersey 07940.
LC/UV MS Procedures
For liquid chromatography (LC)/ultraviolet (UV) mass spectrome-
try (MS) analysis, the samples were dissolved in CH3CN–H2O (1:1)
at concentrations of 100 g/mL to 1000 g/mL. The LC/UV MS
analysis was performed using the HPLC 1100-VG Platform. The
UV and MS instruments were connected in sequence, and the anal-
ysis was carried out in one injection where LC/UV afforded the pu-
rity (%) and MS confirmed the molecular weight. UV analysis was
carried out using a scanning diode array detector (200–300 nm). MS
analysis was carried out in positive scanning mode (100–1000 dal-
tons). A short C18 HPLC column (3 mm ID, 5 cm length) was used
with a flow rate of 1 mL/min. The eluent was split 1:25 after UV de-
tection and 1 part was sent to the MS. The typical HPLC gradient
was H2O–CH3CN (25:75) CH3CN (100%) over 5 min (0.1% for-
mic acid added). Injection volume varied between 1 and 25 L. In
some cases, it was necessary to change certain parameters, e.g., ion
mode (positive or negative), UV wavelength, or solvent buffer (no
buffer, formic acid, HOAc, or ammonia acetate). The data is pre-
sented in Tables 1 and 2.
In conclusion, various halofenozide-N-[(acyloxy)-
alkoxy]carbonyl derivatives (7 and 8) were synthesized.
Also, various halofenozide-N-(acyloxy)alkyl derivatives
(12) were synthesized via a novel route utilizing thiocar-
bonate 10. In general, both the halofenozide-N-[(acy-
loxy)alkoxy]carbonyl (7 and 8) and (acyloxy)alkyl
derivatives (12), ranged in biological activity from 1–
12, in potency in feeding assays relative to the parent
compound, halofenozide (1a). Generally, the [(acy-
Synthesis 2002, No. 1, 53–58 ISSN 0039-7881 © Thieme Stuttgart · New York

56
M. J. Mulvihill et al.
PAPER
N’-Benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)hydrazine-car-
boxylic Acid Chloromethyl Ester (4)
IR (cm–): 1771, 1709, 1678.
1H NMR (300 MHz, CDCl3): = 1.62 (s, 9 H), 2.07 (s, 3 H), 5.65
(m, 2 H), 6.55 (d, 2 H, J = 9.0 Hz), 7.14 (d, 2 H, J = 9.0 Hz), 7.29–
7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): = 20.4, 27.3, 63.3, 81.2, 124.8, 128.2,
128.6, 128.7, 129.2, 132.5, 137.7, 138.2, 152.6, 168.7, 169.5, 171.9.
To a suspension of t-BuOK (18.5 g, 165 mmol) in THF (1500 mL)
was added halofenozide 1a portionwise (40.0 g, 121 mmol) over 5
min. The mixture was heated to reflux for 30 min, allowed to cool
to r.t. and stirred for an additional 30 min. Chloromethyl chlorofor-
mate (2) (13.5 mL, 71.5 mmol) was added dropwise to the yellow
homogeneous mixture over 5 min. The mixture was stirred at r.t. for
1 h, after which time, the THF was removed in vacuo and the result-
ing slurry was taken up into Et2O (800 mL), dried (Na2SO4), filtered
and the solvent removed in vacuo. Silica gel chromatography (hex-
anes–EtOAc, 5:1) afforded the title compound 4 (43.0 g, 85%) as a
white solid; mp = 113–115 °C.
Anal. calcd for C22H23ClN2O6: C, 59.13; H, 5.19; N, 6.27. Found:
C, 58.96; H, 5.22; N, 6.18.
Benzoic Acid N’-Benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)-
hydrazinocarbonyloxymethyl Ester (7b)
Compound 7b (oily solid) was prepared according to the procedure
described for compound 7a above except for the substitution of ben-
zoic acid for HOAc.
IR (cm–1): 2983, 1769, 1711, 1675.
1H NMR (300 MHz, CDCl3): = 1.64 (s, 9 H), 5.64 (s, 2 H), 6.56
IR (cm–1): 1765, 1745, 1709, 1679.
(d, 2 H, J = 9.0 Hz), 7.16 (d, 2 H, J = 9.0 Hz), 7.29–7.37 (m, 5 H).
1H NMR (300 MHz, CDCl3): =1.61 (s, 9 H), 5.91 (m, 2 H), 6.51
(d, 2 H, J = 6.0 Hz), 6.98 (d, 2 H, J = 9.0 Hz), 7.17–7.31 (m, 5 H),
7.52 (m, 2 H), 7.65 (m, 1 H), 8.01 (d, 2 H, J = 9.0 Hz).
13C NMR (75 MHz, CDCl3): = 27.3, 63.3, 81.3, 124.7, 128.1,
128.2, 128.6, 128.7, 128.8, 129.1, 130.1, 132.4, 134.2, 137.7, 138.2,
152.9, 164.3, 169.6, 171.9.
13C NMR (75 MHz, CDCl3): = 26.5, 62.6, 70.2, 123.8, 127.4,
127.8, 128.1, 128.4, 131.1, 136.6, 137.6, 151.3, 168.5, 170.9
Anal. calcd for C20H20Cl2N2O4: C, 56.75; H, 4.76; N, 6.62. Found:
C, 56.71; H, 4.47; N, 6.50.
N’-Benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)hydrazine-car-
boxylic Acid 1-Chloroethyl Ester (5)
Compound 5 was prepared according to the procedure described for
compound 4 above except for the substitution of 1-chloroethyl chlo-
roformate 3 for chloromethyl chloroformate 2; mp = 130–131 °C.
Anal. calcd for C27H25ClN2O6: C, 63.72; H, 4.95; N, 5.50. Found:
C, 63.61; H, 4.77; N, 5.39.
Trimethylacetic Acid N’-Benzoyl-N’-tert-butyl-N-(4-chloro-
benzoyl)hydrazino-carbonyloxymethyl Ester (7c)
Compound 7c (oily solid) was prepared according to the procedure
described for compound 7a above except for the substitution of tri-
methlylacetic acid for HOAc.
IR (cm–1): 1763, 1711, 1680.
1H NMR (300 MHz, CDCl3) = 1.20 (s, 9 H), 1.62 (s, 9 H), 5.69 (s,
IR (cm–1): 2981, 2942, 1768, 1712, 1680.
1H NMR (300 MHz, CDCl3): = 1.48 (d, 3 H, J = 6.0 Hz), 1.63 (s,
9 H), 6.27 (q, 1 H, J = 6.0 Hz), 6.55 (d, 2 H, J = 9.0 Hz), 7.16 (d, 2
H, J = 9.0 Hz), 7.29–7.37 (m, 5 H).
13C NMR (75 MHz, CDCl3): = 24.5, 27.4, 63.2, 83.6, 124.9, 128.3,
128.6, 128.8, 129.2, 132.5, 137.5, 138.3, 151.7, 169.4, 171.9.
2 H), 6.54 (m, 2 H), 7.13 (d, 2 H, J = 9.0 Hz), 7.29–7.31 (m, 5 H).
Anal. calcd for C21H22Cl2N2O4: C, 57.68; H, 5.07; N, 6.41. Found:
C, 57.94; H, 4.98; N, 6.36.
13C NMR (75 MHz, CDCl3): = 26.8, 27.3, 38.8, 63.3, 81.9, 124.7,
128.2, 128.6, 128.7, 129.2, 132.3, 137.7, 138.2, 152.6, 169.6, 171.8,
176.4.
N’-Benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)hydrazine-car-
boxylic Acid Iodomethyl Ester (6)
Anal. calcd for C25H29ClN2O6: C, 61.41; H, 5.98; N, 5.73. Found:
C, 61.21; H, 5.84; N, 5.70.
To a solution of N’-benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)hy-
drazinecarboxylic acid chloromethyl ester 4 (32.0 g, 75.6 mmol) of
acetone (200 mL) was added NaI (22.6 g, 151 mmol) and heated to
30 °C for 3 h. The acetone was removed in vacuo and the slurry was
treated with Et2O. The resulting precipitated white solids were fil-
tered off and the filtrate was concentrated to afford the title com-
pound 6 as a yellow solid (recrystallized from Et2O–hexanes, 36 g,
93%); mp = 123–125 °C.
IR (cm–1): 2980, 1765, 1710, 1675.
1H NMR (300 MHz, CDCl3): = 1.63 (s, 9 H), 5.82 (m, 2 H), 6.55
(d, 2 H, J = 9.0 Hz), 7.17 (d, 2 H, J = 9.0 Hz), 7.26–7.38 (m, 5 H).
13C NMR (75 MHz, CDCl3): = 26.6, 30.4, 62.6, 124.0, 127.6,
128.0, 128.2, 128.5, 131.2, 136.7, 137.7, 151.2, 168.5, 171.0.
Acetic Acid 1-[N’-Benzoyl-N’-tert-butyl-N-(4-chloro-benzoyl)-
hydrazinocarbonyloxy]-ethyl Ester (8a)
Compound 8a was prepared according to the procedures described
for compound 7a above except for the substitution of N’-benzoyl-
N’-tert-butyl-N-(4-chlorobenzoyl)hydrazine-carboxylic acid 1-
chloroethyl ester 5 for N’-benzoyl-N’-tert-butyl-N-(4-chloroben-
zoyl)-hydrazinecarboxylic acid iodomethyl ester 6, the substitution
of Cs2CO3 for DIEA, and the substitution of DMF for THF with a
reaction temperature of 50 °C; mp = 129–131 °C.
IR (cm–1): 1769, 1709, 1679.
1H NMR (300 MHz, CDCl3) = 1.34 (d, 3 H, J = 6.0 Hz), 1.54 (s,
9 H), 1.91 (s, 3 H), 6.45 (d, 2 H, J = 9.0 Hz), 6.63 (q, 1 H, J = 6.0
Hz), 7.05 (d, 2 H, J = 9.0 Hz), 7.20–7.31 (m, 5 H).
13C NMR (75 MHz, CDCl3): = 18.2, 19.5, 26.4, 62.1, 90.0, 123.7,
127.1, 127.6, 127.8, 128.2, 131.7, 136.7, 136.9, 150.6, 167.4, 168.7,
170.8.
Anal. calcd for C20H20ClIN2O4: C, 46.67; H, 3.92; N, 5.44. Found:
C, 46.76; H, 3.88; N, 5.31.
Acetic Acid N’-Benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)-
hydrazinocarbonyloxy-methyl Ester (7a)
To a solution of N’-benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)hy-
drazinecarboxylic acid iodomethyl ester 6 (500 mg, 0.97 mmol) in
THF (10 mL) was added glacial HOAc (0.11 mL, 1.85 mmol) and
diisopropylethylamine (DIEA) (0.34 mL, 1.94 mmol). The mixture
was stirred for 16 h, after which time, the resulting white precipitate
was filtered off and the THF solution was concentrated in vacuo to
an oil. Silica gel chromatography (hexanes–EtOAc, 4:1) afforded
395 mg (91%) of the title compound 7a as an oily solid.
Anal. calcd for C23H25ClN2O6: C, 59.94; H, 5.47; N, 6.08. Found:
C, 59.85; H, 5.44; N, 5.97.
4-Formylbenzoic Acid 1-[N’-Benzoyl-N’-tert-butyl-N-(4-
chlorobenzoyl)hydrazino-carbonyloxy]ethyl Ester (8b)
Compound 8b was prepared according to the procedure described
for compound 8a above except for the substitution of 4-formylben-
zoic acid for HOAc; mp = 137–139 °C.
Synthesis 2002, No. 1, 53–58 ISSN 0039-7881 © Thieme Stuttgart · New York

PAPER
Synthesis of Halofenozide-[(Acyloxy)alkoxy]carbonyl and (Acyloxy)alkyl Derivatives
57
IR (cm–1): 1763, 1743, 1707, 1678.
Benzoic Acid N-tert-Butyl-N’-(4-chlorobenzoyl)-N’-chlorome-
thylhydrazide (11)
1H NMR (300 MHz, CDCl3) = 1.58 (m, 3 H), 1.62 (s, 9 H), 6.48
(m, 2 H), 7.05 (m, 4 H), 7.30 (m, 5 H), 8.00 (d, 2 H, J = 9.0 Hz),
8.07 (d, 2 H, J = 9.0 Hz), 10.11 (s, 1 H);
13C NMR (75 MHz, CDCl3): = 19.8, 27.6, 63.6, 92.0, 125.1, 128.5,
129.0, 129.1, 129.6, 130.1, 130.8, 133.0, 133.6, 138.1, 138.4, 140.2,
152.0, 163.5, 170.0, 172.2, 191.7.
To a suspension of thiocarbonic acid O-[N’-benzoyl-N’-tert-butyl-
N-(4-chlorobenzoyl)hydrazinomethyl] ester S-ethyl ester 10 (5.00
g, 11.14 mmol) in 50 mL of CH2Cl2, cooled to –78 °C in a dry ice/
acetone bath, was added sulfuryl chloride (1.20 mL, 14.48 mmol).
The mixture was allowed to stir at r.t. for 1 h after which time, the
solution was concentrated in vacuo to afford the desired product 11
as a white solid (recrystallized from hot hexanes, 3.7 g, 88% yield);
mp = 116–118 °C.
Anal. calcd for C29H27ClN2O7: C, 63.22; H, 4.94; N, 5.08. Found:
C, 63.29; H, 4.85; N, 5.05.
IR (cm–1): 2944, 1692, 1670.
1H NMR (300 MHz, CDCl3): = 1.71 (s, 9 H), 4.89 (m, 2 H), 7.24–
7.49 (m, 9 H).
13C NMR (75 MHz, CDCl3) = 27.8, 62.6, 65.0, 125.6, 127.8,
128.3, 129.1, 129.9, 131.6, 137.2, 137.6, 170.9, 172.1.
Carboxylic Acid N’-Benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)-
hydrazino-carbonyloxy Methyl and Ethyl Esters 7a-z and 8a-j;
Cyclopropanecarboxylic Acid N’-Benzoyl-N’-tert-butyl-N-(4-
chlorobenzoyl)hydrazinocarbonyloxymethyl Ester (7d);
Typical Parallel Synthesis Procedure
Compound 7d: cyclopropanecarboxylic acid (16 mg, 0.19 mmol) in
THF (350 L) was delivered to a 96 well reaction block (496 MBS,
Advanced Chemtech) followed by DIEA (34 L) in THF (300 L).
The block was stirred at r.t. for 30 min, at which time a solution of
N’-benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)hydrazinecarboxyl-
ic acid iodomethyl ester 6 (50 mg, 0.097 mmol) in THF (350 L)
was delivered. Stirring was continued at r.t. for up to 48 h. The re-
action was monitored by TLC (hexanes–EtOAc, 3:1). The reaction
was filtered into the cleavage block, the solvent was removed in a
Genevac HT-12, and the residue was dissolved in a minimal amount
of CH2Cl2 and placed on a preconditioned (hexanes) 2 g silica solid
phase extraction cartridge. The unreacted starting material was elut-
ed with hexanes (5 mL) and the product with hexanes–EtOAc, 1:1
(5 mL). Alternatively, the compound was purified by preparative
HPLC. The solvent was stripped and the product was dried in vac-
uo, yielding the title compound 7d (40 mg, 87%) (Table 1). Com-
pounds 8 were synthesized according to the method above except
for the substitution of N’-benzoyl-N’-tert-butyl-N-(4-chloroben-
zoyl)hydrazinecarboxylic acid 1-chloroethyl ester 5 for N’-benzoyl-
N’-tert-butyl-N-(4-chlorobenzoyl)hydrazinecarboxylic acid iodom-
ethyl ester 6, the substitution of Cs2CO3 for DIEA and the substitu-
tion of DMF for THF with a reaction temperature of 50 °C
(Table 1).
Anal. calcd for C19H20Cl2N2O2: C, 60.17; H, 5.32; N, 7.39. Found:
C, 59.91; H, 5.07; N, 7.41.
Acetic Acid N’-Benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)-hy-
drazinomethyl Ester (12a)
A solution of benzoic acid N-tert-butyl-N’-(4-chlorobenzoyl)-N’-
chloromethylhydrazide 11 (0.50 g, 1.32 mmol) in THF (1 mL) was
added to a solution of HOAc (0.17 mL, 2.90 mmol) and DIEA (0.52
mL, 2.90 mmol) dissolved in THF (2 mL). The mixture was allowed
to stir at r.t. for 16 h. The THF was removed under reduced pressure
and the resulting slurry was treated with Et2O. The resulting white
precipitated solids were filtered off and the filtrate concentrated in
vacuo. Silica gel chromatography (hexanes–EtOAc, 85:15) afford-
ed the desired product 12a as an oil (360 mg, 76%).
IR (cm–1): 2944, 1752, 1669.
1H NMR (300 MHz, CDCl3) = 1.65 (s, 9 H), 2.02 (s, 3 H), 5.07
(m, 2 H), 7.05 (d, 2 H, J = 6.6 Hz), 7.29–7.47 (m, 7 H).
13C NMR (75 MHz, CDCl3) = 20.9, 27.8, 62.3, 77.3, 125.5, 128.0,
128.2, 129.0, 129.6, 132.0, 137.4, 137.6, 169.2, 171.1, 172.3.
Anal. calcd for C21H23ClN2O4: C, 62.61; H, 5.75; N, 6.95. Found:
C, 62.52; H, 5.57; N, 6.86.
Carboxylic Acid N’-Benzoyl-N’-tert-butyl-N-(4-chlorobenzoyl)-
hydrazino Methyl Esters 12a-y; Isobutyric Acid N’-Benzoyl-N’-
tert-butyl-N-(4-chlorobenzoyl)-hydrazinocarbonyloxymethyl
Ester (12b); Typical Parallel Synthesis Procedure
Compound 12b was prepared according to the parallel synthesis
procedure described for compound 7d above except for the substi-
tution of isobutyric acid for cyclopropanecarboxylic acid and the
substitution of benzoic acid N-tert-butyl-N’-(4-chlorobenzoyl)-N’-
chloromethylhydrazide 11 for N’-benzoyl-N’-tert-butyl-N-(4-chlo-
robenzoyl)hydrazine carboxylic acid iodomethyl ester 6. Com-
pounds 12c y were prepared as described above for compound 12b
and were characterized by LC/UV MS and are shown in Table 2.
IR (cm–1): 2974, 1742, 1690, 1671.
1H NMR (300 MHz, CDCl3) = 1.44 (m, 6 H), 1.66 (s, 9 H), 2.50
(m, 1 H), 5.03 (s, 2 H), 7.06 (d, 2 H, J = 9.0 Hz), 7.35–7.49 (m, 7 H).
13C NMR (75 MHz, CDCl3): = 18.7, 27.7, 33.9, 62.3, 78.1, 125.4,
127.9, 128.2, 128.9, 129.7, 132.0, 137.3, 137.5, 171.1, 172.4, 175.3.
Thiocarbonic Acid O-[N’-Benzoyl-N’-tert-butyl-N-(4-chloro-
benzoyl)hydrazino-methyl] Ester S-Ethyl Ester (10)
To a suspension of halofenozide (N’-benzoyl-N’-tert-butyl-N-[4-
chlorobenzoyl]hydrazide) 1a (0.31 g, 0.93 mmol) in THF (9.3 mL)
was added t-BuOK (0.11 g, 0.93 mmol). The mixture was allowed
to stir at r.t. for 2 h after which time thiocarbonic acid S-ethyl ester
O-iodomethyl ester 95e (0.25 g, 0.93 mmol) was added. The mixture
was allowed to stir at r.t. for 16 h. The THF was removed under re-
duced pressure and the resulting slurry was treated with Et2O. The
resulting white precipitated solids were filtered off and the filtrate
was concentrated to an oil. Silica gel chromatography (hexanes–
EtOAc, 7:3) afforded compound 10 as a white solid (300 mg, 61%);
mp = 125–127 °C.
IR (cm–1): 2944, 1695, 1671.
1H NMR (300 MHz, CDCl3): = 1.31 (t, 3 H, J = 7.2 Hz), 1.65 (s,
9 H), 2.86 (q, 2 H, J = 7.2 Hz), 5.15 (m, 2 H), 7.06 (d, 2 H, J = 9.0
Hz), 7.30–7.47 (m, 7 H).
13C NMR (75 MHz, CDCl3): = 14.8, 25.4, 27.8, 62.5, 78.8, 125.4,
128.1, 128.2, 129.0, 129.6, 131.7, 137.4, 137.5, 170.2, 171.0, 172.4.
Anal. calcd for C23H27ClN2O4: C, 64.11; H, 6.32; N, 6.50. Found:
C, 64.37; H, 6.55; N, 6.26.
Anal. calcd for C22H25ClN2O4S: C, 58.86; H, 5.61; N, 6.24. Found:
C, 58.96; H, 5.45; N, 6.14.
Acknowledgements
We thank Drs. Dennis Patterson and Harvey Scribner for many
fruitful discussions and support of the project as well as Kristen M.
Mulvihill for her help in preparation of the manuscript.
Synthesis 2002, No. 1, 53–58 ISSN 0039-7881 © Thieme Stuttgart · New York

58
M. J. Mulvihill et al.
PAPER
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affords the respective chloroformates (ref.5e). However, in
this case, treatment of thiocarbonate 10 with sulfuryl
chloride afforded chloromethyl derivative 11 with no trace
of the respective chloroformate. Chloromethyl derivative 11
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However, chloromethyl derivative 11 could be recrystallized
from hot hexanes to afford the pure product, which was
stored at –20 °C.
chloroformates 2 and 3 did not afford cyclized oxadiazol-2-
one products but afforded stable isolable compounds 4, 5
and 6 which were further reacted to afford stable isolable
esters 7 and 8.
Synthesis 2002, No. 1, 53–58 ISSN 0039-7881 © Thieme Stuttgart · New York