Efficient synthesis of bifenazate

Article abstract of DOI:10.1080/00397910600636683

The synthesis of bifenazate using a two-step procedure has been accomplished with an overall yield of 26%. The procedure involved the Lewis acid-catalyzed electrophilic aromatic substitution of 4-methoxybiphenyl with diisopropyl azodicarcoxylate (DIAD) to give a hydrazinedicarboxylate intermediate that was then subjected to a decarboxylation reaction to give bifenazate. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600636683

This article was downloaded by: [Washington University in St Louis]
On: 28 April 2013, At: 14:17
Publisher: Taylor & Francis
Informa Ltd Registered in England and Wales Registered Number: 1072954 Registered office:
Mortimer House, 37-41 Mortimer Street, London W1T 3JH, UK
Synthetic Communications: An International
Journal for Rapid Communication of
Synthetic Organic Chemistry
Publication details, including instructions for authors and subscription
information:
http://www.tandfonline.com/loi/lsyc20
Efficient Synthesis of Bifenazate
Gaik‐Lean Chee a
a Crompton Co./Cie, Guelph, Ontario, Canada
Version of record first published: 16 Feb 2007.
To cite this article: Gaik‐Lean Chee (2006): Efficient Synthesis of Bifenazate, Synthetic Communications: An
International Journal for Rapid Communication of Synthetic Organic Chemistry, 36:15, 2151-2156
To link to this article: http://dx.doi.org/10.1080/00397910600636683
PLEASE SCROLL DOWN FOR ARTICLE
Full terms and conditions of use: http://www.tandfonline.com/page/terms-and-conditions
This article may be used for research, teaching, and private study purposes. Any substantial
or systematic reproduction, redistribution, reselling, loan, sub-licensing, systematic supply, or
distribution in any form to anyone is expressly forbidden.
The publisher does not give any warranty express or implied or make any representation that the
contents will be complete or accurate or up to date. The accuracy of any instructions, formulae,
and drug doses should be independently verified with primary sources. The publisher shall not
be liable for any loss, actions, claims, proceedings, demand, or costs or damages whatsoever or
howsoever caused arising directly or indirectly in connection with or arising out of the use of this
material.

Synthetic Communicationsw, 36: 2151–2156, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600636683
Efficient Synthesis of Bifenazate
Gaik-Lean Chee
Crompton Co./Cie, Guelph, Ontario, Canada
Abstract: The synthesis of bifenazate using a two-step procedure has been accom-
plished with an overall yield of 26%. The procedure involved the Lewis acid–
catalyzed electrophilic aromatic substitution of 4-methoxybiphenyl with diisopropyl
azodicarcoxylate (DIAD) to give a hydrazinedicarboxylate intermediate that was
then subjected to a decarboxylation reaction to give bifenazate.
Keywords: Bifenazate, diisopropyl azodicarboxylate, fluoroalcohols, 4-methoxy-
biphenyl, nitromethane
INTRODUCTION
Bifenazate[1,2] (1) is an acaricide effective against pest mites such as European
red mites and two-spotted spider mites, but has low toxicity to predaceous
mites and other beneficial arthropods (Scheme 1). In addition to being safe
to nontargets, bifenazate also has very little impact on the environment and
is highly compatible with the integrated pest-management programs. The
combining advantages have earned bifenazate the designation of a “reduced
risk” pesticide from the U.S. Environmental Protection Agency.
Three different methods, as depicted in Scheme 2, have been reported for
the preparation of bifenazate.[3–5] There are advantages and disadvantages of
each of the reported methods, but all these methods require a total of three
steps in the preparation of bifenazate from commercially available starting
materials. It remains important to search for alternative and more efficient
Received in the USA January 27, 2006
Address correspondence to Gaik-Lean Chee, Crompton Co./Cie, a Chemtura
Company, Research Laboratories, P.O. Box 1120, 120 Huron Street, Guelph,
Ontario N1H 6N3, Canada. Tel.: (519) 822-3790; Fax: (519) 822-8976; E-mail:
gaik-lean.chee@chemtura.com
2151

2152
G.-L. Chee
Scheme 1.
methods to reduce the cost and time for the production of this commercial
acaricide. During our search for an alternative route, we have developed a
two-step procedure for the preparation of bifenazate from relatively inexpen-
sive and commercially available 4-methoxybiphenyl (Scheme 3). Our method
offers the shortest alternative route to bifenazate in two easy-to-handle
reaction steps.
RESULTS AND DISCUSSION
The electrophilic aromatic substitution of electron-rich arenes such as
phenolic derivatives with electron-deficient azodicarboxylic acid esters
under thermal or acid catalysis is an efficient method for the introduction of
a masked hydrazine or amino group to an arene.[5,6] Although the introduction
Scheme 2.

Efficient Synthesis of Bifenazate
2153
Scheme 3.
of a hydrazine functionality on 4-methoxybiphenyl via this approach has not
been reported, we have been successful in adapting this approach to afford the
bifenazate intermediate 2 in 57% yield after purification by chromatography.
.
The optimum condition for this reaction involved the use of BF3 OEt2 as
catalyst and dichloromethane as solvent. The yields of this reaction dropped
significantly when the reaction was performed under heterogeneous con-
ditions using catalysts of lower solubility or reactivity. For instances, the
use of AlCl3, ZnI2, ZnCl2, ZrCl4, and H2SO4 as catalyst failed to afford any
significantamountof2,givingpredominantlytheunreacted4-methoxybiphenyl
and a mixture of unidentified impurities. Solvents such as ether, toluene, and
ethyl acetate were also found to be unsuitable for the reaction, affording
hydrazinedicarboxylate 2 in lower and inconsistent yields.
Our initial attempts to selectively cleave N1-carboxylate group using acid
and base hydrolysis to afford bifenazate were totally unsuccessful. The
hydrolysis reactions were performed using aqueous HCl, H2SO4, and NaOH
in solvents such as 2-propanol, toluene, and DMSO under various conditions.
In all instances, we either obtained the unreacted hydrazinedicarboxylate 2 or
observed the decarboxylation reaction occurring at an extent where predomi-
nantly 4-methoxybiphenyl was isolated as decomposition product. Other
decarboxylation attempts that we made without success were the nonsaponi-
fication SN2-type dealkylation reactions using aluminum chloride as catalyst
and a thiol or sodium iodide as nucleophile.
During our search for a method to prepare bifenazate from hydrazinedi-
carboxylate 2, we have discovered a facile method for selective deprotection
of isopropyl esters, carbamates, and carbonates with aluminum chloride in
nitromethane.[7] When the same procedure was applied to hydrazinedicarboxy-
late 2, a minor amount of bifenazate was observed when the reaction was
largely incomplete after overnight stirring at room temperature. This encoura-
ging observation prompted us to investigate other conditions to increase the
rate of the deprotection reaction without compromising the selectivity.
Increasing the reaction temperature somewhat facilitated the reaction but sig-
nificantly increased the amount of impurities formed. We investigated the use
of other acids, such as TiCl4, BF3OEt2, SnCl4, ZnCl2, ZrCl4, trifluoroacetic
acid, H2SO4, Et3Al, (Et2AlCl)2, and trifluorosulfuric acid, even though we

2154
G.-L. Chee
have previously observed that AlCl3 was the acid of choice for activating the
deprotection reaction. TiCl4 afforded a result similar to that obtained for
AlCl3, whereas the remaining acids were found to be ineffective as activators,
giving either no reactions or a mixture of unknown components. When
elevated temperatures were employed, most of these ineffective acids had
only facilitated the formation of impurities. The unsuccessful attempts
caused us to turn our attention to other solvents such as ethyl acetate, nitroben-
zene, dichloromethane, and ether. These attempts were similarly unsuccessful.
Because the use of a fluorous phase has been proven to present some advan-
tages in certain organic reactions,[8] we chose to use a fluoroalcohol as
cosolvent. Using a 1 : 1 mixture of nitromethane and 1,1,1,3,3,3-hexafluoro-
2-propanol (HFIP) as solvent and AlCl3 as catalyst, the decarboxylation
reaction was found to be more than 80% complete by TLC analysis after
stirring overnight at 408C. Bifenazate appeared to be the major product, and
4-methoxybiphenyl and an unknown component, presumably the N2-decar-
boxlated product, were present as minor components. The reaction was sub-
sequently quenched with water and worked up to afford bifenazate in 46%
yield after purification by column chromatography. 2,2,2-Trifluoroethanol
was found to be as equally suitable a cosolvent as HFIP. Using nitromethane
or the fluoroalcohols alone gave lower yields, and other ratios did not improve
upon the yield obtained using the 1 : 1 mixture.
In conclusion, we have successfully synthesized bifenazate from 4-meth-
oxybiphenyl in an overall yield of 26% using a two-step procedure. Although
it was extremely challenging to develop the procedure, each reaction step was
easy to handle and did not require the use of special apparatus or an inert
atmosphere.
EXPERIMENTAL
Melting points were measured on a hot-stage instrument and are uncorrected.
1H and 13C NMR spectra were recorded on a Bruker AM-300 FT instrument
using tetramethylsilane as internal standard. IR spectra were recorded on a
Perkin-Elmer 283B spectromer. HRMS/mass spectra were obtained on an
Analytical VG 7070E-HP instrument. Aldrich 28859-4 silica gel was used
for all column chromatography.
Hydrazinedicarboxylate 2
.
BF3 OEt2 (0.7 mL) was added to a solution of 4-methoxybiphenyl (1.0 g,
5.4 mmol) in dichloromethane (6 mL) at room temperature. The solution
mixture was cooled to 08C, and DIAD (2.1 mL, 5.4 mmol) was added
dropwise over a period of 10 min. The resulting blue-green solution was
stirred at that temperature for 1 day and allowed to warm to room temperature

Efficient Synthesis of Bifenazate
2155
before it was worked up by adding water (10 mL) and extracting with dichlor-
omethane (2 ꢀ 10 mL). The extract was concentrated under reduced pressure,
and the crude product was chromatographed on silica gel (30–50% ethyl
acetate/hexanes) to give hydrazinedicarboxylate 2 as a beige solid (1.2 g,
57%): mp 137–137.58C; IR (KBr): 3600 (NH), 1735 (CO), 1690 (CO)
1
cm21; H NMR (DMSO-d6) d: 1.19 (br d, 12H, J ¼ 6.0); 3.82 (s, 3H), 4.82
(br septet, 2H, J ¼ 3.0), 7.15 (m, 1H), 7.33 (m, 1H), 7.45 (m, 2H), 7.53–
7.62 (m, 4H), 9.83 (br s, NH); 13C NMR (CDCl3) d: 22.37 (2 ꢀ CH3),
22.45 (2 ꢀ CH3), 56.11 (CH), 70.09 (CH), 70.94 (CH3), 111.95 (2 ꢀ C),
127.15 (2 ꢀ CH), 127.33 (CH), 127.93 (2 ꢀ CH), 129.12 (3 ꢀ CH), 134.13
(C), 140.37 (C), 154.38 (C), 156.15 (C); mass spectrum m/e (% rel): 386
(9%, Mþ), 300 (34%, M-CO2iPr), 301 (MH-CO2iPr, 50%); HRMS calcd.
for [C21H26N2O5 H]þ 387.1920, found [MH]þ 387.1927.
Bifenazate[1]
2,2,2-Trifluoroethanol (2 mL) was added to a stirred suspension of hydrazine-
dicarboxylate 2 (0.52 g, 1.34 mmol) in nitromethane (2 mL) at room tempera-
ture. The resulting green mixture was cooled to 08C, AlCl3 (0.44 g,
3.30 mmol) was added, and the mixture was subsequently heated at 408C
with stirring for 12 h. The resulting red solution was cooled to 08C, water
was added (15 mL) slowly, and it was then stirred at room temperature for
10 min. The mixture was extracted with ethyl acetate (3 ꢀ 5 mL), and the
combined organic phase was concentrated under reduced pressure. The
resulting brown residue was chromatographed on silica gel (30–50% ethyl
acetate/hexanes) to afford bifenazate as beige solid (0.19 g, 46%). Melting
1
points[9] and H NMR spectral data[3a] were consistent with those published
previously.
ACKNOWLEDGMENT
The author gratefully acknowledges Sheldon Park for helpful discussion and
Wan Yu for providing analytical services.
REFERENCES
1. Dekeyser, M. A.; McDonald, P. T.; Angle, G. W., Jr. The discovery of bifenazate, a
novel carbazate acaricide. Chimia 2003, 57 (11), 702–704.
2. Dekeyser, M. A. Uniroyal Chemical develops a new miticide. Can. Chem. News
2000, 52 (7), 11–12.
3. (a) Dekeyser, M. A.; McDonald, P. T. Insecticidal phenylhydrazine derivatives.
US Patent 5,367,093, November 22, 1994; (b) Jin, H. Process for the preparation

2156
G.-L. Chee
of insecticidal phenylhydrazine derivatives. US Patent 6,278,022, August 21,
2001.
4. Park, S.B.; Chee, G.-L.; Dekeyser, M. A. 4-Methoxybiphenyl hydrazone deriva-
tives.. US Patent 6,706,895, March 16, 2004.
5. Chee, G. L.; Park, S. B.; Dekeyser, M. A. 4-Hydroxybiphenyl hydrazide deriva-
tives. US Patent 6,093,843, July 25, 2000.
6. (a) Zaltsgendler, I.; Leblanc, Y.; Bernstein, M. A. Synthesis of aromatic amines
from electron-rich arenas and bis(2,2,2-trichloroethyl) azodicarboxylate. Tetrahe-
dron Lett. 1993, 34 (15), 2441–2444; (b) Mitchell, H.; Leblanc, Y. Amination of
arenes with electron-deficient azodicarboxylates. J. Org. Chem. 1994, 59,
682–687; (c) Leblanc, Y.; Boudreault, N. Para-directed amination of electron-
rich arenas with bis(2,2,2-trichloroethyl) azodicarboxylate. J. Org. Chem. 1995,
60, 4268–4271; (d) Yadav, J. S.; Subba Reddy, B. V.; Mahesh Kumar, G.;
Madan, C. InCl3-SiO2 catalyzed electrophilic amination of arenas: A facile
and rapid synthesis of aryl hydrazides. Synlett 2001, 11, 1781–1783;
(e) Bombek, S.; Lanarsic, R.; Kocevar, M.; Saint-Jalmes, L.; Desmurs, J-R.;
Polanc, S. ZrCl4-promoted halogen migration during an electrophilic amination
of halogenated phenols. Chem. Commun. 2002, 1494–1495.
7. Chee, G. Selective deprotection of isopropyl esters, carbamates and carbonates
with aluminum chloride. Synlett 2001, 10, 1593–1595.
8. Ravikumar, K. S.; Zhang, Y. M.; Begue, J-P.; Bonnet-Delphon, D. Role of
hexafluoro-2-propanol in selective oxidation of sulfide to sulfoxide: Efficient
preparation of glycosyl sulfoxides. Eur. J. Org. Chem. 1998 (2937–2940), and
references cited therein.
9. Thompkins, G. J. US EPA new pesticide fact sheet: Bifenazate. EPA-738-F-97,
June 1999.