Synthesis and properties of axially-chiral N-(2,6-disubstituted)phenyl triazolones

Article abstract of DOI:10.1016/j.tet.2004.03.056

Certain ortho-substituted phenyl triazolone compounds are fungicidal. When two ortho-substituents are present, stable atropisomers can be isolated. Several methods for resolving racemic intermediates into the enantiomers are described, including separations of diasteromeric ester derivatives and diasteromeric salts. The intermediates were converted into products in which the absolute configuration can be correlated to biological activity.

Full text of DOI:10.1016/j.tet.2004.03.056

Tetrahedron 60 (2004) 4361–4375
Synthesis and properties of axially-chiral
N-(2,6-disubstituted)phenyl triazolones
a
a
a
a
Richard J. Brown,a Gary Annis, Albert Casalnuovo, Dominic Chan, Rafael Shapiro
,
*
and William J. Marshallb
aDuPont Crop Protection, Stine-Haskell Research Center, Newark, DE 19714, USA
bCentral Research and Development Department, E.I. DuPont de Nemours, Experimental Station, Wilmington, DE 19880, USA
Received 20 November 2003; revised 18 March 2004; accepted 19 March 2004
Abstract—Certain ortho-substituted phenyl triazolone compounds are fungicidal. When two ortho-substituents are present, stable
atropisomers can be isolated. Several methods for resolving racemic intermediates into the enantiomers are described, including separations
of diasteromeric ester derivatives and diasteromeric salts. The intermediates were converted into products in which the absolute configuration
can be correlated to biological activity.
q 2004 Elsevier Ltd. All rights reserved.
1. Introduction
respiration inhibition4a and in vivo fungicidal activity5
(see Table 1).
For some time, we have been investigating phenyl
triazolones such as 1 and 2 as agricultural fungicides.1
These compounds are inhibitors of mitochondrial respira-
tion by blocking electron transport of the cytochrome bc1
complex. Like the commercial fungicides azoxystrobin2
and kresoxim methyl,3 they bind at the ubihydroquinone:
cytochrome-c oxidoreductase site.4
Crystallographic studies of the 2,6-disubstituted compounds
showed that the solid-state conformation has the triazolone
nearly perpendicular to the phenyl ring. We reasoned that
the buttressing of the second ortho-group might force the
triazolone to remain in a conformation most suited for
binding at the active site of the enzyme. We then wondered
whether the rotational barrier in these molecules was
sufficient to allow us to isolate stable enantiomers
(atropisomers).6,7 Small quantities of the atropisomers of
1a were separated by preparative HPLC using a chiral
stationary-phase column. However, complete racemization
of the individual enantiomers occurred within hours.
Racemic 1b was also resolved chromatographically, but in
this case the enantiomers proved to be completely stable at
ambient temperature; after the fact, the rotational barrier
was calculated to be about 40–50 kcal/mol.8 As might be
expected, one enantiomer is significantly more active than
the other.9 In both 1b and 2b, the (þ)-enantiomer is the
more active (see Table 1).
The steric interaction between the triazolone ring and the
large o-substituent disfavors co-planarity of the system. The
resulting twist may contribute to the observed biological
activity, since aryl triazolones and related respiration
inhibitors without an ortho-group are inactive.4b As part
of our exploration of structure–activity relationships,
additional substituents on the phenyl ring were investigated.
For example, a methyl group at the second ortho-position
(as in compounds 1b and 2b) provided excellent in vitro
Since we believed that chromatographic separation would
not be a practical strategy to pursue in our attempt to
develop a non-racemic aryl triazolone as a commercial
fungicide, we began an investigation of various synthetic
approaches. Enantioselective or diastereoselective synthe-
sis, though a proven strategy for other types of chiral non-
racemic products, would probably be difficult to apply to our
case of axial-chirality. Thus, we decided that we might be
more successful in trying to find a suitable method to resolve
a readily accessible racemic intermediate. This intermediate
Keywords: Atropisomers; Triazolones.
*
Corresponding author. Address: E323/3302, Experimental Station,
Wilmington, DE 19880 USA. Tel.: þ1-302-695-2217; fax: þ1-302-
695-2568; e-mail address: richard.j.brown@usa.dupont.com
0040–4020/$ - see front matter q 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2004.03.056

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R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
Table 1.
Compound
Enantiomeric excess
Wheat powdery mildew
Tomato late blight
Rate (ppm)
(% Control)
Rate (ppm)
(% Control)
1a
Racemic-1b
—
0
200
200
2
93
100
53
200
20
64
99
(þ)-1b
84
2
100
200
2
200
200
10
100
98
0
93
42
83
(2)-1b
2a
99
—
10
200
2
28a
100
95
100
52
99
95
0
Racemic-2b
0
2
200
0.4
40
2
(þ)-2b
83
96
(2)-2b
2
a
Low levels of biological activity may be due to the presence of minor amounts of the active enantiomer.
would be required to have a rotational barrier around the
chiral axis high enough to maintain its integrity during
further processing to the final compound, but sufficiently
low to allow thermal racemization for recycling to the
process.10 Because the atropic asymmetry does not arise
unless the triazolone ring is completely formed, this also
influenced the point when an asymmetric synthesis could be
envisioned. Compound 3 can be used to prepare 1b and
compound 4 can be used to prepare 2b. The phenol moiety
in compound 3 and the benzylic alcohol moiety in
compound 4 appeared to be useful groups for preparing
covalent diastereomeric derivatives. We also considered
that the phenol moiety in 3 also may be sufficiently acidic to
prepare diastereomeric salts. Enzymatic kinetic resolutions
of 3 or 4 also appeared to be potentially viable methods.11
Therefore, we began to investigate methods of resolution of
these key materials.
2. Results and discussion
2.1. Synthesis of racemic intermediates
Compound 3 may be readily prepared according to
Scheme 1. Our synthesis began with commercially available
5, which was treated with phosgene to provide the
isocyanate 6. The crude 6 was treated with dimethyl-
hydrazine to provide the semicarbazide 7. Cyclization with
excess phosgene12 provided chlorotriazolone 8. To mini-
mize undesirable side reactions, this reaction was best
conducted by continuous addition of 7 to a hot solution of
phosgene in ethyl acetate in order to maintain a large excess
of phosgene relative to substrate. Deprotection of the phenol
was accomplished with aluminum trichloride to yield 9,13
which was then treated with sodium methoxide to yield 3.
The synthesis of 4 (Scheme 2) began with the selective
monochlorination of 2-isocyanato-1,3-dimethylbenzene.
Reaction of 11 with dimethylhydrazine provided the
semicarbazide 12 that was cyclized with phosgene as
previously described. Direct introduction of the methoxy
group to the triazolone was complicated by competing
reaction with the benzylic chloride. An improved procedure
was effected by preparation of the tricyclic sulfone 15.
Methanolysis of 15 resulted in clean introduction of the
Scheme 1. (a) COCl2; (b) NH2NMe2; (a),(b) 98% overall; (c) COCl2, 98%; (d) AlCl3, 96%; (e) NaOMe, 57%.

R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
4363
Scheme 2. (a) i COCl2, 92%; ii Cl2, 84.5%; (b) NH2NMe2; (c) COCl2; (b),(c) 66% overall; (d) Na2S, 59%; (e) H2O2, 83%; (f) NaOMe; (g) Br2; (f),(g) 84%
overall; (h) tetrabutylammonium bromide, 78%; (i) H2O, 86%.
methoxy group into the triazolone, providing the sulfinic
acid salt 16. This compound was converted into the benzylic
bromide 18 by formation of the sulfonyl bromide followed
by sulfur dioxide expulsion.14 Finally, hydrolysis of 18
using calcium carbonate in aqueous dioxane15 provided
benzylic alcohol 4.
Selective fractional crystallization of a single diastereomer
from methanol, followed by X-ray crystallographic analysis
(see Fig. 1) allowed us to correlate the stereochemistry of
the atropic axis with that of the known naproxen moiety. In
this view, the a-methyl of the naproxen moiety and the
methoxy group of the triazolone are oriented toward the
viewer. The absolute configuration of the atropic axis is thus
aR.7 It is interesting to note that the triazolone and the
naphthalene group are very nearly parallel and stacked
together, indicating a possible p-stacking interaction
between the two groups. The distance from the center of
the triazolone ring to the mean plane of the naphthalene
2.2. Resolution methods
2.2.1. Separation of diastereomeric esters. Chemical
separation of enantiomers by the preparation and separation
of covalently bonded diastereomeric derivatives is perhaps
the most commonly practised method for effecting
resolutions of alcohols and phenols. Separation of the
diastereomers can be accomplished by crystallization or
chromatography.
˚
group is 3.93 A.
The mother liquors contained a mixture of diastereomers
enriched in the aS diastereomer. Following methanolysis of
the enriched diastereomers to remove the naproxen moiety,
recrystallization of the partially-enriched (aS)-3 provided
further enrichment by removal of additional racemic 3 from
the mixture. This two-step process allowed us to obtain
both enantiomers of 3 in high enantiomeric purity. We
subsequently determined that the aS configuration provided
the more fungicidally-active enantiomer (see below).
We began our efforts at resolving 3 by surveying several
common resolving agents, including mandelate derivatives,
(2)-menthyl chloroformate and R-(þ)-a-methyl benzyliso-
cyanate. We were unable to achieve efficient diastereomer
separations with these resolving agents.
Our first successful resolution of 3 used 19, the acid chloride
of the readily available (S)-(þ)-6-methoxy-a-methyl-2-
naphthaleneacetic acid (naproxen)16 to prepare the corre-
sponding esters (Scheme 3).
Enantiomerically enriched 3 can be readily racemized
thermally by, for example, heating the neat solid above its
melting point for a few minutes. After cooling, the resulting

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R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
Scheme 3. (a) Et3N, 33%; (b) MeOH, Fractional Crystallisation; (c) NaOMe, 87%; (d) NaOMe, 85%.
solid was found to be completely racemic. Thus, we could
recycle the undesired enantiomer to the process. On a
manufacturing scale, the ability to use all of a late-stage
intermediate such as 3 is very important for a cost-effective
synthesis.
We also discovered that racemic 3 forms a dimer of the two
enantiomers in the crystalline state. The dimer appears to
have matched hydrogen bonds between the phenol of one
enantiomer and the triazolone carbonyl of the other
enantiomer (see Fig. 2). Enantiomerically pure 3 does not
Figure 1. ORTEP drawing of (aR)-20. Thermal ellipsoids drawn to the 50%
probability level.
Figure 2. ORTEP drawing of racemic 3 showing hydrogen-bonded dimer.
Thermal ellipsoids drawn to the 50% probability level.

R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
4365
2.2.2. Separation of camphorsulfonate derivatives.
Although resolution with naproxen can be used to prepare
enantiomerically enriched triazolones, it is unsuitable for
scale-up, since it required multiple recrystallizations to
obtain high-purity diastereomers. Furthermore, the less
soluble diasteromer provided the undesired enantiomer of
3. As only one enantiomer of the 6-methoxy-a-methyl-2-
naphthaleneacetic acid is commercially available, we were
limited in our ability to switch to the opposite antipode to
carry out a more efficient synthesis of the desired aS-3.
Therefore, we wanted to investigate other resolving agents
in order to find a system to resolve the preferred aS
configuration more effectively. We settled upon 10-cam-
phorsulfonyl chloride, both enantiomers of which are
commercially available for a similar price. Thus, we
would not be restricted by availability of the resolving
agent, no matter which one proved more suitable for
processing.
Figure 3. ORTEP drawing of (þ)-3 showing hydrogen-bonded chain.
Thermal ellipsoids drawn to the 50% probability level.
Compound 3 was coupled with 1S-(þ)-10-camphorsulfonyl
chloride to yield a mixture of diastereomers that we could
not separate by fractional crystallization (Scheme 4).
However, careful chromatography provided separation of
the two diastereomers. Removal of the camphorsulfonate by
methanolysis followed by comparison to the enantiomers of
3 showed that the diastereomer with the desired aS
configuration at the atropic axis was the first eluting
component. This allowed us to obtain the desired enantio-
mer of 3 in high enantiomeric excess. But, because of the
need for chromatography, we still did not have a method
suitable for large-scale preparations of (þ)-3.
form similar dimers, instead forming extended hydrogen-
bonded chains (see Fig. 3).
We also observed that the aggregation behavior of racemic 3
and (þ)-3 differed in aprotic solvents (compare the partial
1H NMR spectra of racemic 3 in Fig. 4(A) to that of (þ)-3 in
Fig. 4(B)). It appears that formation of dimeric racemic
pairs is preferred over more extensive chain aggregation in
enantiomerically enriched samples, resulting in different
NMR signals for the paired and unpaired molecules (Fig.
4(C)). The NMR signals shift depending on concentration
and level of enrichment. Analysis of the spectra enabled
us to calculate enantiomeric excesses of partially enriched 3
by comparing the integrations of the signals from the dimer
to those from the enantiomer in excess. In protic solvents,
the difference in NMR signals disappears (Fig. 4(D)),
apparently due to solvent disruption of the hydrogen-bonded
aggregation.
Following the successful resolution of 3 using the
camphorsulfonate, we investigated the resolution of 4 by a
similar strategy. In addition to the other advantages of the
camphorsulfonates described above, the camphorsulfonate
ester of 4 could itself act as a leaving group, thus
Figure 4. Partial 1H NMR (300 MHz) spectra of 3. (A) Racemic 3 in CDCl3; (B) (2)-3 (.95% ee, determined by HPLC) in CDCl3; (C) 3 (40% ee, determined
by HPLC) in CDCl3; (D) 3 (40% ee) in CD3OD.

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R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
Scheme 4. (a) NaH, (aS)-21 34%, (aR)-21 28%; (b) Chromatography; (c) NaOMe, 75%.
streamlining the synthesis of 2b. Treatment of 4 with
triethylamine and camphorsulfonyl chloride in tetrahydro-
furan provided the camphorsulfonate in high yield and good
purity (Scheme 5). With (1S)-(þ)-10-camphorsulfonyl
chloride, we obtained a 1:1 mixture of diastereomers 22
that did not appear to separate by thin-layer chromatog-
raphy. Crystallization from ethereal solvents did not provide
any diastereomeric enrichment. Flash chromatography with
somewhat arbitrary breaks in the fractions gave four
portions that were enriched, to varying degrees, in one or
the other diastereomer. Each of those portions was then
crystallized from ether. The crystalline material from the
ether crystallizations proved to be a 1:1 mixture of both
diastereomers, with the mother liquors .90% pure for the
diastereomer which had been in excess! This selective
co-crystallization of a 1:1 mixture of two different
diastereomers was unexpected.
albeit convoluted, of the two diastereomers. We expected
that some refinement in chromatography to get better
enrichment, followed by crystallization from ether to
remove the minor diastereomer (in a 1:1 crystal with some
of the major diastereomer) would allow us to generate
reasonable amounts of quite pure diastereomers for further
investigation.
However, the individual (nearly pure) diastereomers were
non-crystalline following the ether crystallization, so we
tried to crystallize them. Ether or ethyl acetate had not
proven useful for fractional crystallization of the mixed
diastereomers, so we looked at other solvents. We have
found 1-chlorobutane to be a useful solvent for inducing
crystallization of a number of varied compounds. 1-Chloro-
butane has a Hildebrand solubility parameter [d(H)]17
greater than ether or hexane and comparable to ethyl
acetate, but is a less polar solvent than ethyl acetate.
Chilling 1-chlorobutane solutions of the separated
By this procedure, we had obtained a workable separation,
Scheme 5.

R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
4367
Scheme 6.
diastereomers resulted in one diastereomer (diasteromer
22a) precipitating out, while the other (diastereomer 22b)
remained in solution. This dramatic difference in solubility
between the diastereomers was not anticipated, but certainly
fortuitous. Therefore, we returned to the 1:1 mixture of
diastereomers: a hot solution of the diastereomer mixture
was seeded with a crystal of diastereomer 22a and the
resulting crystals collected by filtration. A single recrys-
tallization of the 1:1 mixture of diastereomers from
1-chlorobutane provided separation of the two diastereo-
mers in .90% efficiency (Scheme 6). Diastereomer 22b
could then be crystallized from ether. This separation
method has been subsequently scaled up to several hundred
grams.
scaleable resolution of 3 was achieved by converting it to a
hemisulfate salt. As noted above, we initially thought that
phenol 3 would be sufficiently acidic to allow us to develop
a resolution using a basic resolving agent. However, several
attempts to prepare crystalline salts from alkaloid bases such
as cinchonine were unsuccessful, apparently because of the
low acidity of 3. In order to increase the acidity of the
triazolone, we converted it to the hemisulfate.
Thus treatment of 3 in dichloromethane with an excess of a
sulfating agent such as DMF·SO3 followed by the addition
of (R)-(þ)-a-methylbenzylamine afforded a 1:1 mixture of
the diastereomeric hemisulfate salts 23 in high conversion
(Scheme 7). Solvent exchange with toluene induced the
preferential crystallization of the aS,R diastereomeric salt
(aS,R)-23a which was then purified by trituration in toluene
We also found that the purified diastereomers could be
interconverted thermally, to afford mixtures of about equal
amounts of both diastereomers. Heating a solution of highly
enriched 22a in refluxing xylene for 48 h provided a 1:1
mixture of 22a and 22b.
Removal of the camphorsulfonate groups from the
diastereomers 22a and 22b by hydrolysis provided the
resolved enantiomers of benzyl alcohol 4. Diastereomer 22a
provided (2)-4 and 22b provided (þ)-4. However, for the
purposes of preparing fungicidal derivatives, it was more
desirable to use the camphorsulfonate as a leaving group in
nucleophilic displacements (see below).
We did not observe any differences between the NMR
spectra of racemic 4 and enantiomerically enriched 4, as
was observed for the phenolic triazolones 3. This suggests
that the hydrogen-bond-mediated aggregation is not as
significant for the benzyl alcohol 4 as for the phenolic 3.
Figure 5. ORTEP drawing of (aS,R)-23a. Thermal ellipsoids drawn to the
50% probability level.
2.2.3. Separation of diastereomeric salts. A more readily
Scheme 7. (a) i DMF·SO3, ii (R)-(þ)-alpha-methylbenzylamine; (b) toluene extraction; (a),(b) 65% overall; (c) H2SO4, 99%.

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R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
2.3. Synthesis of fungicidal derivatives
With the successful production and separation of the
enantiomers of 3 and 4, we needed to correlate their
absolute configuration with their biological activity.
Samples of the enantiomerically enriched (aR)-1b and
(aS)-1b were prepared from the phenols using a modifi-
cation of Barton’s copper mediated O-phenylation with
triphenyl bismuth and triethylamine as a promoter18
(Scheme 8). Biological testing and comparison to material
previously separated by chiral-phase HPLC allowed us to
assign the aS configuration to the more active enantiomer.
After the successful production and separation of the
camphorsulfonate derivatives of 4, we used the camphor-
sulfonate esters as the leaving group directly in displace-
ment reactions with 1-[3-(trifluoromethyl)phenyl]ethanone
oxime 24 (Scheme 9). As envisioned, displacements of the
camphorsulfonate moiety went very well, leading to high
conversions of both diastereomers to the enantiomers of 2b.
Biological testing of both enantiomers of 2b indicated that
diastereomer 22b provided the more active enantiomer.
Assuming that the chirality about the atropic axis was
conserved for the fungicidally-active enantiomers with
either ortho group, we hypothesised that the absolute
configuration of diastereomer 22b at the atropic axis was
also aS as shown.
Scheme 8. (a) Triphenylbismuthine, Cu(OAc)2, Et3N, (þ)-1b 90%, (2)-1b
93%.
(2£). We confirmed the structure and absolute configuration
of (aS,R)-23a by a single crystal X-ray diffraction analysis
(see Fig. 5). Hydrolysis of (aS,R)-23a in aqueous sulfuric
acid afforded the desired aS-enantiomer of 3 in 90–94% ee
and 65–75% overall yield. In one case, 83% of the
remaining aR-enriched 3 (68% ee) was recovered by acid
hydrolysis of the toluene filtrate. With this procedure we
were able to resolve up to 300 g of racemic 3. Although this
resolution is relatively straightforward, the use of excess
DMF·SO3 must be minimized and all reagents and solvents
used before the addition of toluene must be rigorously
dried to reduce the formation of byproduct sulfate salts
that interfere with the crystallization and purification of
(aS,R)-23a.
2.4. Biological activity
Biological activity was assayed by measuring plant disease
control using the pathogen–host complex grown in green-
house or growth chambers. Test compounds were applied at
rates ranging from 0.4 to 200 parts per million (ppm) and an
assessment of the prevention of disease was made by
visually scoring the diseased area of the foliage relative to
untreated checks.19
Test compounds were first dissolved in acetone in an
amount equal to 3% of the final volume and then suspended
at a concentration of 200 ppm in purified water containing
250 ppm of the surfactant Tremw 014 (polyhydric alcohol
Scheme 9. (a) NaH, 1-[3-(trifluoromethyl)phenyl]ethanone oxime, (2)-2b 70%, (þ)-2b 65%.

R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
4369
esters). The resulting test suspensions were then used in the
following tests, either at the 200 ppm rate or at lower rates
after serial dilution. Spraying these 200 ppm test suspen-
sions to the point of runoff on the test plants is the equivalent
of a rate of 500 g/ha.
reported in ppm downfield from tetramethylsilane; s¼
singlet, d¼doublet, t¼triplet, q¼quartet, m¼multiplet,
dd¼doublet of doublets and br s¼broad singlet.
Except where indicated, analyses of enantiomeric excesses
(%ee) were carried out on an HP 1090 HPLC equipped
with a 25 cm£4.6 mm (R,R) Whelk-O1 column (Regis
Technologies Inc., Morton Grove, IL, USA), column
temperature¼40 8C, detector l¼230, 254 nm) using solvent
mixtures, flow rates and elution times as indicated for each
example.
2.4.1. Wheat powdery mildew. The test suspension was
sprayed to the point of run-off on wheat seedlings. The
following day the seedlings were inoculated with a spore
dust of Erysiphe graminis f. sp. tritici, (the causal agent of
wheat powdery mildew) and incubated in a growth chamber
at 20 8C for 7 days, after which disease ratings were made.
Crystallographic data (excluding structure factors) for the
structures in this paper have been deposited with the
Cambridge Crystallographic Data Centre as supplementary
publication numbers CCDC223076, CCDC223077,
CCD223629 and CCD223630. Copies of the data can be
obtained, free of charge, on application to CCDC, 12 Union
Road, Cambridge, CB2 1EZ, UK [fax: þ44-1223-336033 or
e-mail: deposit@ccdc.cam.ac.uk].
2.4.2. Tomato late blight. The test suspension was sprayed
to the point of runoff on tomato seedlings. The following
day the seedlings were inoculated with a spore suspension of
Phytophthora infestans (the causal agent of potato and
tomato late blight) and incubated in a saturated atmosphere
at 20 8C for 24 h, and then moved to a growth chamber at
20 8C for 5 days, after which disease ratings were made.
In Table 1, a rating of 100 indicates 100% disease control
and a rating of 0 indicates no disease control (relative to the
checks).
4.1.1. N-(2-Methoxy-6-methylphenyl)-2,2-dimethyl-
hydrazinecarboxamide (7). To a stirred solution of
phosgene (108 g, 1.09 mol) in ethyl acetate (750 mL) at
0 8C was added dropwise 2-methoxy-6-methylaniline 5a
(125.0 g, 912 mmol) dissolved in ethyl acetate (250 mL)
over 20 min. The reaction mixture was slowly warmed to
room temperature and was then heated at reflux for 1 h.
The solution was cooled to room temperature and was
concentrated under reduced pressure to provide the crude
isocyanate 6a as a dark red liquid that was redissolved in
ethyl acetate (1 L) and cooled to 0 8C. 1,1-Dimethylhydra-
zine (55.0 g, 911 mmol) was added dropwise over 30 min
and then the mixture was allowed to warm to room
temperature and stirred for 16 h. The mixture was cooled
and filtered, and the solid was washed with ethyl acetate and
dried to provide 200.0 g (98% yield) of the title compound 7
as a white solid, mp 151–153 8C; dH (300 MHz, CDCl3)
7.58 (1H, br s, NH), 7.10 (1H, t, J¼8 Hz, ArH), 6.84 (1H, d,
J¼8 Hz, ArH), 6.74 (1H, d, J¼ 8 Hz, ArH), 5.22 (1H, br s,
NH), 3.80 (3H, s, OCH3), 2.63 (6H, s, N(CH3)2), 2.31 (3H, s,
ArCH3).
3. Conclusions
Certain biologically active phenyl triazolones exhibit
atropisomerism. We successfully investigated different
approaches to resolving atropic phenyl triazolones having
either phenolic or benzylic alcohol moieties, including
separation of diasteromeric esters and sulfonates and
selective crystallization of diasteromeric salts. The various
methods were evaluated in terms of their suitability for
manufacturing-scale synthesis. In the benzylic alcohol
resolution, the separation of diastereomeric sulfonate
derivatives was impacted by some dramatic differences in
fractional crystallization using different solvents. We also
briefly investigated thermal interconversions of the enriched
materials. The results of these studies are highly efficient
resolution/reaction sequences to prepare enantiomerically
enriched fungicides from the racemic materials.
4.1.2. 5-Chloro-2,4-dihydro-4-(2-methoxy-6-methylphe-
nyl)-2-methyl-3H-1,2,4-triazol-3-one (8). The compound
7 (100.0 g, 448 mmol) was suspended in ethyl acetate (1 L)
and added dropwise, via mechanical pump, over 3.5 h to a
stirring solution of phosgene (177 g, 1.79 mol) in ethyl
acetate (1.5 L) that was heated at reflux. After the addition
was complete, the mixture was heated at reflux for a further
3 h, cooled to room temperature and stirred for 16 h. The
solution was concentrated under reduced pressure and the
residue was dissolved in ethyl acetate and water and
extracted four times with ethyl acetate. The combined
organic phases were washed with saturated aqueous NaCl,
dried (MgSO4), filtered and concentrated to afford 111.4 g
(98% yield) of the title compound 8 as a pale yellow solid,
mp 132–134 8C; dH (300 MHz, CDCl3) 7.34 (1H, t, J¼8 Hz,
ArH), 6.93 (1H, d, J¼8 Hz, ArH), 6.85 (1H, d, J¼8 Hz, ArH),
3.79 (3H, s, OCH3), 3.54 (3H, s, NCH3), 2.20 (3H, s, ArCH3).
In addition, during these studies we discovered an interest-
ing aspect of the phenolic triazolones. Racemic phenolic
triazolones form dimers, while the corresponding enantio-
merically enriched compounds form extended chains. These
differences in aggregation behavior were observed in the
crystalline states and in aprotic solvents.
4. Experimental
4.1. General
Percentages are by weight except for chromatographic
solvent mixtures or where otherwise indicated. Parts and
percentages for chromatographic solvent mixtures are by
volume unless otherwise indicated. Melting points were
obtained using a MEL-TEMPw capillary melting point
apparatus and are uncorrected. 1H NMR spectra were
obtained on a Varian Unity Plus at 300 MHz and are
4.1.3. 5-Chloro-2,4-dihydro-4-(2-hydroxy-6-methyl-
phenyl)-2-methyl-3H-1,2,4-triazol-3-one (9). To a stirring

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R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
solution of 8 (15.0 g, 59.3 mmol) in benzene (200 mL) at
0 8C was added aluminum chloride (23.7 g, 178 mmol) in
small portions. The mixture was warmed to room
temperature and stirred for 2 days. The mixture was poured
over ice and water and then extracted four times with ethyl
acetate. The combined organic phases were washed with
saturated aqueous NaCl, dried (MgSO4), filtered and
concentrated to an oil that was purified by flash chroma-
tography on silica gel to provide 13.6 g (96% yield) of the
title compound 9 as a pale orange solid, mp 175–178 8C; dH
(300 MHz, CDCl3) 8.11 (1H, s, ArOH), 6.92 (1H, t,
J¼8 Hz, ArH), 6.71 (1H, d, J¼8 Hz, ArH), 6.41 (1H, d,
J¼8 Hz, ArH), 3.56 (3H, s, NCH3), 2.12 (3H, s, ArCH3).
(aS)-20:(aR)-20). The mother liquors were fractionally
crystallized from ether to give 4.3 g of a white solid (8.4:1
mixture of (aS)-20:(aR)-20). This material was recrystal-
lized from ethyl acetate/hexane to give 4.0 g (9% yield) of
an 8.4:1 mixture of the diastereomers of the title compound
(aS)-20:(aR)-20) as a white solid, mp 98–101 8C; dH
(300 MHz, CDCl3) (of the major diastereomer (aS)-20;
signals from the minor diastereomer (aR)-20 are not
reported) 7.7 (3H, m, ArH), 7.39 (1H, dd, J¼1.9, 8 Hz,
ArH), 7.30 (1H, t, J¼8 Hz, ArH), 7.15 (3H, m, ArH), 7.02
(1H, d, J¼8 Hz, ArH) 4.00 (1H, q, J¼7 Hz, ArCH(CH3)-
CvO), 3.92 (3H, s, OCH3), 3.75 (3H, s, ArOCH3), 3.20
(3H, s, NCH3), 2.19 (3H, s, ArCH3), 1.60 (3H, d, J¼7 Hz,
ArCH(CH3)CvO).
4.1.4. 2,4-Dihydro-4-(2-hydroxy-6-methylphenyl)-5-
methoxy-2-methyl-3H-1,2,4-triazol-3-one (3). To a stirred
solution of 9 (133.5 g, 557.0 mmol), prepared as above, in
tetrahydrofuran (1.5 L) was added dropwise sodium meth-
oxide (25% by weight in methanol, 382 mL, 1.67 mol). The
mixture was heated at reflux for 3 h, cooled to room
temperature and then diluted with aqueous ammonium
chloride and ethyl acetate. The aqueous layer was acidified
(to pH 45) with 1 N HCl and extracted three times with ethyl
acetate. The combined organic phases were washed with
saturated aqueous NaCl, dried (MgSO4), filtered and
concentrated to a dark brown solid that was triturated with
ethyl acetate to afford 75.0 g (57% yield) of the racemic title
compound 3 as a white solid, mp 194–196 8C; dH
(300 MHz, DMSO-d6) 9.91 (1H, s, ArOH), 7.17 (1H, t,
ArH), 6.78 (2H, m, ArH), 3.84 (3H, s, OCH3), 3.30 (3H, s,
NCH3), 2.03 (3H, s, ArCH3).
4.1.6. (aS)-2,4-Dihydro-4-(2-hydroxy-6-methylphenyl)-
5-methoxy-2-methyl-3H-1,2,4-triazol-3-one ((1)-3). To
a suspension of 4.0 g (8.9 mmol) of the 8.4:1 mixture of
diastereomers (aS)-20:(aR)-20 in 40 mL of methanol was
added 2.0 mL of 30% sodium methoxide in methanol.
The mixture was stirred at room temperature for 30 min.
The mixture was diluted with 40 mL of water and extracted
with dichloromethane (3£40 mL). The aqueous phase was
made acidic with 1 N hydrochloric acid and extracted again
with dichloromethane (3£40 mL). These combined extracts
were dried (MgSO4), filtered and concentrated by rotary
evaporation. The glassy residue was triturated in hexane to
give a white solid that was collected by filtration to afford
1.82 g (87% yield) of the title compound (þ)-3, mp 178–
180 8C; dH (300 MHz, CDCl3) 7.95 (1H, s, ArOH), 6.85
(1H, t, J¼8 Hz, ArH), 6.68 (1H, d, J¼8 Hz, ArH), 6.41 (1H,
d, J¼8 Hz, ArH), 3.92 (3H, s, OCH3), 3.48 (3H, s, NCH3),
2.12 (3H, s, ArCH3); [a]2D0¼þ113.1 (c 5.53, CH2Cl2).
HPLC analysis [75% hexanes, 25% isopropyl alcohol,
0.1% acetic acid, 0.7 mL/min elution time 8.5 min]
indicates 86% ee.
4.1.5. [2-(1,5-Dihydro-3-methoxy-1-methyl-5-oxo-4H-1,
2,4-triazol-4-yl)-3-methylphenyl] 6-methoxy-a-methyl-
2-naphthaleneacetate (20). S-(þ)-6-Methoxy-a-methyl-2-
naphthaleneacetic acid (23.03 g) was treated with 75 mL of
oxalyl chloride at room temperature for 1 h. The excess
oxalyl chloride was removed by rotary evaporation. The
crude acid chloride was dissolved in 100 mL of tetra-
hydrofuran and added dropwise to a solution of 3 (23.5 g,
100 mmol) and triethylamine (14 mL) in 500 mL of
tetrahydrofuran. After addition was complete, the mixture
was allowed to stir at room temperature for 1 h. The
precipitated triethylamine hydrochloride was removed by
filtration and the filtrate was concentrated to yield orange
oil. The crude material was purified by flash chroma-
tography on silica gel (gradient from 1:1 ethyl acetate
hexane to 100% ethyl acetate as eluant) to provide a mixture
of two diastereomers in a 1:1 ratio as colorless oil.
Trituration in ether provided a solid (15.4 g) that was
enriched in one diastereomer. This material was fractionally
crystallized from methanol (two recrystallizations) to
provide a single diastereomer of the title compound (aR)-
20 as a white solid, mp 147 8C; dH (300 MHz, CDCl3) 7.7
(3H, m, ArH), 7.3 (2H, m, ArH), 7.15 (4H, m, ArH), 3.99
(1H, q, J¼7.1 Hz, ArCH(CH3)CvO), 3.93 (3H, s, OCH3),
3.61 (3H, s, ArOCH3), 3.10 (3H, s, NCH3), 2.15 (3H, s,
ArCH3), 1.61 (3H, d, J¼7.1 Hz, ArCH(CH3)CvO).
4.1.7. (aR)-2,4-Dihydro-4-(2-hydroxy-6-methylphenyl)-
5-methoxy-2-methyl-3H-1,2,4-triazol-3-one ((2)-3). To
a suspension of 1.34 g (3 mmol) of (aR)-20, obtained as
described above, in 10 mL of methanol was added 0.6 mL
of 30% sodium methoxide in methanol. The mixture was
stirred at room temperature for 30 min. The mixture was
diluted with 10 mL of water and extracted with dichloro-
methane (3£15 mL). The aqueous phase was made acidic
with 1 N hydrochloric acid and extracted again with
dichloromethane (3£15 mL). These combined extracts
were dried (Mg SO4), filtered and concentrated by rotary
evaporation. The glassy residue was triturated in hexane to
give a white solid that was collected by filtration to provide
600 mg (85% yield) of the title compound (2)-3, mp
184 8C; dH (300 MHz, CDCl3) 7.95 (1H, s, ArOH), 6.85
(1H, t, J¼8 Hz, ArH), 6.68 (1H, d, J¼8 Hz, ArH), 6.41 (1H,
d, J¼8 Hz, ArH), 3.92 (3H, s, OCH3), 3.48 (3H, s, NCH3),
2.12 (3H, s, ArCH3); [a]2D0¼138.6 (c 5.53, CH2Cl2). HPLC
analysis [75% hexanes, 25% isopropyl alcohol, 0.1%
acetic acid, 0.7 mL/min, elution time 7.10 min] indicates
.95% ee.
The ether-soluble material (12 g) was enriched in the other
diastereomer of the title compound (aS)-20 (4:1 mixture of
(aS)-20:(aR)-20). This material was fractionally crystallized
from methanol to give 3.15 g of a white solid (4:1 mixture of
4.1.8. (aS)-2,4-Dihydro-5-methoxy-2-methyl-4-(2-methyl-
6-phenoxyphenyl)-3H-1,2,4-triazol-3-one ((1)-1b). To
a solution of (þ)-3, prepared as above, (0.79 g,
3.4 mmol, 86% ee) in dichloromethane(16 mL) was added

R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
4371
triphenylbismuth (2.98 g, Aldrich Chemical Co.), anhy-
drous cupric acetate (0.61 g), and triethylamine (0.70 g).
After stirring at room temperature for 70 h, the crude
reaction mixture was directly subjected to flash chroma-
tography purification (silica gel, 30–40% ethyl acetate in
hexane) to give 0.95 g (90% yield) of the title compound
(þ)-1b as a white solid, mp 61–64 8C; dH (300 MHz,
CDCl3) 7.32–7.23 (3H, m, PhH and ArH), 7.10 (1H, tt,
J¼7.5, 1.0 Hz, PhH), 7.04 (1H, d, J¼7.0 Hz, ArH), 6.99
(2H, m, PhH), 6.80 (1H, d, J¼7 Hz, ArH), 3.86 (3H, s,
OCH3), 3.38 (3H, s, NCH3), 2.27 (3H, s, ArCH3). [a]2D0¼
þ16.78 (c 2.55, CH2Cl2). HPLC analysis [20% isopropyl
alcohol/80% hexane, 0.8 mL/min, elution time 12.04 min]
indicates 84% ee.
and slurried in tetrahydrofuran). The resulting mixture was
stirred at ambient temperature for 16 h, becoming a thick
paste. An additional 150 mL of tetrahydrofuran was added
and the mixture was stirred for one week. The reaction
mixture was cooled in an ice-water bath and quenched with
100 mL of water, then diluted with 500 mL of ethyl ether.
The phases were separated and the organic phase washed
with 100 mL water, 100 mL of saturated sodium carbonate
solution, 100 mL of water, then 100 mL of saturated sodium
chloride solution. The organic phase was dried (MgSO4)
and concentrated in vacuo. The residue was triturated in
ether and the solid collected by filtration to yield 35.5 g of a
white solid. Flash chromatography on silica gel (9:1 ether/
hexane as eluent), after concentrating the appropriate
fractions, afforded 12.85 g (34% yield) of the first eluting
component, which was recrystallized from ethyl acetate/
hexane to yield the title compound aS-21, as a white solid;
dH (300 MHz, CDCl3) 7.4 (2H, m, ArH), 7.25 (1H, m, ArH),
3.96 (3H, s, OCH3), 3.63 (1H, d, J¼16 Hz, SO2CHaHb),
3.45 (3H, s, NCH3), 3.17 (1H, d, J¼16 Hz, SO2CHaCHb),
2.4 (2H, m), 2.26 (3H, s, ArCH3), 2.0 (3H, m), 1.7 (1H, m),
1.45(1H, m), 1.09(3H, s, CCH3CH30 ), 0.88(3H, s, CCH3CH30 ).
4.1.9. (aR)-2,4-Dihydro-5-methoxy-2-methyl-4-(2-
methyl-6-phenoxyphenyl)-3H-1,2,4-triazol-3-one ((2)-
1b). To a solution of (2)-3, prepared as above, (0.38 g,
1.7 mmol, .95% ee) in dichloromethane(8 mL) was added
triphenylbismuth (1.41 g, Aldrich Chemical Co.), anhy-
drous cupric acetate (0.29 g), and triethylamine (0.34 g).
After stirring at room temperature for 94 h, an additional
0.2 g of triphenylbismuth was added. After a total of 160 h
of stirring, the crude reaction mixture was directly subjected
to flash chromatography purification (silica gel, 30% ethyl
acetate in hexane) to give 0.46 g (93% yield) of the title
compound (2)-1b, as a white solid, mp 69–71 8C; dH
(300 MHz, CDCl3) 7.32–7.23 (3H, m, PhH and ArH), 7.10
(1H, tt, J¼7.5, 1.0 Hz, PhH), 7.04 (1H, d, J¼7.0 Hz, ArH),
6.99 (2H, m, PhH), 6.80 (1H, d, J¼7 Hz, ArH), 3.86 (3H, s,
OCH3), 3.38 (3H, s, NCH3), 2.27 (3H, s, ArCH3); [a]2D0¼
19.33 (c 2.55, CH2Cl2). HPLC analysis [20% isopropyl
alcohol/80% hexane, 0.8 mL/min, elution time 9.8 min]
indicates approximately 99% ee.
Also, 10.6 g (28% yield) of the second eluting component,
the enantiomer of the title compound aR-21, as a white
solid; dH (300 MHz, CDCl3) 7.4 (2H, m, ArH), 7.3 (1H, m,
ArH), 3.94 (3H, s, OCH3), 3.74 (1H, d, J¼16 Hz, SO2CHa
Hb), 3.45 (3H, s, NCH3), 3.15 (1H, d, J¼16 Hz, SO2CHa
Hb), 2.4 (2H, m), 2.26 (3H, s, ArCH3), 2.0 (3H, m), 1.7 (1H,
m), 1.45 (1H, m), 1.11 (3H, s, CCH3CH30 ), 0.89 (3H, s,
CCH3CH30 ). Some mixed fractions were discarded.
4.2.2. (aS)-2,4-Dihydro-4-(2-hydroxy-6-methylphenyl)-
5-methoxy-2-methyl-3H-1,2,4-triazol-3-one ((1)-3). Dia-
stereomer aS-21 (12.85 g, 29 mmol) was suspended in
100 mL of methanol and 14.6 mL of 30% sodium
methoxide in methanol was added. The reaction mixture
was stirred at ambient temperature for 4 h. The mixture was
concentrated in vacuo to remove most of the methanol and
the remainder was diluted with 200 mL of ethyl acetate and
washed with 100 mL of 1 N hydrochloric acid, 50 mL of
water, then 100 mL of saturated sodium chloride solution.
The organic phase was dried (MgSO4) and concentrated in
vacuo to yield 5.1 g (75% yield) of the title compound (þ)-3
as a white solid, mp 183 8C; dH (300 MHz, CDCl3) 8.05
(1H, br s, ArOH), 6.85 (1H, t, J¼8 Hz, ArH), 6.7 (1H, d,
J¼8 Hz, ArH), 6.4 (1H, d, J¼8 Hz, ArH), 3.9 (3H, s,
OCH3), 3.45 (3H, s, NCH3), 2.1 (3H, s, ArCH3). HPLC
analysis indicates .95% ee.
4.2. Separation of enantiomers of 2,4-dihydro-5-meth-
oxy-2-methyl-4-(2-methyl-6-phenoxyphenyl)-3H-1,2,4-
triazol-3-one (1b)
A sample of racemic 1b (650 g) (similarly prepared as
above) was separated in portions on a Chiralcel OJ HPLC
column, 50 cm£10 cm (inner diameter) [7:3 hexanes/
ethanol, flow rate 200 mL/min, 25 8C, UV detection at
290 nm, sample concentration 40 mg/mL in 7:3 hexanes/
ethanol, 100 mL injection volume] to separate the enantio-
mers of the title compound (þ)-1b; elution time 21 min; and
(2)-1b; elution time 27 min. Following solvent removal
from the appropriate fractions, a total of 306 g (47% yield)
of the (aS)-diastereomer of the title compound (þ)-1b was
isolated as a white solid, mp 78–80 8C; 95.6% chemical
purity; 94% ee; and a total of 279 g (43% yield) of the
(aR)-diastereomer of the title compound (2)-1b was
isolated as a white solid, mp 82–84 8C; 99.2% chemical
purity; 94% ee.
4.2.3. (aS)-2,4-Dihydro-5-methoxy-2-methyl-4-[2-
methyl-6-(sulfooxy)phenyl]-3H-1,2,4-triazol-3-one (R)-a-
methylbenzenemethanamine ((aS,R)-23a). In a 500 mL
round-bottomed flask, equipped with a condenser, addition
funnel, thermometer and nitrogen inlet, sulfur trioxide·N,N-
dimethylformamide complex (39.16 g, 255.6 mmol) was
added as a solid to a slurry of racemic 3, (50.00 g,
212.5 mmol) in 300 mL of dichloromethane (distilled
from phosphorus pentoxide). The resulting homogeneous
light brown solution was refluxed under nitrogen for 1 h.
1H NMR analysis showed a 95:5 ratio of the sulfate to
unreacted 3, so an additional 1.63 g of sulfur trioxide·N,N-
dimethylformamide complex (10.64 mmol, 0.05 equiv.)
4.2.1. [aS-[2-(R p)]]-4-[2-[[[(7,7-Dimethyl-6-oxobicyclo-
[2.2.1]heptan-1-yl)methyl]sulfonyl]oxy]-6-methylphenyl]-
2,4-dihydro-5-methoxy-2-methyl-3H-1,2,4-triazol-3-one
(aS-21). To a solution of racemic 3 (similarly prepared as
above) (20.0 g, 85 mmol) in 300 mL of tetrahydrofuran and
150 mL of dimethylformamide was added (1S)-(þ)-10-
camphorsulfonyl chloride (27.8 g). To this mixture was
added 50% sodium hydride (5.12 g, washed with hexanes

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R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
was added to the reaction mixture. A solution of 41.30 g,
340.8 mmol) (R)-(þ)-a-methylbenzylamine (98% purity,
96% ee, passed through a pad of neutral alumina prior to
use), in 20 mL of dichloromethane was then added dropwise
to the reaction mixture over about 20 min. This slightly
exothermic reaction was maintained between 25–30 8C
with an ice bath. After the addition was complete, the
solution was refluxed for 15 min, whereupon a gray solid
precipitated from the reaction mixture. The hot solution was
filtered and the solids rinsed with 50 mL of dichloro-
methane. The filtrate was concentrated in vacuo until about
260 mL of dichloromethane had been removed and then
350 mL of toluene was added to the viscous residue. The
resulting two-phase (liquid/liquid) mixture was heated to
60 8C whereupon white solids precipitated. The hot mixture
was filtered and the solids washed with two 20 mL portions
4.2.5. 1-(Chloromethyl)-2-isocyanato-3-methylbenzene
(11). Step A. To 1.1 L of ethyl acetate, cooled in an ice-
water bath under nitrogen atmosphere was added condensed
phosgene (693 g, 7 mol). A solution of 2,6-dimethylaniline
(10) (424.5 g, 3.5 mol) in 250 mL of ethyl acetate was
added dropwise. A slight exotherm occurred and a
precipitate formed during the addition. After addition was
complete, the cooling bath was removed and the slurry
heated to reflux, monitoring the reaction by IR. Heating was
continued until a clear solution resulted. After 2 h, IR
analysis showed a strong cyano band at 2270 cm21. The
ethyl acetate was then removed by distillation at atmos-
pheric pressure and the product was distilled (7 mm Hg,
80 8C) to yield 2,6-dimethyl phenylisocyanate as clear
colorless oil, (472.9 g, 92% yield); nmax(Nujol) 2270 cm21
;
dH (300 MHz, CDCl3) 6.9 (3H, m, ArH), 2.3 (6H s, ArCH3).
1
of toluene. H NMR analysis of the solids showed a 95:5
ratio of the title compound (aS,R)-23a to the other
diastereomeric sulfate (aR,R)-23b. The solids were tritu-
rated with an additional 250 mL of toluene at 60 8C, filtered,
washed with 50 mL toluene followed by two 40 mL
portions of hexanes, then dried in vacuo (0.2 Torr) for
16 h to provide 32.45 g (65% of theoretical based on a
formulation of (aS,R)-23a·(toluene)0.36, MW¼469.7 g/mol)
of the title compound (aS,R)-23a as a white solid, mp
121–129 8C; [Found, C 54.41; H 5.75; N 11.51; S 6.94;
C11H12N3O6S·C8H12N, with 6% toluene by weight, requires
C 54.60; H 5.73; N 12.07; S 6.91]; dH (300 MHz, CDC l3)
7.42 (d, J¼7.5 Hz, 1H, ArH), 7.2–7.4 (m, ArH), 7.15 (d,
J¼9.4 Hz, 1H, ArH), 7.09 (d, J¼7.7 Hz, 1H, ArH), 3.92 (q,
J¼6.9 Hz, 1H, CH(CH3)), 3.89 (s, 3H, OCH3), 3.27 (s, 3H,
NCH3), 2.35 (s, CH3(toluene)), 2.18 (s, 3H, ArCH3), 1.43
(d, J¼6.7 Hz, 3H, CH(CH3)); the NH resonances were not
clearly observed but may be broadened under the aromatic
Step B. The isocyanate from Step A (424.4 g, 2.89 mol) and
VAZOw 88 (1,10-azobis(cyclohexanecarbonitrile) (4.0 g)
were heated to 80 8C and chlorine (102.6 g, 1.45 mol),
condensed with a dry ice condenser, was added over 2 h.
After the addition was complete the reaction was held at
80 8C for 15 min, then distilled under reduced pressure to
remove unreacted starting material (310 g, 79% pure). The
crude product was collected from the pot residue and saved
for further handling. The recovered starting material was
recycled with 3.5 g VAZOw 88 and 61.4 g chlorine as
above. After distillation, 213.2 g of starting material was
recovered and the crude product was combined with the
crude product from the first cycle and distilled (7 mm Hg,
127135 8C) to obtain 223.2 g of colorless oil (90% pure).
Both fractions from this distillation were recombined and
redistilled through a Vigreaux column (7 mm Hg,
130135 8C) to obtain the title compound 11 (237.1 g, 93%
pure) as clear colorless oil, dH (300 MHz, CDCl3) 7.0–7.25
(3H, m, ArH), 4.6 (2H, s, ArCH2Cl), 2.3 (3H, s, ArCH3).
1
region; [a]2D0¼þ1.3 (c 10.2 g/100 mL CHCl3). H NMR
analysis showed a 97:3 ratio of the diastereomers (aS,R)-
23a:(aR,R)-23b and the presence of 0.36 equiv. of toluene.
In CDCl3, the ratio of diastereomers can be obtained via
integration of their respective NMe singlets ((aS,R)-23a
d¼3.27, (aR,R)-23b: d¼3.31).
4.2.6. 5-Chloro-4-[2-(chloromethyl)-6-methylphenyl]-
2,4-dihydro-2-methyl-3H-1,2,4-triazol-3-one (13). The
distilled material 11 (237.6 g, 1.3 mol) was dissolved in
3 L of ethyl acetate. The solution was cooled to 10–15 8C
and 1,1-dimethylhydrazine was added dropwise, resulting in
a white suspension of crude 12. The addition funnel was
rinsed into the reaction vessel with 250 mL of ethyl acetate,
the cooling bath was removed and the slurry held at room
temperature until used in a second operation. To 1 L of ethyl
acetate in a separate vessel was added 322 g (3.25 mol) of
condensed phosgene. This phosgene solution was heated to
reflux and the slurry described above was added via a
Masterflex peristaltic pump over 1.5 h. After about 2/3 of
the slurry was added, the remaining slurry was diluted with
1 L of ethyl acetate to facilitate the transfer. After all the
slurry was added, the slurry vessel was rinsed into the
reactor with 1 L of ethyl acetate. The reaction mixture was
heated until a clear solution resulted (about 2 h). The
reaction mixture was transferred into distillation vessel,
followed by a rinse with 1 L of ethyl acetate. Atmospheric
distillation removed about 5 L of ethyl acetate and the
remaining solution was allowed to cool to room temperature
for 16 h. The solution was diluted with 2 L of hexane and
the resulting solid collected by filtration and washed with
warm water (3£) then dried under nitrogen on the filter for
16 h to provide 220.9 g (66% yield from 11) of the title
4.2.4. (aS)-2,4-Dihydro-4-(2-hydroxy-6-methylphenyl)-
5-methoxy-2-methyl-3H-1,2,4-triazol-3-one ((1)-3). In a
round-bottomed 300 mL flask equipped with a condenser,
(þ)-23a (containing 0.36 equiv. of toluene, 32.45 g,
69.1 mmol, 94% diastereomeric excess) was heated to
60 8C in 100 mL of 2 N sulfuric acid for 3 h. The initially
thick slurry dissolved upon heating and then (þ)-3 slowly
precipitated from the solution. The reaction mixture was
cooled to room temperature and extracted with three
200 mL portions of dichloromethane. The organic extracts
were extracted once with 30 mL of water, dried (MgSO4),
filtered and concentrated to dryness in vacuo. The solid was
further dried in vacuo (0.2 Torr) for about 1 h to give
16.53 g (99% yield) of the title compound (þ)-3 as a white
solid; dH (300 MHz, CDCl3) 6.79 (t, J¼7.9 Hz, 1H, ArH),
6.65 (d, J¼7.3 Hz, 1H, ArH), 6.31 (d, J¼8.0 Hz, 1H, ArH),
3.91 (s, 3H, OCH3), 3.46 (s, 3H, NCH3), 2.11 (s, 3H, ArCH3).
1H NMR analysis showed the presence of 0.086 equiv. of
toluene in addition to (þ)-3. HPLC analysis (Chirobiotic T
column purchased from Astec (i.e., Advanced Separations
Technologies, Inc.), 80:20 hexanes/EtOH, 1.0 mL/min, 40 8C;
9.64 min for (þ)-3, 11.3 min for (2)-3) showed 94% ee.

R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
4373
compound 13 as fluffy white solids; dH (300 MHz, CDCl3)
7.4 (3H, m, ArH), 4.45(2H, AB quartet), 3.5 (3H, s, NCH3),
2.17 (3H, s, ArCH3).
ration to yield an orange semisolid (crude 16), which was
dissolved in1.7 L of water and brought to pH¼5 with 48%
HBr (approximately 100 mL). The aqueous solution was
diluted with 1.7 L of dichloromethane and cooled in an ice/
water bath. Bromine (150 mL was added dropwise over
45 min to provide a pale orange mixture, which was stirred
for 45 min. The phases were separated and the organic
phase was washed with water, dried (MgSO4), filtered and
concentrated. The residue was triturated in petroleum ether
and the resulting solid collected by filtration to give 946 g
(84% yield) of the title compound 17 as an off-white solid,
mp 119–122 8C; dH (300 MHz, CDCl3) 7.4–7.5 (3H, m,
ArH), 5.20(1H, J¼14 Hz, 1/2AB quartet, CHaHbSO2)
4.90(1H, J¼14 Hz, 1/2AB quartet, CHaHbSO2), 3.93 (3H,
s, OCH3), 3.49 (3H, s, NCH3), 2.20 (3H, s, ArCH3).
4.2.7. 2,9-Dimethyl-5H-[1,2,4]triazolo[4,3-a][3,1]benzo-
thiazin-1(2H)-one (14). To a solution of 13 (2.18 g,
8 mmol), prepared similarly as above, in 20 mL of tetra-
hydrofuran and 5 mL of water was added sodium sulfide
nonahydrate (1.92 g) and tetrabutylammonium bromide (9 g)
and the resulting mixture was heated to reflux for 2 h. The
mixture was cooled and diluted with 50 mL of water and
50 mL of ethyl acetate. The organic phase was separated,
dried (MgSO4), filtered and concentrated to give a dark
semisolid. The crude material was triturated in ether/hexane
to yield 1.1 g (59% yield) of 14 as a tan solid, mp 153–155 8C;
dH (300 MHz, acetone-d6) 7.3 (3H, m, ArH), 4.13 (2H, br s,
ArCH2S), 3.43 (3H, s, NCH3), 2.42 (3H, s, ArCH3).
4.2.11. 4-[2-(Bromomethyl)-6-methylphenyl]-2,4-di-
hydro-5-methoxy-2-methyl-3H-1,2,4-triazol-3-one (18).
To a suspension of 17 (946 g, 2.52 mol) in 2.2 L of toluene
was added tetrabutylammonium bromide (80 g). The
mixture was heated to 60 8C for 16 h, resulting in an
amber solution. The reaction mixture was cooled and added
to 4 L of ice/water and the phases separated. The organic
phase was washed with water, dried (MgSO4), filtered and
concentrated. The crude product was purified by applying to
700 g of silica gel and eluting first with hexanes and then
with 2:1 hexanes/ethyl acetate to recover the product.
Removal of solvents gave 616 g (78% yield) of the title
compound 18 as an off-white solid, mp 115–116 8C; dH
(300 MHz, CDCl3) 7.22–7.35 (3H, m, ArH), 4.45(1H,
J¼10.7 Hz, 1/2AB quartet, CHaHbBr), 4.30(1H, J¼10.7 Hz,
1/2AB quartet, CHaHbBr), 3.93 (3H, s, OCH3), 3.49 (3H, s,
NCH3), 2.16 (3H, s, ArCH3).
4.2.8. 2,9-Dimethyl-5H-[1,2,4]triazolo[4,3-a][3,1]benzo-
thiazin-1(2H)-one (14). To a solution of 13 (832 g,
3.08 mol), prepared similarly as above, in 4 L of ethanol
was added thiourea (281 g, 3.7 mol) and sodium bromide
(9 g, 87 mmol) and the resulting mixture was heated to
reflux for 16 h. To the refluxing mixture was added 50%
sodium hydroxide (735 g, 9 mol) dropwise over 45 min,
then the mixture was heated at reflux for an additional 1 h.
The reaction mixture was cooled to room temperature then
added to 4 L of ice/water and the mixture was stirred for
15 min. The resulting solids were collected by filtration and
rinsed with water, then dried under vacuum in an inert
atmosphere to yield the title compound (620 g, 83% yield)
as a pale yellow solid, mp 155–157 8C; dH (300 MHz,
CDCl3) 7.3 (1H, d, J¼7 Hz, ArH), 7.2 (1H, t, J¼7 Hz, ArH),
7.13 (1H, d, J¼7 Hz, ArH), 3.9 (2H, br s, ArCH2S), 3.52
(3H, s, NCH3), 2.43 (3H, s, ArCH3).
4.2.12. 2,4-Dihydro-4-[2-(hydroxymethyl)-6-methyl-
phenyl]-5-methoxy-2-methyl-3H-1,2,4-triazol-3-one (4).
To a solution of 18, prepared as above, (50 g, 160 mmol) in
500 mL of p-dioxane and 500 mL of water was added
calcium carbonate (80.2 g), and the mixture was heated to
reflux for 2 h. The dioxane was removed by rotary
evaporation and the residue was diluted with 400 mL of
1 N hydrochloric acid. The pH was adjusted to 3 by the
addition of concentrated hydrochloric acid and ice was
added to cool. The aqueous mixture was extracted with
dichloromethane (3£200 mL). The combined organic
phases were washed with 500 mL of aqueous sodium
bicarbonate, dried (MgSO4), filtered and concentrated to
yield a pale yellow solid. The crude product was triturated in
hexanes and filtered to yield 34.1 g (86% yield) of the title
compound 4 as a white solid, mp 132–134 8C; dH
(300 MHz, CDCl3) 7.35–7.43 (2H, m, ArH), 7.3 (1H, m,
ArH), 4.48 (1H, 1/2ABX, JAB¼12.3 Hz, JAX¼2.5 Hz,
CH2OH), 4.40 (1H, 1/2ABX, JAB¼12.3 Hz, JAX¼9.0 Hz,
CH2OH), 3.94 (3H, s, OCH3), 3.48 (3H, s, NCH3), 3.27 (1H,
dd, J¼9.0, 2.5 Hz, CH2OH), 2.15 (3H, s, ArCH3).
4.2.9. 2,9-Dimethyl-5H-[1,2,4]triazolo[4,3-a][3,1]benzo-
thiazin-1(2H)-one 4,4-dioxide (15). To a suspension of
14 (400 g, 1.86 mol) in 1.6 L of acetic acid was added an
aqueous solution of sodium tungstate (17.6 g, 60 mmol in
10 mL) and the mixture heated to 55 8C. Hydrogen peroxide
(30%, 425 g) was added dropwise to the mixture over a 1-h
period while maintaining a temperature of about 70 8C. Initial
oxidation to the sulfoxide was rapid. The clear solution resul-
ting after the addition of hydrogen peroxide was maintained
at 7580 8C for 2.5 h. As the reaction progressed, the title com-
pound precipitated as a white solid. The reaction mixture was
cooled to 40 8C and was diluted with ice/water. The solids
were removed by filtration, rinsed with water and dried under
vacuum in an inert atmosphere to yield 443 g (83% yield) of
the title compound 15 as a white solid, mp .240 8C; dH
(300 MHz, CDCl3) 7.41 (1H, d, J¼7 Hz, ArH), 7.32 (1H, t,
J¼7 Hz, ArH), 7.2 (1H, d, J¼7 Hz, ArH), 4.2 (2H, br s,
ArCH2SO2), 3.68 (3H, s, NCH3), 2.5 (3H, s, ArCH3).
4.2.10. 4-[2-[(Bromosulfonyl)methyl]-6-methylphenyl]-
2,4-dihydro-5-methoxy-2-methyl-3H-1,2,4-triazol-3-one
(17). To a suspension of 15 (800 g, 3.0 mol), prepared
similarly as above, in 2.4 L of methanol was added sodium
methoxide (25% in methanol, 829 mL) dropwise over
25 min, resulting in an exotherm to 34 8C. The mixture
was heated to 60 8C for 1 h, giving an orange solution. The
majority of the methanol was removed by rotary evapo-
4.2.13. [aR-[2-(R p)]]-4-[2-[[[[(7,7-Dimethyl-6-oxobicyclo-
[2.2.1]heptan-1-yl)methyl]sulfonyl]oxy]methyl]-6-methyl-
phenyl]-2,4-dihydro-5-methoxy-2-methyl-3H-1,2,4-tri-
azol-3-one (22a) and [aS-[2-(R p)]]-4-[2-[[[[(7,7-dimethyl-
6-oxobicyclo[2.2.1]heptan-1-yl)methyl]sulfonyl]oxy]-
methyl]-6-methylphenyl]-2,4-dihydro-5-methoxy-2-
methyl-3H-1,2,4-triazol-3-one (22b). To a solution of

4374
R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
62.0 g, (249 mmol) 4, prepared as above, in 1000 mL of
tetrahydrofuran was added 87.4 g of (1S)-(þ)-camphorsul-
fonyl chloride and then 52 mL of triethylamine dropwise
with ice-bath cooling. The resulting mixture was stirred at
room temperature for 18 h. The solvents were removed by
rotary evaporation and the residue was taken up in 500 mL
of dichloromethane and washed with 500 mL of 1 N HCl,
then 500 mL of water. The organic phase was dried
(MgSO4), filtered and concentrated to give 120.4 g of
be .98% ee [90% hexanes/10% ethanol, flow rate 0.8 mL/
min, 40 8C, elution time 10.4 min]. (Under the same
conditions the other enantiomer (2)-4 eluted at 11.4 min).
4.2.15. 1-[3-(Trifluoromethyl)phenyl]ethanone oxime
(24).20 To 320 mL (1.08 mol) of 4 N sulfuric acid in a
three-neck indented, Morton-style flask, equipped with a
sidearm for thermometer, was added 40 mL (320 mmol) of
3-(trifluoromethyl)aniline. The resulting solution was
cooled to about 25 8C using an acetone/ice bath to provide
a slurry. To the slurry was added a solution of 28.0 g
(406 mmol) of sodium nitrite in 80 mL of water. The rate of
addition was carefully adjusted so the internal reaction
temperature was maintained between 25 and 0 8C. The
mixture was stirred at that temperature for 30 min to provide
the diazonium salt derived from 3-(trifluoromethyl)aniline
(which was not characterized) in a thin slurry. The slurry
thickened when a solution of 15 g (183 mmol) of sodium
acetate in 100 mL of water was added. Meanwhile, in
another flask, 80 mL (1350 mmol) of acetaldoxime, 6.0 g
(32 mmol) of copper (II) acetate, 2.0 g (16 mmol) of sodium
sulfite, and 240 g (2.9 mol) of sodium acetate were
combined and cooled to about 10 8C. To this solution was
added via a cannula the mixture containing the diazonium
salt. Immediate gas (N2) evolution was observed, and a two-
phase mixture (dark green oil and aqueous) was obtained.
The mixture was stirred for 30 min at room temperature.
The oil on the bottom was separated from the aqueous phase
and transferred to another flask. Hydroxylamine (11.0 g,
320 mmol) and potassium carbonate (22.0 g, 320 mmol)
were added together with 200 mL of water. The resulting
mixture was subjected to a steam distillation. Over a period
of 2 h, a total of 1700 mL of distillate was obtained. The
product first existed as slightly yellow oil depositing on the
bottom of the collecting flask. Upon chilling, product
solidified. A total of 35.9 g (55% yield) of the title
compound 24, with an assay purity of 89.7%, was obtained
as a white solid after filtration, mp 56–62 8C; dH (300 MHz,
CDCl3) 8.36 (1H, br s, vNOH), 7.89 (1H, d, J¼0.5 Hz,
ArH), 7.81 (1H, d, J¼8.0 Hz, ArH), 7.63 (1H, d, J¼8.0 Hz,
ArH), 7.53–7.49 (1H, m, ArH), 2.32 (3H, s, CH3).
1
orange oil. Analysis by H NMR showed a 1:1 ratio of
diastereomers. The crude product was taken up in 500 mL
of 1-chlorobutane and refrigerated for 72 h. The precipitated
crystals were collected by filtration and dried under vacuum
to yield 59.3 g of the title compound 22a white crystals, mp
121–127 8C. NMR analysis showed a mixture of 22a and
22b in about 9:1 ratio with approximately 0.5 mol equiv. of
1-chlorobutane incorporated into the crystals (47% yield,
after correction for the 1-chlorobutane present); dH
(300 MHz, CDCl3) 7.4 (3H, m, ArH), 5.24 (1H, 1/2AB,
JAB¼11.5 Hz, CH2O), 5.18 (1H, 1/2AB, JAB¼11.5 Hz,
CH2O), 3.97 (3H, s, OCH3), 3.47 (3H, s, NCH3), 3.46 (1H,
d, J¼16 Hz, SO2CHaCHb), 2.85 (1H, d, J¼16 Hz, SO2CHa-
CHb), 2.4 (2H, m), 2.18 (3H, s, ArCH3), 2.1 (2H, m), 1.93
(1H, d, J¼0 18 Hz, CH), 1.6 (1H, m), 1.4 (1H, m), 1.07 (3H, s,
CCH3CH3), 0.81 (3H, s, CCH3CH30 ). (Signals from 22b and
1-chlorobutane are not reported.)
The mother liquors from the crystallization were concen-
trated to yield 63 g of orange oil. The oil was triturated in
ether/hexanes to obtain 49.3 g (43% yield) of the title
compound 22b as a white solid, mp 104–110 8C;
[a]2D0¼þ64.0 (c 5.62, CH2Cl2); dH (300 MHz, CDCl3) 7.4
(3H, m, ArH), 5.26 (1H, 1/2AB, JAB¼11.8 Hz, CH2O), 5.13
(1H, 1/2AB, JAB¼11.8 Hz, CH2O), 3.95 (3H, s, OCH3),
3.52 (1H, d, J¼15 Hz, SO2CHaCHb), 3.47 (3H, s, NCH3),
2.94 (1H, d, J¼15 Hz, SO2CHaCHb), 2.4 (2H, m), 2.18 (3H,
s, ArCH3), 2.1 (2H, m), 1.93 (1H, d, J¼19 Hz, CH), 1.6 (1H,
m), 1.4 (1H, m), 1.08 (3H, s, CCH3CH30 ), 0.86 (3H, s,
0
1
CCH3CH3). Analysis by H NMR showed the oil to be
.95% pure for a single diastereomer (22b).
4.2.14. (aS)-2,4-Dihydro-4-[2-(hydroxymethyl)-6-
methylphenyl]-5-methoxy-2-methyl-3H-1,2,4-triazol-3-
one ((1)-4). To a solution of 22b (930 mg, 2 mmol), in
8 mL of 1,4dioxane and 8 mL of water was added 1.0 g of
calcium carbonate. The mixture was heated for 5 h at reflux.
The mixture was diluted with ethyl acetate and neutralized
with 1 N hydrochloric acid. The phases were separated and
the aqueous phase extracted with ethyl acetate. The
combined extracts were dried (MgSO4), filtered and
concentrated to provide colorless oil. The crude product
was purified by flash chromatography (1:2 hexanes/ethyl
acetate) to provide colorless oil which solidified on
standing. Trituration in hexanes gave 230 mg (46% yield)
of the title compound (þ)-4as a white crystalline solid,
mp 119–121 8C; [a]2D0¼þ100.3 (c 4.68, CH2Cl2); dH
(300 MHz, CDCl3) 7.4 (2H, m, ArH), 7.3 (1H, m, ArH),
4.48 (1H, 1/2ABX, JAB¼12.3 Hz, JAX¼3.6 Hz, CH2OH),
4.40 (1H, 1/2ABX, JAB¼12.3 Hz, JAX¼9.2 Hz, CH2OH),
3.94 (3H, s, OCH3), 3.48 (3H, s, NCH3), 3.25 (1H, dd, J¼
9.2, 3.6 Hz, CH2OH), 2.16 (3H, s, ArCH3). HPLC analysis
as described above using a Chiralpak AD column
(25 cm£0.46 cm (inner diameter)) showed the material to
4.2.16. (aR)-2,4-Dihydro-5-methoxy-2-methyl-4-[2-
methyl-6-[[[[1-[3-(trifluoromethyl)phenyl]ethylidene]-
amino]oxy]methyl]phenyl]-3H-1,2,4-triazol-3-one ((aR)-
2b). To a solution of 160 mg (0.79 mmol) of oxime 24,
prepared as above, in 10 mL of tetrahydrofuran was added
40 mg of sodium hydride (50% oil dispersion). Gas
evolution was observed and the mixture was stirred at
room temperature for 20 min. A solution of 366 mg
(0.69 mmol) of 22a (approximately 95% pure) in 10 mL
of tetrahydrofuran was added and the mixture stirred at
room temperature for 16 h. The mixture was diluted with
water and extracted with ethyl acetate (2£25 mL). The
combined extracts were dried (MgSO4), filtered and
concentrated to provide amber oil. The crude product was
purified by flash chromatography (1:1 hexanes/ethyl
acetate) to give 240 mg (70% yield) of the title compound
(aR)-2b as a colorless oil; [a]2D0¼257.1 (c 4.98, CH2Cl2);
dH (300 MHz, CDCl3) 7.86 (1H, s, ArH), 7.8 (1H, d, J¼
8 Hz, ArH), 7.6 (1H, d, J¼8 Hz, ArH), 7.45 (1H, t, J¼8 Hz,
ArH), 7.38 (2H, m), 7.3(1H, m), 5.21 (1H, 1/2AB, JAB
¼
12.8 Hz, CH2O), 5.14 (1H, 1/2AB, JAB¼12.8 Hz, CH2O),

R. J. Brown et al. / Tetrahedron 60 (2004) 4361–4375
4375
5. (a) Brown, R. J.; Castro, P. P.; Chan, D. M. -T.; Daub, J. P.;
Koether, G. M.; Selby, T. P. PCT Patent Application
Publication WO98/23156. (b) Ohsumi, T.; Hirose, T.; Ujihara,
K.; Matsunaga, R. PCT Patent Application Publication WO96/
38425.
3.89 (3H, s, OCH3), 3.41 (3H, s, NCH3), 2.22 (3H, s,
ONvCCH3), 2.18 (3H, s, ArCH3). HPLC analysis using a
Chiralpak AD column (25 cm£0.46 cm (inner diameter))
showed the material to be 92% ee [4:1 hexanes/2-propanol,
flow rate 0.8 mL/min, elution time 10.3 min].
6. Wiberg, K. Physical Organic Chemistry; Wiley: New York,
1964; pp 364–369.
4.2.17. (aS)-2,4-Dihydro-5-methoxy-2-methyl-4-[2-
methyl-6-[[[[1-[3-(trifluoromethyl)phenyl]ethylidene]-
amino]oxy]methyl]phenyl]-3H-1,2,4-triazol-3-one ((aS)-
2b). By a procedure similar to that described for the
preparation of (aR)-2b, 310 mg (0.67 mmol) of 22b
(approximately 90% pure) was converted to 190 mg (65%
yield) of the title compound as colorless oil; [a]2D0¼þ53.0
(c 5.0, CH2Cl2); dH (300 MHz, CDCl3) 7.86 (1H, s), 7.79
(1H, d, J¼8 Hz, ArH), 7.59 (1H, d, J¼8 Hz, ArH), 7.45 (1H,
t, J¼8 Hz, ArH), 7.38 (2H, m), 7.3(1H, m), 5.21 (1H,
7. For a general reference on atropic enantiomers and stereo-
chemistry, see Eliel, E. E.; Wilen, S. H. Stereochemistry of
Organic Compounds; Wiley: New York, 1994; pp 1142–
1155.
8. Zheng, Y. J.; Kleier, D. Unpublished results.
9. Brown, R. J.; Casalnuovo, A. L.; Chan, D. M. -T. PCT Patent
Application Publication WO99/11129.
10. Kinetic resolutions of the thiomethyl analogs of 1b using
chiral titanium catalysts for enantioselective S-oxidation
followed by methanolysis provided enantiomerically enriched
1b, but the undesired enantiomer of the thiomethyl inter-
mediate is not readily racemized. Shapiro R. Unpublished
results.
1/2AB, JAB¼12.8 Hz, CH2O), 5.14 (1H, 1/2AB, JAB
¼
12.8 Hz, CH2O), 3.89 (3H, s, OCH3), 3.41 (3H, s, NCH3),
2.22 (3H, s, ONvCCH3), 2.18 (3H, s, ArCH3). HPLC
analysis using a Chiralpak AD column (25 cm£0.46 cm
(inner diameter)) showed the material to be 83% ee [4:1
hexanes/2-propanol, flow rate 0.8 mL/min, elution time
8.2 min].
11. Enzymatic kinetic resolutions have been successful in
resolving phenol 3. Stieglitz, B.; Wu, W.; Brown, R. J.
Unpublished results.
12. Cooley, J. H.; Evain, E. J.; Willet, R. D.; Blanchette, J. T.
J. Org. Chem. 1989, 54, 1048–1051.
Acknowledgements
13. On larger scales, synthesis of 9 started with di-t-butyl cresol
followed by nitration, methylation and reduction to provide
the 3,5-di-t-butyl analog of 5. Formation of the triazolone
moiety according to the procedures described in Scheme 1,
followed by concommitent demethylation and debutylation by
treatment with excess aluminum trichloride, allowed us to
obtain 9 in a more cost-effective synthesis.
The authors wish to thank all those who made significant
contributions to this project, especially our co-workers
involved in the synthesis, characterization, biological
testing and mode of action studies of these compounds.
14. King, J. F.; Smith, D. J. H. J. Am. Chem. Soc. 1967, 89,
4803–4804.
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