Synthesis and application of novel glyoxylate-derived chloroformates

Article abstract of DOI:10.1055/s-2002-20036

A convenient process for the synthesis of glyoxylate-derived chloroformates has been developed. The approach involves the reaction of glyoxylate esters with triphosgene and pyridine in various solvent systems. These novel glyoxylate-derived chloroformates are multifunctional, possessing a chloroformate, ester, and haloalkyl moiety. Further elaboration via a thiocarbonate route afforded highly functionalized carboxylic acid-derived alkoxycarbonyl-chlorocarbonyloxy-methyl esters. Application of a benzyl glyoxylate-derived chloroformate to halofenozide was also accomplished, affording halofenozide-N-carbonyloxy-chloro/iodoacetic acid benzyl ester derivatives, which-were further derivatized to carboxylic acid-derived (halofenozide-N-carbonyloxy)-benzyloxycarbonyl-methyl esters. The trifunctional nature of the glyoxylate moiety was demonstrated through conversion of the benzyloxycarbonyl moiety of a carboxylic acid-derived (halofenozide-N-carbonyloxy)-benzyloxycarbonyl-methyl ester to its respective diethylamide.

Full text of DOI:10.1055/s-2002-20036

PAPER
365
Synthesis and Application of Novel Glyoxylate-derived Chloroformates
S
ynthesis and Applica
t
a
ion of Nove
r
l
G
lyox
k
ylate-derived Chlor
J
oformate
.
Mulvihill,* James Gallagher,* Brian S. MacDougall, Damian G. Weaver, Duyan V. Nguyen, KiHo Chung,
William Mathis
Rohm and Haas Company, 727 Norristown Road, Spring House, Pennsylvania, 19477, USA
Fax +1(914)3453565; E-mail: mark.mulvihill@osip.com
Received 20 October 2001; revised 4 January 2002
1 (R1 = H)
2 (R1 = Me)
3 (R1 = Ph)
O
R1
Abstract: A convenient process for the synthesis of glyoxylate-de-
rived chloroformates has been developed. The approach involves
the reaction of glyoxylate esters with triphosgene and pyridine in
various solvent systems. These novel glyoxylate-derived chlorofor-
mates are multifunctional, possessing a chloroformate, ester, and
haloalkyl moiety. Further elaboration via a thiocarbonate route af-
Cl
O
Cl
Figure 1 Chloroformates 1–3
forded highly functionalized carboxylic acid-derived alkoxycarbo- The benzyl glyoxylate-derived chloroformate 5a
(R2 = benzyl) was prepared first by adding pyridine over
nyl-chlorocarbonyloxy-methyl esters. Application of a benzyl
glyoxylate-derived chloroformate to halofenozide was also accom-
plished, affording halofenozide-N-carbonyloxy-chloro/iodoacetic
osgene in THF at –20 °C. The reaction was allowed to
acid benzyl ester derivatives, which were further derivatized to car-
5 minutes to a solution of benzyl glyoxylate 4a and triph-
warm to r.t. and then heated to 60 °C with stirring for 2 h.
boxylic acid-derived (halofenozide-N-carbonyloxy)-benzyloxycar-
The solution was cooled, the precipitates formed were fil-
tered, and the filtrate was concentrated to afford the de-
sired chloroformate 5a as a clear colorless oil in 90% yield
(Entry 1, Table). We screened five solvents, carbon tetra-
chloride, tetrahydrofuran, dioxane, toluene and diethyl
ether, for each aldehyde 4a–f, in an attempt to optimize
the reaction conditions. In the case of glyoxylates 4a–c,
THF proved to be the best solvent while dioxane was best
for glyoxylates 4d–f (Table).
bonyl-methyl esters. The trifunctional nature of the glyoxylate
moiety was demonstrated through conversion of the benzyloxycar-
bonyl moiety of a carboxylic acid-derived (halofenozide-N-carbon-
yloxy)-benzyloxycarbonyl-methyl ester to its respective diethyl-
amide.
Key words: glyoxylate esters, chloroformates, alkyl halide, car-
boxylic acids, aldehydes
Chloroformates such as formaldehyde-, acetaldehyde-
and benzaldehyde-derived chloroformates, chloromethyl
chloroformate (1, R1 = H), 1-chloroethyl chloroformate
(2, R1 = Me), and chlorobenzyl chloroformate (3,
R1 = substituted phenyl), respectively, have been exten-
sively utilized due to their bifunctional nature
(Figure 1).1–10 They have received much attention due to
their ability to undergo reaction at the chloroformate as
well as at the chloroalkyl/benzyl moiety. In studies utiliz-
ing commercially available chloroalkyl/benzyl chlorofor-
O
OR2
Cl
O
O
OR2
O
triphosgene
pyridine, solvent
Cl
O
5
4
Scheme 1 Synthesis of glyoxylate-derived chloroformates 5
For certain applications, it would be advantageous to pre-
pare advanced carbonochloridates by reaction of the chlo-
roalkyl moiety of 5 with a carboxylic acid prior to reaction
at the chloroformate group. For example, amines, alco-
hols, or thiols with sensitive functional groups, which
would not survive or would interfere with the subsequent
Finkelstein and/or carboxylate alkylation reactions,
would benefit from a completely prepared chloroformate,
which would require a straightforward one-step reaction
at the chloroformate moiety. To do this, we applied the
thiocarbonate route developed by Folkman and Lund for
formaldehyde-based chloroalkyl chloroformates.10 As an
example, n-butyl glyoxylate-derived chloroformate 5c
was treated with sodium ethanethiolate in diethyl ether to
cleanly afford thiocarbonate 6 in 94% yield. Thiocarbon-
ate 6 was converted into iodo analog 7 via the Finkelstein
reaction,11 and subsequently treated with various carbox-
ylic acids (Z1CO2H) to afford compounds 11 (Z1 = t-bu-
tyl, 86%), 12 (Z1 = phenyl, 91%), and 13 (Z1 = 2-propyl,
88%). Compounds 11, 12, and 13 were each treated with
mates,1,2 we developed
a need for trifunctional
chloroformates in which R1 could be a moiety other than
hydrogen, alkyl, or aryl. To develop such novel trifunc-
tional chloroformates, we decided that incorporation of a
carboxy ester functional group at R1 would provide a suit-
able handle for further chemical manipulation, thereby
creating a class of trifunctional chloroformates from
which amine, alcohol, and thiol containing compounds
could be attached and further elaborated. Here we report
studies toward the synthesis of novel, highly functional-
ized glyoxylate-derived chloroformates (5, Scheme 1)
and their application toward the synthesis of novel alkyl
2-acetoxy-2-[(chlorocarbonyl)oxy]
acetates
14–16
(Scheme 2) and glyoxylate-derived halofenozide deriva-
tives 19–22 (Scheme 3).
Synthesis 2002, No. 3, 18 02 2002. Article Identifier:
1437-210X,E;2002,0,03,0365,0370,ftx,en;M04201SS.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0039-7881

366
M. J. Mulvihill et al.
PAPER
Table Synthesis of Glyoxylate-derived Chloroformates 5 From
Glyoxylate Esters 4
sulfuryl chloride in methylene chloride to afford quantita-
tively the highly functionalized chloroformates 14, 15,
and 16, respectively.
En- Glyoxylate Esters 4 Glyoxylate-derived
Sol- Yield
try
Chloroformates 5
vent (%)
With the glyoxylate-derived chloroformates in hand, we
focused our attention on their application towards the syn-
thesis of carboxylic acid-derived (halofenozide-N-carbo-
nyloxy)-benzyloxycarbonyl-methyl esters. Halofenozide
[17, N -benzoyl-N -(tert-butyl)-4-chlorobenzohydrazide,
Scheme 3], won the Presidential Green Chemistry Award
for its environmental friendliness and is commercially
used as an ecdysone agonist to selectively control Co-
leoptera and Lepidoptera in turf and ornamentals.12,13
However, due to its highly crystalline nature and low wa-
ter solubility (12.3 ppm), it tends to have a non-optimal
use rate and formulation difficulties.14 Our previous work
in the synthesis of diacylhydrazine-N-[(acyloxy)benzyl-
oxy]carbonyl, diacylhydrazine-N-(acyloxy)alkoxy]carbo-
nyl and diacylhydrazine-N-(acyloxy)alkyl derivatives
afforded compounds with biological activities
>10 times in potency in feeding assays relative to their
parent diacylhydrazine compounds.1,2 With this success,
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 the newly synthesized glyoxylate-derived
chloroformates. The synthesis of glyoxylate-derived ha-
lofenozide species began with the reaction of benzyl gly-
oxylate-derived chloroformate 5a with the potassium salt
of halofenozide (18) to afford halofenozide-N-carbonyl-
oxy-chloroacetic acid benzyl ester 19 in 75% yield
(Scheme 3). Treatment of compound 19 with NaI in ace-
tone afforded iodo intermediate 20,11 which was reacted
1
THF 90
O
O
O
O
O
O
O
Cl
Cl
4a
5a
2
THF 89
THF 95
O
O
O
O
O
O
O
O
O
Cl
Cl
4b
5b
3
4
O
O
O
O
O
Cl
Cl
4c
5c
diox- 97
ane
O
O
O
O
O
O
O
O
O
O
O
4d
O
Cl
Cl
5d
5
6
diox- 85
ane
O
O
O
O
4e
O
Cl
Cl
5e
diox- 98
ane
O
O
O
O
Cl
Cl
4f
5f
Bu
O
Bu
O
O
OBu
X
O
O
OBu
X
O
O
O
O
O
O
O
O
O
O
SO2Cl2
DIEA, THF
EtSNa
ether
94%
Cl
O
EtS
EtS
O
Z1
Cl
O
Z1
Z1CO2H
CH2Cl2
5c (X = Cl)
quantitative
8 (Z1 = t-Bu)
9 (Z1 = Ph)
10 (Z1 = 2-propyl)
11 (Z1 = t-Bu)
12 (Z1 = Ph)
13 (Z1 = 2-propyl)
14 (Z1 = t-Bu)
15 (Z1 = Ph)
16 (Z1 = 2-propyl)
6 (X = Cl)
7 (X = I)
NaI,
acetone
88-91%
Scheme 2 Synthesis of alkyl 2-acetoxy-2-[(chlorocarbonyl)oxy] acetates 14–16
O
O
OBn
X
O
O
O
O
Cl
N
N
O
N
O
Z2CO2H
N
N
N
5a (X = Cl)
M
O
O
X
O
O
DIEA, THF
75-80%
Cl
Cl
O
O
Cl
O
O
O
75%
17 (M = H)
18 (M = K)
Z2
KOtBu
THF
OBn
OBn
21 (Z2 = tBu)
22 (Z2 = Ph)
19 (X = Cl)
20 (X = I)
NaI,
acetone
Scheme 3 Application of glyoxylate-derived chloroformate 5a to the synthesis of halofenozide derivatives 21 and 22
Synthesis 2002, No. 3, 365–370 ISSN 0039-7881 © Thieme Stuttgart · New York

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Synthesis and Application of Novel Glyoxylate-derived Chloroformates
367
O
O
O
N
O
N
O
N
O
N
N
N
N
SO2Cl2
NHEt2
H2, Pd/C
EtOAc
21
O
O
O
O
O
O
Cl
O
O
O
Cl
O
O
O
Cl
O
O
O
OH
Cl
23
24
25
Scheme 4 Conversion of pivalic acid [halofenozide-N-carbonyloxy]-benzyloxycarbonyl-methyl ester 21 to diethylamide 25
directly with pivalic acid (Z2CO2H = t-BuCO2H) and ben- triphosgene with pyridine in either THF or dioxane. These
zoic acid (Z2CO2H = PhCO2H) to afford carboxylic acid- novel glyoxylate-derived chloroformates are multifunc-
derived (halofenozide-N-carbonyloxy)-benzyloxycarbon- tional, possessing a chloroformate, ester, and haloalkyl
yl-methyl esters 21 (Z2 = t-Bu) and 22 (Z2 = Ph) in 80% moiety. Further elaboration via thiocarbonate 6 afforded
and 75% yield, respectively. In order to further demon- the highly functionalized chloroformates 14–16. Applica-
strate the trifunctional nature of chloroformate 5a, the tion of benzyl glyoxylate-derived chloroformate 5a to ha-
benzyl group, which initially was incorporated in the gly- lofenozide was also accomplished, affording carboxylic
oxylate stage due to its ease of deprotection under mild acid (halofenozide-N-carbonyloxy)-benzyloxycarbonyl-
conditions, was removed from compound 22 with H2 and methyl esters 21 and 22. The trifunctional nature of the
Pd/C to afford carboxylic acid 23. Carboxylic acid 23 was glyoxylate moiety was exercised through deprotection of
reacted directly with thionyl chloride to afford acid chlo- the benzyl moiety from compound 22 with H2 and Pd/C to
ride 24, which was reacted directly with diethylamine to afford carboxylic acid 23. Carboxylic acid 23 was reacted
afford amide 25 in 64% yield (Scheme 4).
directly with thionyl chloride to afford acid chloride 24,
which was reacted directly with diethylamine to afford
amide 25. The potential exists for the application of the
glyoxylate-derived chloroformates 5a–f, 14, 15 and 16 to
other -NH, -OH, -SH and -COOH containing nucleophiles
including both agricultural and pharmaceutical-derived
compounds to afford a variety of glyoxylate-derived spe-
cies.
In general, the halofenozide-glyoxylate derivatives 21,
22, and 25 were 2-3 times more potent in feeding assays
relative to the parent compound, halofenozide (17). Also,
compounds 21, 22, and 25 were oily solids in comparison
to the highly crystalline parent compound, halofenozide.
Hydrolytic stability tests at pH = 4.5, 6.5, and 8.5 deter-
mined that halofenozide-glyoxylate derivatives 21, 22,
and 25 were stable for up to 500 h at all three pH’s. It
should be noted that carboxylate 23 was stable in CDCl3
for >48 h. However, in DMSO with a few drops of D2O,
or in buffered solutions at pH = 4.5, 6.5, and 8.5, carbox-
ylate 23 rapidly degraded to the parent compound, ha-
lofenozide (17). This interesting result led us to postulate
that labile glyoxylate esters (CO2CH3), which would hy-
drolyze to the free carboxylic acid before hydrolysis of the
Reagents and solvents were used as received from commercial ven-
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
Z1 or Z2 ester moiety, would trigger the breakdown of the relative to the central line of the triplet for CDCl3 at 77.00 ppm.
Melting points were obtained on a Thomas Hoover capillary melt-
complex and therefore release the biologically active mo-
ing point apparatus and are uncorrected. IR spectra (reported in cm–
tif.15 The release of the entire complex would be indepen-
1) were obtained on a Mattson Genesis II FT-IR spectrophotometer
dent of the stability of the Z1 or Z2 ester moiety, providing
after dissolving the compound in chloroform and then applying the
solution to a polyethylene film. Elemental analyses were performed
a prodrug system quite different than the formaldehyde-
or acetaldehyde-based systems which are solely depen-
dent upon the Z1 or Z2 ester moiety for both rate of release
(Z1 or Z2 = CH3 versus t-butyl) and control of physical
properties (Z1 or Z2 = CH3 versus dodecyl). The hydrolyt-
ic stability and biological results in accordance with the
entire library of compounds synthesized will be reported
at a later date.
by Robertson Microlit Laboratories, Inc., 29 Samson Avenue, P.O.
Box 927, Madison, New Jersey 07940. High resolution and high ac-
curacy mass spectra of the samples were obtained using a Bruker 7T
Fourier Transform mass spectrometer (FTMS). Samples were ana-
lyzed by either electrospray ionization (ESI) or chemical ionization
(CI) mass spectrometry. Methane was used as the CI reagent gas in
the chemical ionization. Protonated molecular ions are shown in the
positive ESI and CI mass spectra. The molecular anions in the neg-
ative CI spectra were obtained through electron attachment or chlo-
ride anion attachment. The average resolution of the spectra is better
than 25,000 and the error of the mass measurement is less than
0.003 Da. The empirical formula obtained from the accurate mass
perfectly matched the molecular structure.
In conclusion, a convenient process for the synthesis of
novel glyoxylate-derived chloroformates has been devel-
oped. The approach involves the reaction of glyoxylate
esters with phosgene generated in situ from the reaction of
Synthesis 2002, No. 3, 365–370 ISSN 0039-7881 © Thieme Stuttgart · New York

368
M. J. Mulvihill et al.
PAPER
–
Benzyl Chloro[(chlorocarbonyl)oxy]acetate (5a)
HRMS (CI): m/z calcd for C9H11Cl4O6 [M + C2HCl2O2 ], 354.9309;
To a 3-neck round-bottom flask, equipped with nitrogen inlet and a
thermometer, was added THF (500 mL) followed by benzyl glyox-
ylate (106 g, 640 mmol) and triphosgene (211 g, 710 mmol) (CAU-
TION: Proper handling should be exercised when using
triphosgene). The solution was cooled with dry ice/acetone to –78
°C and pyridine (5.2 mL, 64.0 mmol) was added slowly over 5 min,
maintaining the temperature between –50 °C and –65 °C. The reac-
tion was gradually warmed to r.t. and then heated to 60 °C and
stirred at that temperature for 2 h. Next, the precipitates were fil-
tered by gravity through a fritted glass funnel, washing with THF.
The solvent was removed in vacuo at 30–50 °C, affording 145 g of
the desired chloroformate 5a as a clear colorless oil in 90% yield;
decomposed upon attempted distillation.
found, 354.9287.
Ethyl Chloro[(chlorocarbonyl)oxy]acetate (5e)
Compound 5e (10.9 g, 85% yield) was obtained from ethyl glyoxy-
late (6.50 g, 64.0 mmol), triphosgene (21.1 g, 71.0 mmol), and py-
ridine (0.52 mL, 6.40 mmol), using dioxane (50 mL) as the solvent
instead of THF, following the general procedure described for com-
pound 5a.
Bp 82 °C (at 15.1 mmHg).
IR: 1792, 1767 cm–1.
1H NMR (300 MHz, CDCl3): = 1.36 (t, 3 H, J = 6.0 Hz), 4.36 (q,
2 H, J = 6.0 Hz), 6.48 (s, 1 H).
IR: 1770 cm–1.
13C NMR (75 MHz, CDCl3): = 14.2, 64.2, 80.1, 149.6, 163.1.
1H NMR (300 MHz, CDCl3): = 5.30 (s, 2 H), 6.51 (s, 1 H), 7.38
(m, 5 H).
HRMS (CI): m/z calcd for C5H6Cl3O4 [M + Cl–], 234.9331; found,
234.9312.
13C NMR (75 MHz, CDCl3): = 69.1, 79.6, 128.5, 128.8, 129.0,
133.9, 149.2, 162.6.
HRMS (CI): m/z calcd for C10H8Cl3O4 [M + Cl–], 296.9488; found,
Methyl Chloro[(chlorocarbonyl)oxy]acetate (5f)
Compound 5f (11.7 g, 98% yield) was obtained from methyl glyox-
ylate (5.60 g, 64.0 mmol), triphosgene (21.1 g, 71.0 mmol), and py-
ridine (0.52 mL, 6.40 mmol), using dioxane (50 mL) as the solvent
instead of THF, following the general procedure described for com-
pound 5a.
296.9481.
Isopropyl Chloro[(chlorocarbonyl)oxy]acetate (5b)
Compound 5b (12.2 g, 89% yield) was obtained from isopropyl gly-
oxylate (7.42 g, 64.0 mmol), triphosgene (21.1 g, 71.0 mmol), and
pyridine (0.52 mL, 6.40 mmol) following the general procedure de-
scribed for compound 5a.
Bp 77 °C (at 15.1 mmHg).
IR: 1795, 1775 cm–1.
1H NMR (300 MHz, CDCl3): = 3.91 (s, 3 H), 6.51 (s, 1 H).
13C NMR (75 MHz, CDCl3): = 54.3, 79.7, 149.4, 163.4.
HRMS (CI): m/z calcd for C4H4Cl3O4 [M + Cl–], 220.9175; found,
Bp 70 °C (at 15.0 mmHg).
IR: 2989, 2837, 1788, 1765 cm–1.
1H NMR (300 MHz, CDCl3): = 1.34 (d, 6 H, J = 6.0 Hz), 5.16 (q,
1 H, J = 6.0 Hz), 6.44 (s, 1 H).
220.9159.
13C NMR (75 MHz, CDCl3): = 21.5, 21.6, 72.4, 80.2, 149.3, 162.5.
Butyl Chloro{[(ethylthio)carbonyl]oxy}acetate (6)
A 500 mL round bottom flask was charged with sodium ethanethi-
olate (4.0 g, 48.0 mmol) and 150 mL of anhyd Et2O and the mixture
was cooled to –78 °C. Chloroformate 5c (11.0 g, 48.0 mmol) was
added as a Et2O solution (20 mL) over 5 min at such a rate that the
reaction temperature did not exceed –65 °C. The reaction was al-
lowed to warm to r.t. and stirred for 16 h. The reaction was vacuum-
filtered through a plug of silica gel, and the filtrate was dried over
MgSO4, filtered, and concentrated under reduced pressure to yield
11.5 g of compound 6 in 94% yield as a clear oil.
HRMS (CI): m/z calcd for C6H8Cl3O4 [M + Cl–], 248.9488; found,
248.9459.
n-Butyl Chloro[(chlorocarbonyl)oxy]acetate (5c)
Compound 5c (13.9 g, 95% yield) was obtained from n-butyl gly-
oxylate (8.32 g, 64.0 mmol), triphosgene (21.1 g, 71.0 mmol), and
pyridine (0.52 mL, 6.40 mmol) following the general procedure de-
scribed for compound 5a.
Bp 93 °C (at 6.3 mmHg).
IR: 1793, 1770 cm–1.
1H NMR (300 MHz, CDCl3): = 0.96 (t, 3 H, J = 7.5 Hz), 1.41 (m,
2 H), 1.71 (m, 2 H), 4.30 (t, 2 H, J = 6.6 Hz), 6.48 (s, 1 H).
IR: 2963, 1766, 1727 cm–1.
1H NMR (300 MHz, CDCl3): = 0.95 (t, 3 H, J = 6.0 Hz), 1.33–1.43
(m, 5 H), 1.67–1.72 (m, 2 H), 2.93 (q, 2 H, J = 6.0 Hz), 4.28 (t, 2 H,
J = 6.0 Hz), 6.65 (s, 1 H).
13C NMR (75 MHz, CDCl3): = 13.8, 19.1, 30.4, 67.7, 79.9, 149.5,
163.0.
13C NMR (75 MHz, CDCl3): = 12.8, 13.9, 18.1, 25.0, 29.5, 66.0,
76.4, 163.1, 168.7.
HRMS (CI): m/z calcd for C7H10Cl3O4 [M + Cl–], 262.9644; found,
HRMS (CI): m/z calcd for C9H15Cl2O4S [M + Cl–], 289.0068; found,
262.9628.
289.0052.
t-Butyl Chloro[(chlorocarbonyl)oxy]acetate (5d)
Compound 5d (14.2 g, 97% yield) was obtained from t-butyl glyox-
ylate (8.32 g, 64.0 mmol), triphosgene (21.1 g, 71.0 mmol), and py-
ridine (0.52 mL, 6.40 mmol) using dioxane (50 mL) as the solvent
instead of THF, following the general procedure described for com-
pound 5a.
2-Butoxy-1-{[(ethylthio)carbonyl]oxy}-2-oxyethyl Pivalate (11)
NaI (4.3 g, 29.0 mmol) was added to a solution of ester (6, 5.0 g,
19.6 mmol) in anhyd acetone (20 mL). The mixture was stirred for
4 h at r.t., after which time the acetone was removed and the remain-
ing slurry was diluted with Et2O (20 mL). The mixture was filtered
through silica gel, and the filtrate was concentrated under reduced
pressure to afford 6.5 g of ester 7 in 96% yield as a tan oil. Com-
pound 7 (2.0 g, 5.8 mmol) was dissolved in THF (12 mL), and
charged with pivalic acid (0.77 g, 7.5 mmol) and DIEA (1.3 mL, 7.5
mmol). The reaction was allowed to stir at r.t. for 12 h, after which
time the THF was removed in vacuo, and the crude mixture was
chromatographed on silica gel (hexanes–EtOAc, 5:1) to afford 1.6
g of compound 11 as an oil in 86% yield.
Bp 84 °C (at 14.1 mmHg).
IR: 2920, 2891, 2848, 1792, 1765 cm–1.
1H NMR (300 MHz, CDCl3): = 1.50 (s, 9 H), 6.32 (s, 1 H).
13C NMR (75 MHz, CDCl3): = 27.8, 80.4, 85.7, 149.4, 161.7.
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Synthesis and Application of Novel Glyoxylate-derived Chloroformates
369
IR: 2966, 1764, 1727 cm–1.
7.49 (t, 2 H, J = 7.5 Hz), 7.63 (t, 1 H, J = 7.5 Hz), 8.10 (d, 2 H,
J = 7.5 Hz).
13C NMR (75 MHz, CDCl3): = 13.9, 19.3, 30.7, 67.5, 88.4, 127.8,
129.1, 130.8, 134.9, 149.5, 163.6, 164.0;
1H NMR (300 MHz, CDCl3): = 0.93 (t, 3 H, J = 7.0 Hz), 1.25 (s,
9 H), 1.33–1.43 (m, 5 H), 1.62–1.70 (m, 2 H), 2.92 (q, 2 H, J = 7.0
Hz), 4.24 (m, 2 H), 6.93 (s, 1 H).
13C NMR (75 MHz, CDCl3): = 13.6, 14.7, 18.9, 25.6, 26.7, 30.3,
38.8, 66.4, 85.5, 164.7, 169.7, 175.9.
HRMS (CI): m/z calcd for C14H16ClO6 [M + H+], 315.0635; found,
315.0625.
Anal. Calcd for C14H24O6S: C, 52.48; H, 7.55. Found: C, 52.70; H,
7.65.
2-Butoxy-1-[(chlorocarbonyl)oxy]-2-oxyethyl Isobutyrate (16)
Compound 16 (0.87 g, 100% yield; oil) was obtained from com-
pound 13 (0.95 g, 3.10 mmol) following the general procedure de-
scribed for compound 14.
2-Butoxy-1-{[(ethylthio)carbonyl]oxy}-2-oxyethyl Benzoate
(12)
Compound 12 (1.79 g, 91% yield; oil) was obtained from benzoic
acid (0.92 g, 7.50 mmol) following the general procedure described
for compound 11.
IR: 1796, 1770 cm–1.
1H NMR (300 MHz, CDCl3): = 0.93 (t, 3 H, J = 7.2 Hz), 1.22 (d,
3 H, J = 6.9 Hz), 1.23 (d, 3 H, J = 6.9 Hz), 1.40 (m, 2 H), 1.67 (m,
2 H), 2.71 (m, 1 H), 4.26 (t, 2 H, J = 6.6 Hz), 6.81 (s, 1 H).
IR: 2962, 1746, 1729 cm–1.
1H NMR (300 MHz, CDCl3): = 0.92 (t, 3 H, J = 7.2 Hz), 1.31–1.42
(m, 5 H), 1.65–1.70 (m, 2 H), 2.92 (q, 2 H, J = 7.5 Hz), 4.28 (t, 2 H,
J = 6.6 Hz), 7.20 (s, 1 H), 7.47 (t, 2 H, J = 7.5 Hz), 7.60 (t, 1 H,
J = 7.5 Hz), 8.10 (d, 2 H, J = 7.5 Hz).
13C NMR (75 MHz, CDCl3): = 14.0, 15.1, 19.3, 26.0, 30.7, 66.9,
86.0, 128.5, 129.0, 130.6, 134.5, 164.4, 165.0, 170.2.
13C NMR (75 MHz, CDCl3): = 15.9, 20.8, 21.3, 32.6, 36.0, 69.3,
90.1, 151.4, 165.6, 176.4.
HRMS (CI): m/z calcd for C11H18ClO6 [M + H+], 281.0792; found,
281.0820.
2-(Benzoyloxy)-1-chloro-2-oxoethyl 2-Benzoyl-2-tert-butyl-1-
(4-chlorobenzoyl)hydrazinecarboxylate (19)
Anal. Calcd for C16H20O6S: C, 56.46; H, 5.92. Found: C, 56.70; H,
6.02.
To a suspension of potassium tert-butoxide (7.50 g, 66.8 mmol) in
THF (500 mL) was added halofenozide 17 portionwise (17.0 g, 51.4
mmol) over 5 min. The mixture was heated to reflux for 30 min, al-
lowed to cool to r.t. and stirred for an additional 30 min. The solu-
tion was then cooled to –78 °C and ester 5a (17.6 g, 66.8 mmol) was
added dropwise over 5 min. The mixture was allowed to warm to r.t.
and stirred for 2 h, after which time the THF was removed in vacuo.
The resulting slurry was taken up into EtOAc (400 mL) and washed
with H2O (3 200 mL) followed by brine. The organic layer was
dried over Na2SO4, filtered, and concentrated in vacuo. Silica gel
chromatography (hexanes–EtOAc, 70:30) afforded the title com-
pound 19 (21.8 g, 75% yield) as a white solid.
2-Butoxy-1-{[(ethylthio)carbonyl]oxy}-2-oxyethyl Isobutyrate
(13)
Compound 13 (1.56 g, 88% yield; oil) was obtained from isobutyric
acid (0.66 g, 7.50 mmol) following the general procedure described
for compound 11.
IR: 2971, 1768, 1728 cm–1.
1H NMR (300 MHz, CDCl3): = 0.94 (t, 3 H, J = 7.2 Hz), 1.21–1.43
(m, 11 H), 1.64–1.70 (m, 2 H), 2.68 (m, 1 H), 2.93 (q, 2 H, J = 7.5
Hz), 4.24 (t, 2 H, J = 6.6 Hz), 6.94 (s, 1 H).
13C NMR (75 MHz, CDCl3): = 13.2, 14.3, 18.1, 18.5, 25.2, 29.9,
33.3, 66.0, 84.9, 164.2, 169.3, 174.1.
Mp 125–127 °C.
IR: 1765, 1715, 1680 cm–1.
1H NMR (300 MHz, CDCl3): = 1.61 (s, 9 H), 5.19 (s, 2 H), 6.34
(s, 1 H), 6.61 (d, 2 H, J = 9.0 Hz), 7.13 (d, 2 H, J = 9.0 Hz), 7.29–
7.40 (m, 10 H).
Anal. Calcd for C13H22O6S: C, 50.96; H, 7.24. Found: C, 51.13; H,
7.09.
2-Butoxy-1-[(chlorocarbonyl)oxy]-2-oxyethyl Pivalate (14)
Sulfuryl chloride (0.33 mL, 4.0 mmol) was added over 1 min to
compound 11 (1.0 g, 3.1 mmol), cooled at 5 °C in a 100 mL flask.
After 30 min, the cold bath was removed and the reaction was al-
lowed to stir for 3 h at r.t. and then concentrated under reduced pres-
sure to afford 900 mg of compound 14 as an oil in 99% yield.
13C NMR (75 MHz, CDCl3): = 27.3, 63.5, 68.9, 78.2, 124.8, 128.1,
128.3, 128.5, 128.7, 128.8, 129.0, 129.3, 131.7, 133.8, 137.3, 138.5,
151.4, 163.0, 169.1, 171.8.
Anal. Calcd for C28H26Cl2N2O6: C, 60.33; H, 4.70; N, 5.03. Found:
C, 60.24; H, 4.72; N, 4.72.
IR: 2970, 1794, 1768 cm–1.
2-(Benzoyloxy)-1-[(2,2-dimethylpropanoyl)oxy]-2-oxoethyl 2-
Benzoyl-2-tert-butyl-1-(4-chlorobenzoyl)hydrazinecarboxylate
(21)
1H NMR (300 MHz, CDCl3): = 0.95 (t, 3 H, J = 7.0 Hz), 1.27 (s,
9 H), 1.34–1.44 (m, 2 H), 1.63–1.72 (m, 2 H), 4.23–4.32 (m, 2 H),
6.82 (s, 1 H).
13C NMR (75 MHz, CDCl3): = 13.9, 19.2, 27.0, 30.6, 39.2, 67.2,
88.2, 149.4, 163.6, 175.8.
HRMS (CI): m/z calcd for C12H20ClO6 [M + H+], 295.0948; found,
295.0966.
To a solution of ester 19 (4.75 g, 8.52 mmol) in acetone (70 mL)
was added NaI (2.55 g, 17.0 mmol) and heated to 30 °C for 2 h. The
acetone was removed in vacuo, and the slurry was treated with Et2O
and filtered through Celite®. The filtrate was concentrated in vacuo
to afford compound 20 as an oil (5.0 g, 90% yield), which was im-
mediately taken on to the next reaction. Compound 20 (2.6 g, 4.0
mmol) was added to a solution of diisopropylethylamine (1.05 mL,
6.0 mmol) and pivalic acid (0.61 g, 6.0 mmol) in THF (50 mL). The
mixture was stirred for 16 h at r.t., after which time the THF was re-
moved in vacuo, and the resulting slurry dissolved in Et2O and
washed with H2O (2 50 mL), followed by brine. Silica gel chro-
matography (hexanes–EtOAc, 70:30) afforded the title compound
21 (2.0 g, 80% yield) as an oily solid.
2-Butoxy-1-[(chlorocarbonyl)oxy]-2-oxyethyl Benzoate (15)
Compound 15 (0.96 g, 99% yield; oil) was obtained from com-
pound 12 (1.05 g, 3.10 mmol) following the general procedure de-
scribed for compound 14.
IR: 2962, 1791, 1766, 1753 cm–1.
1H NMR (300 MHz, CDCl3): = 0.94 (t, 3 H, J = 7.5 Hz), 1.36–1.44
(m, 2 H), 1.65–1.72 (m, 2 H), 4.28 (t, 2 H, J = 6.6 Hz), 7.01 (s, 1 H),
IR: 2979, 1765, 1715, 1682 cm–1.
Synthesis 2002, No. 3, 365–370 ISSN 0039-7881 © Thieme Stuttgart · New York

370
M. J. Mulvihill et al.
PAPER
1H NMR (300 MHz, CDCl3): mixture of rotational isomers: = 1.15
and 1.23 (two s, 9 H), 1.60 (s, 9 H), 5.26 (m, 2 H), 6.54 (m, 2 H),
6.74 (s, 1 H), 7.08 (d, 2 H, J = 9.0 Hz), 7.23–7.39 (m, 10 H).
Anal. Calcd for C30H38ClN3O7: C, 61.27; H, 6.51; N, 7.15. Found:
C, 61.21; H, 6.31; N, 7.08.
13C NMR (75 MHz, CDCl3): mixture of rotational isomers: = 26.6,
26.7, 27.2, 38.8, 38.9, 63.4, 63.5, 68.4, 68.5, 86.4, 86.6, 124.7,
124.9, 128.1, 128.5, 128.7, 128.8, 128.9, 129.0, 129.1, 129.2, 131.9,
134.1, 137.5, 138.3, 151.6, 151.8, 163.7, 169.3, 169.4, 171.9, 175.4,
175.5.
Acknowledgements
We thank Kristen M. Mulvihill for her help in preparation of this
manuscript, Tianlan Zhang for high resolution mass spectra deter-
minations, and Drs. Clark Carpenter and Steven Shaber for many
fruitful discussions.
Anal. Calcd for C33H35ClN2O8: C, 63.61; H, 5.66; N, 4.50. Found:
C, 63.71; H, 5.53; N, 4.53.
References
1-(Benzoyloxy)-2-(benzyloxy)-2-oxoethyl 2-Benzoyl-2-tert-
butyl-1-(4-chlorobenzoyl)hydrazinecarboxylate (22)
Compound 22 (1.93 g, 75% yield; oily solid) was obtained from
benzoic acid (0.73 g, 6.0 mmol) following the general procedure de-
scribed for compound 21.
(1) (a) Mulvihill, M. J.; MacDougall, B.; Ajello, C.; Martinez-
Teipel, B.; Joseph, R.; Nguyen, D. V.; Weaver, D. G.;
Chung, K.; Gusev, A.; Wierenga, J. M.; Mathis, W. D.
Synthesis 2002, 53. (b) Chem. Abstr. 2001, 135, 152561.
(c) Chem. Abstr. 2001, 135, 163628.
IR: 2912, 1766, 1714, 1680 cm–1.
(2) (a) Mulvihill, M. J.; Nguyen, D. V.; MacDougall, B.;
Martinez-Teipel, B.; Joseph, R.; Gallagher, J.; Weaver, D.;
Gusev, A.; Chung, K.; Mathis, W. Tetrahedron Lett. 2001,
42, 7751. (b) Chem. Abstr. 2001, 135, 152823.
(3) Silverman, R. B. The Organic Chemistry of Drug Design
and Drug Action; Academic Press: San Diego, 1992, 362–
363.
(4) King, F. D. Medicinal Chemistry: Principles and Practice;
The Royal Society of Chemistry: Carmbridge, 1994, 216–
227.
(5) (a) Sun, X.; Zeckner, D. J.; Current, W. L.; Boyer, R.;
McMillian, C.; Yumibe, N.; Chen, S. H. Bioorg. Med. Chem.
Lett. 2001, 11, 1875. (b) Omar, F. A.; Farag, H. H.; Bodor,
N. J. Drug Target. 1994, 2, 309.
(6) Gogate, U. S.; Repta, A. J.; Alexander, J. Int. J. Pharm.
1987, 40, 235.
(7) Gogate, U. S.; Repta, A. J. Int. J. Pharm. 1987, 40, 249.
(8) Coghlan, M. J.; Caley, B. A. Tetrahedron Lett. 1989, 30,
2033.
(9) Barcelo, G.; Senet, J. P.; Sennyey, G. Synthesis 1986, 627.
(10) Folkmann, M.; Lund, F. J. Synthesis 1990, 1159.
(11) (a) Finkelstein, H. Ber. 1910, 43, 1528. (b) Ingold, C. K.
Structure and Mechanism in Organic Chemistry, 2nd ed.;
Cornell Univ. Press: London, 1969, 435.
(12) James, W. N. Jr; Aller, H. E. U.S. 5358966, 1994;Chem.
Abstr. 1994, 122, 3593.
(13) The Presidential Green Chemistry Award for Rohm and
Haas diacyl hydrazines can be found on the following web
pages: http://www.turfnet.com/news/rohm_haas.asp and
http://www.epa.gov/greenchemistry/past.htm.
1H NMR (300 MHz, CDCl3): mixture of rotational isomers: = 1.58
and 1.59 (two s, 9 H), 5.28 (m, 2 H), 6.42 and 6.63 (two br s, 2 H),
6.92–8.10 (m, 18 H).
13C NMR (75 MHz, CDCl3): mixture of rotational isomers: = 27.2,
63.4, 63.5, 68.6, 86.1, 86.4, 124.7, 124.8, 127.3, 128.1, 128.5,
128.6, 128.7, 128.8, 128.9, 129.0, 129.1, 130.2, 130.3, 134.1, 134.5,
134.7, 137.5, 138.3, 151.7, 163.6, 163.7, 169.4, 171.9.
Anal. Calcd for C35H31ClN2O8: C, 65.37; H, 4.86; N, 4.36. Found:
C, 65.40; H, 4.84; N, 4.39.
2-Diethylamino-1-[(2,2-dimethylpropanoyl)oxy]-2-oxyethyl 2-
Benzoyl-2-tert-butyl-1-(4-chlorobenzoyl)hydrazinecarboxylate
(25)
A solution of ester 21 (500 mg, 0.80 mmol) in EtOAc (10 mL) was
purged with nitrogen. Pd/C (10%, 40 mg) was added and the reac-
tion was placed in a parr shaker under a hydrogen atmosphere of 55
psi. After 1 h, the Pd/C was filtered and washed with EtOAc. The
filtrate was removed in vacuo to afford 420 mg of carboxylic acid
23 as a white solid in 100% yield. Carboxylic acid 23 (420 mg, 0.80
mmol) was taken directly to the next reaction by dissolving it in
thionyl chloride (10 mL) and DMF (2 drops). The solution was
heated to 60 °C for 1 h, after which time the solution was concen-
trated in vacuo, redissolved in toluene, and then concentrated in
vacuo to afford 400 mg (92% yield) of acid chloride 24. A solution
of acid chloride 24 (400 mg, 0.73 mmol) was dissolved in THF (5
mL) and charged with DIEA (0.25 mL, 1.5 mmol) and diethylamine
(0.15 mL, 1.5 mmol). The solution was allowed to stir at r.t. for 1 h,
after which time the solvent was removed in vacuo, and the crude
mixture purified by silica gel chromatography (EtOAc–hexanes,
30:70) to afford 275 mg (64% yield) of the desired title compound
25 as an oily solid.
(14) Tomlin, C. D. S. The Pesticide Manual, 11th ed.; British
Crop Protection Council: Farnham Surrey GU9 7PH UK,
1997, 388–389.
IR: 2979, 1760, 1712, 1678 cm–1.
(15) One could imagine the attack of the free carboxylate at the
Z1/Z2 ester or the carbamate moiety therefore forming a
mixed anhydride, which would rapidly degrade to the
aldehyde, CO2, and the parent biologically active molecule
(in our case, halofenozide 17). Also, a simple hydrogen
bonding effect from the free carboxylic acid to the ester or
carbamate moiety under aqueous conditions could afford
activation of the system and subsequent degradation.
1H NMR (300 MHz, CDCl3): mixture of rotational isomers:
1.08–1.69 (m, 24 H), 3.12–3.47 (m, 4 H), 6.61–7.40 (m, 10 H).
=
13C NMR (75 MHz, CDCl3): mixture of rotational isomers: = 13.0,
14.6, 14.8, 27.0, 27.2, 27.6, 39.2, 39.4, 41.3, 41.4, 41.7, 63.7, 63.8,
86.1, 86.4, 125.2, 125.5, 128.2, 128.5, 128.9, 129.0, 129.5, 129.6,
129.7, 132.3, 132.4, 137.8, 137.9, 138.6, 151.8, 152.3, 162.0, 162.2,
169.7, 172.5, 176.3, 176.6.
Synthesis 2002, No. 3, 365–370 ISSN 0039-7881 © Thieme Stuttgart · New York