Utility of Complementary Molecular Reactivity and Molecular Recognition (CMR/R) Technology and Polymer-Supported Reagents in the Solution-Phase Synthesis of Heterocyclic Carboxamides

Article abstract of DOI:10.1021/jo970571i

The use of our recently reported chemical library purification strategy in the development of a herbicidal lead, N-(3-benzoylphenyl)-3-(1,1-dimethylethyl)-1-methyl-1H-pyrazole-5-carboxamide (3), is described. The approach applying fundamental properties of complementary molecular reactivity and molecular recognition (CMR/R) as the basis for a general purification strategy was utilized. Polymeric reagents were used in the synthesis to generate reactive species involved in product formation, and complementary molecular reactivity/molecular recognition polymer 8 (CMR/R polymer 8) was used in the solution-phase syntheses of building blocks, primary libraries, and lead refinement libraries. An extension of the CMR/R methodology was applied, utilizing a sequestration enabling reagent (SER), transforming a reactant into an electrophilic species sequestrable by CMR/R polymer 8. This library purification strategy enabled rapid lead generation and lead refinement to afford herbicide 27o. The CMR/R solid-phase purification technique enabled a simple, general, and powerful protocol, eliminating the usual tedious and time-consuming methods required for solution-phase product purification. The result was the synthesis of hundreds of compounds, prepared in a relatively short time, leading to a compound with a 4-fold improvement in herbicidal activity over the initial lead.

Full text of DOI:10.1021/jo970571i

5908
J . Org. Chem. 1997, 62, 5908-5919
Utility of Com p lem en ta r y Molecu la r Rea ctivity a n d Molecu la r
Recogn ition (CMR/R) Tech n ology a n d P olym er -Su p p or ted
Rea gen ts in th e Solu tion -P h a se Syn th esis of Heter ocyclic
Ca r boxa m id es
J ohn J . Parlow,* Deborah A. Mischke, and Scott S. Woodard
Monsanto Company-U2D, Ceregen, 800 North Lindbergh Boulevard, St. Louis, Missouri 63167
Received March 31, 1997X
The use of our recently reported chemical library purification strategy in the development of a
herbicidal lead, N-(3-benzoylphenyl)-3-(1,1-dimethylethyl)-1-methyl-1H-pyrazole-5-carboxamide (3),
is described. The approach applying fundamental properties of complementary molecular reactivity
and molecular recognition (CMR/R) as the basis for a general purification strategy was utilized.
Polymeric reagents were used in the synthesis to generate reactive species involved in product
formation, and complementary molecular reactivity/molecular recognition polymer 8 (CMR/R
polymer 8) was used in the solution-phase syntheses of building blocks, primary libraries, and
lead refinement libraries. An extension of the CMR/R methodology was applied, utilizing a
sequestration enabling reagent (SER), transforming a reactant into an electrophilic species
sequestrable by CMR/R polymer 8. This library purification strategy enabled rapid lead generation
and lead refinement to afford herbicide 27o. The CMR/R solid-phase purification technique enabled
a simple, general, and powerful protocol, eliminating the usual tedious and time-consuming methods
required for solution-phase product purification. The result was the synthesis of hundreds of
compounds, prepared in a relatively short time, leading to a compound with a 4-fold improvement
in herbicidal activity over the initial lead.
In tr od u ction
Limitations of the solid support technique have included
reaction-scale restriction (amount of the solid support and
its loading capacity) and the need for validation of
heterogeneous reactions. Solution-phase synthetic tech-
niques have the advantage of nonlimiting scale and can
be easily manipulated as well. Moreover, organic reac-
tions performed in solution phase decrease the validation
time. However, in a solution-phase synthesis, isolation
or purification of the reaction products away from the
reaction medium, e.g., reactants, reagents, side products,
etc., may prove to be a difficult task, especially for
mixtures of products. A recently described strategy based
on principles of complementary molecular reactivity and
Combinatorial chemistry has become a powerful tool
for drug discovery in the pharmaceutical arena1 and has
recently found utilization in other areas.2 As a result,
combinatorial synthesis of libraries containing small
organic molecules has become a rapidly evolving area of
research. While both solid-phase3 and solution-phase4
synthetic techniques have been employed to generate
libraries, the majority of the compound libraries have
been synthesized on a solid support. The solid support
technique offers many advantages: two of the more
important advantages being the ease of separating the
product away from the reaction medium and the ma-
nipulation of the beads using volumetric techniques.
(3) (a) Nefzi, A.; Ostresh, J . M.; Meyer, J . P.; Houghten, R. A.
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S0022-3263(97)00571-9 CCC: $14.00 © 1997 American Chemical Society

CMR/R in Synthesis of Heterocyclic Carboxamides
J . Org. Chem., Vol. 62, No. 17, 1997 5909
Sch em e 1
Ch a r t 1
Sch em e 2
mixture exhibited herbicidal activity in a high-through-
put whole plant assay, and N-(3-benzoylphenyl)-3-(1,1-
dimethylethyl)-1-methyl-1H-pyrazole-5-carboxamide (3)
was found to be responsible for the herbicidal activity.
It controlled (80% or better) several weed species at 100
g/ha and exhibited symptoms as low as 10 g/ha.
recognition (CMR/R) employs both solid-phase techniques
with solution-phase synthesis.5,6 The CMR/R strategy
relies on inherent or artificially imparted molecular
recognition and/or molecular reactivity functionality as
the basis for product purification and isolation. We
would like to report the successful use of this CMR/R
strategy for the development of a herbicidal lead to
generate heterocyclic carboxamides as potential herbi-
cides. Polymeric reagents were used in the synthesis to
generate reactive species for product formation, and
solution-phase CMR/R scavenging resins were used to
remove unreacted or derivatized starting materials from
solution-phase product mixtures affording purified prod-
uct by direct filtration. This technique was utilized in
the preparation of building blocks (BB), primary screen-
ing libraries, and lead refinement libraries. This simple
and general strategy enabled all syntheses to be per-
formed in a high-speed parallel fashion.
In an effort to increase the herbicidal activity, synthetic
efforts to prepare analogs based on lead compound 3 were
initiated. Pure compounds in known quantities would
be required to develop the structure-activity relationship
(SAR), and it was desirable for the synthesis to be
amenable to a high-speed parallel methodology. The
pyrazolecarboxamide 3 itself offers many possibilities for
analog synthesis and initial SAR work. We approached
analog synthesis by considering the molecule as being
composed of two halves (Chart 1). Syntheses allowing
for variations on both sides of the molecule were then
developed. The first approach involved variation of the
pyrazole, including alternative heterocycles, while leaving
the aniline side constant, and the second approach
involved synthesis directed at variations of the aniline
side leaving the pyrazole portion constant.
Resu lts a n d Discu ssion
The CMR/R methodology was used for the synthesis
of analogs of the lead compound 3 enabling a high-speed
parallel format. Scheme 2 illustrates the CMR/R ap-
proach for a chemical library step which relies on the
inherent molecular reactivity properties of reactants8
and/or the inherent molecular recognition properties of
byproducts as the basis for product purification and
isolation. In parallel reaction vials, excess reactants B
are utilized to drive the solution-phase reactions of A to
completion (formation of products C). After the reactions
are complete, the excess reactants B are selectively
removed from each reaction medium by CMR/R resin X.
In a recent communication,7 a library of 8000 com-
pounds containing amides and esters was prepared by
reacting a single nucleophile with a mixture of polymer-
bound activated esters. One such mixture was prepared
as shown in Scheme 1. Polymer 1 containing a mixture
of activated heterocyclic esters was reacted with 3-ami-
nobenzophenone (2) to afford a mixture of 10 amides. This
(5) Flynn, D. L.; Crich, J . Z.; Devraj, R. V.; Hockerman, S. L.; Parlow,
J . J .; South, M. S.; Woodard, S. S. J . Am. Chem. Soc. 1997, 119, 4874-
4881.
(6) Other reported similar strategies include: (a) Booth, R. J .; Hodge,
J . C. J . Am. Chem. Soc. 1997, 119, 4882-4886. (b) Gayo, L. M.; Suto,
M. J . Tetrahedron Lett. 1997, 38, 513. (c) Kaldor, S. W.; Siegel, M. G.;
Fritz, J . E.; Dressman, B. A.; Hahn, P. J . Tetrahedron Lett. 1996, 37,
7193.
(8) The terms reactant and reagent have explicit meanings in the
context of this strategy. A reactant is a starting material which
becomes chemically incorporated into the product. A reagent is a
(7) (a) Parlow, J . J .; Normansell, J . E. Mol. Diversity 1996, 1, 271.
(b) Parlow, J . J .; Woodard, S. S.; Mischke, D. A.; Normansell, J . E.
U.S. Patent Application 08/623,444.
chemical which mediates
a transformation but does not become
incorporated into the product.

5910 J . Org. Chem., Vol. 62, No. 17, 1997
Parlow et al.
Sch em e 3
Resin X contains functionality complementary to the
reactive functionality of B. Reaction with, and seques-
tration of, the remaining excess B forms the polymer-
bound adducts I. Simple incubation of the parallel
reaction mixtures with resin X, followed by filtration and
concentration, affords purified product C. If sequestrable
byproducts D (containing inherently accessible molecular
recognition functionality) are also formed, the concomi-
tant use of a second CMR/R resin (Y) is also used to
chemoselectively sequester D as the polymer-bound
adducts II (resin I could contain molecular recognition
functionality complementary to D, thus utilizing only one
resin). If the reaction can not be driven to completion
and the reaction medium has remaining reactant A, a
sequestration enabling reagent (SER) (III) is added,
transforming A into a species (IV) sequestrable by
CMR/R resin Z as the polymer-bound adducts V.
It was envisioned that a CMR/R approach for prepara-
tion of heterocyclic carboxamides could be accomplished
through a simple amide bond-forming reaction. Thus,
reacting heterocyclic acid chlorides with 3-aminoben-
zophenone (2) would afford analogs with variations of the
pyrazole and alternative heterocycles. However, few
heterocyclic carboxylates are available as acid chlorides.
Converting the more readily available heterocyclic car-
boxylic acid to the acid chloride would require an ad-
ditional step, and a single condition for acid chloride
formation would be unlikely to be compatible for all
heterocycles used. Taking advantage of the dehydrating
power of polymer-bound 1-ethyl-3-[3-(dimethylamino)-
propyl]carbodiimide (P-EDC)9 (4), it was found that
heterocyclic carboxylic acids could be easily converted
into their respective anhydrides (6 in Scheme 3). The
anhydride in turn could then be reacted with the aniline
2 to afford the carboxamide product. In this procedure,
determining the appropriate amount of P-EDC (4) to be
used for the reaction was critical. The diimide loading
of polymer 4 was determined by mixing a weighed
amount of P-EDC (4) in deuteriochloroform at 0 °C with
an excess of acetic acid (carefully measured). The solu-
tion was stirred for 15 min at room temperature, filtered,
and analyzed by 1H NMR. The integration ratio of acetic
acid to acetic anhydride was determined, and the amount
of anhydride formed was calculated. Using this tech-
nique, it was possible to calculate the precise loading of
available carbodiimide in 4. For a single batch of 4, the
loading was determined to be 0.917 mmol/g (based on the
loading of the Merrifield’s resin used to make the P-EDC
and assuming 100% conversion of Merrifield’s resin to
P-EDC, the theoretical loading of carbodiimide was
calculated to be 0.914 mmol/g). Scheme 3 shows the
optimized synthesis in which 1.5 equiv of P-EDC (4) was
stirred with 3.0 equiv of the heterocyclic carboxylic acid
5 in dichloromethane at 0 °C for 15 min, at which point
the anhydride 6 was formed. The solution was stirred
at room temperature for 30 min, and 1.0 equiv of the
aniline 2 was added, and the slurry was heated to 50 °C.
In some cases, the reactions were slow enough to require
up to 7 days for completion. After total consumption of
the aniline 2 was observed by GC, the reaction contained
the product 7, excess anhydride 6, byproduct acid 5, and
reacted P-EDC. The CMR/R amine polymer 8 was added
(9) Desai, M. C.; Stramiello, S. L. M. Tetrahedron Lett. 1993, 34,
7685.

CMR/R in Synthesis of Heterocyclic Carboxamides
J . Org. Chem., Vol. 62, No. 17, 1997 5911
Ta ble 1. Ca r boxa m id es 7a -r Con ta in in g a P yr a zole
Heter ocycle P r ep a r ed by th e Syn th esis in Sch em e 3
Ta ble 2. Ca r boxa m id es 7A-Z Con ta in in g a 5-Mem ber ed
Heter ocyclic Rin g P r ep a r ed by th e Syn th esis in
Sch em e 3
compd
N2
Me
Me
Me
Me
Me
Me
Me
N3
R4
neo-pent
Me
Me
H
CF3
CF3
R5
% yieldb
7a
H
H
Br
H
H
Cl
Cl
H
H
H
H
H
H
Cl
H
H
Br
H
86
93
93
77
99
88
67
63
91
69
48
100
93
82
82
81
66
77
compd X2 X3 X4 R2
R3
R4
R5 % yieldb
7b
7Aa
7B
S
S
S
S
O
O
O
O
O
O
C
C
S
S
S
S
S
S
S
S
S
C
C
C
C
C
C
C
C
C
C
O
O
C
C
C
C
C
C
C
C
C
C
C
C
N
N
C
C
C
C
C
C
C
C
C
C
C
C
N
N
N
N
N
N
N
N
N
N
N
N
C
N
H
t-Bu
Cl
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
Me
Me
CF3
i-Pr
Me
Br
Me
Me
Me
Me
Ph
CF3
Cl
Me
100
66
87
60
100
75
83
80
84
93
53
78
100
83
75
79
94
36
70
77
65
64
72
70
35
67
7ca
7d a
7e
7Ca
7Da
7Ea
7F a
7Ga
7Ha
7Ia
3-thiophene
H
t-Bu
H
H
7fa
7ga
7h a
7i
4-Cl-2-F-benzene
H
H
Et
PhCH2
t-Bu
t-Bu
SiMe3
Cl
t-Bu
Me
t-Bu
neo-pent
Me
7j
7k
7l
7m
7n a
7oa
7p a
7qa
7r a
Cl
Me
Me
Me
Me
Me
Me
Me
Ph
7J
Me
Me
Me
Ph
7Ka
7La
7M
7Na
7Oa
7P a
7Qa
7Ra
7S
Me
Me
Cl
Me
i-Pr
OMe
Cl
H
CO2Me
CF3
CF3
Me
a
b
H
Addition of 11 was required for removal of aniline. Yields
4-Cl-Ph
Ph
4-CF3-Ph
3-CF3-Ph
Cl
are based on mass recovery.
7T
7U
7V
and reacted with anhydride 6 and also sequestered the
heterocyclic acid byproduct 5, forming polymer-bound
adducts 9 and 10. Simple filtration and rinsing with
dichloromethane yielded a filtrate whereupon evapora-
tion of the solvents left highly purified product 7.
S
S
O
S
N
7Wa
7Xa
7Ya
7Za
NHt-Bu
Cl
3-CF3-Ph
a
Addition of 11 was required for removal of aniline. bYields are
In the synthesis shown in Scheme 3, some of the
reactions could not be driven to completion even with a
large excess of anhydride and/or extended reaction times.
In these cases, the product mixtures contained product
7, anhydride 6, heterocyclic carboxylic acid 5, and also
unreacted aniline 2. CMR/R polymer 8 could not remove
the aniline 2 from the mixture in its present form. Thus,
it was anticipated that a SER could be added that would
react with the aniline 2, transforming it into an electro-
philic species sequestrable by CMR/R polymer 8. This
strategy was realized by reacting hexafluoroisopropyl
oxalate (11) with aniline 2, resulting in exclusive forma-
tion of the monoaddition product 12 (shown in Scheme
3) possessing an activated ester to react with the CMR/R
amine polymer 8. After the mixture stirred at 50 °C for
1 h, the CMR/R polymer 8 was added to remove the
anhydride 6, the heterocyclic carboxylic acid 5, and any
remaining SER 11, as well as the derivatized aniline 12,
leaving pure product 7 after simple filtration.10 This
procedure clearly demonstrates how a purification strat-
egy based on principles of complementary molecular
reactivity and molecular recognition (CMR/R) can be
employed in a solution-phase synthesis to purify a
reaction mixture that would otherwise require a tedious,
time-consuming purification process. Moreover, strate-
gies for sequestration of multiple solution-phase species
(5, 6, 11, and 12) with a single CMR/R resin further
illustrate the power of this method. Compounds pre-
pared by this route are shown in Tables 1-3.11
based on mass recovery.
Ta ble 3. Ca r boxa m id es 7a a -ll Con ta in in g a
6-Mem ber ed Rin g P r ep a r ed by th e Syn th esis in
Sch em e 3
compd X2 X4 X5
R2
R3
R4
R5 % yieldb
7a a
7bb
7cc
7d d
7ee
7ff
C
C
C
C
C
C
C
C
N
N
N
C
C
C
C
C
C
C
C
C
C
C
C
N
C
C
C
C
C
C
C
C
N
N
C
C
CF3
H
H
Cl
F
NO2
t-Bu
H
H
CF3
H
H
H
H
H
CF3
Cl
F
CF3
t-Bu
H
H
Me
H
H
49
81
100
93
96
97
H
H
H
H
H
H
H
H
H
7gga
7h h
7ii
73
86
CHMe(CN)
H
H
Cl
Cl
100
95
7jj
7k k a
7ll
CF3
Cl
71
83
H
a
b
Addition of 11 was required for removal of aniline. Yields
are based on mass recovery.
The CMR/R polyamine polymer 8 was prepared as
shown in Scheme 4 by taking Merrifield’s resin (14) (2%
cross-linked) and heating to 100 °C in diethylenetriamine
(15) for 4 h followed by rinsing with base to remove
residual salts. Diethylenetriamine (15) was used as the
solvent to minimize the amount of cross-linking. Com-
pound 15 can displace the chlorine by attack of the
primary nitrogen or the secondary nitrogen to afford
either secondary or tertiary amines (16 or 17). Because
of the complex nature of the polymer, containing primary,
(10) Further experiments demonstrated that succinic anhydride and
tetrafluorophthalic anhydride also worked to derivatize the aniline for
removal.
(11) All of the compounds depicted in Tables 1-7 were characterized
by GC/MS and reported with yields, with
compounds characterized by 1H NMR.
a random 60% of the

5912 J . Org. Chem., Vol. 62, No. 17, 1997
Parlow et al.
Sch em e 4
Sch em e 5
secondary, and tertiary amines, the resin will be drawn
herein as the generic form 8. Combustion analysis
showed that all of the chloride atoms were completely
displaced and that the CMR/R polymer 8 contained 2.36
mmol/g nitrogen. This analysis would fit a polymer with
64% monoalkylation and 36% dialkylation (cross-linking).
Commercial polymer-bound amines could have been
utilized; however, the use of a triamine such as 15 yielded
a polyamine polymer with a much higher scavenging
capacity and was much more economical. Typically the
polymer 8 has 2-3 times the loading capacity than that
of the commercially available polyamine polymers at a
4-10 times lower cost.
Sch em e 6
After biological evaluation of the analogs from Tables
1- 3, it was determined that the original pyrazole (Chart
1) was optimal for activity. Thus, our attention turned
to variation of the aniline side leaving the pyrazole
portion constant. Since rapid preparation of analogs, in
which the aniline portion was varied, could be done by
reacting the pyrazole acid chloride with various anilines,
it was necessary to prepare the pyrazole acid chloride
on larger than normal scale, as shown in Scheme 5.12
Using the CMR/R strategy, the pyrazole acid chloride
25 was coupled with anilines 26 to prepare analogs in a
high-speed fashion as single compounds per well (Scheme
6). Compound 25, 1.2 equiv, was reacted with the aniline
26 in dichloromethane in the presence of pyridine. The
excess 25 assures total consumption of the aniline 26,
leaving product 27, acid chloride 25, and pyridine hy-
drochloride (28) as the product mixture. The CMR/R
strategy was utilized in the purification of the product
mixture. The polyamine CMR/R polymer 8 (scavenger)
was added to each product mixture vessel. The CMR/R
polymer 8 sequestered the remaining acid chloride 25 and
also removed the hydrochloric acid salt (byproduct) from
the pyridine leaving a solution of pyridine and product
27 in dichloromethane. Simple filtration and rinsing
with dichloromethane yielded a filtrate whereupon evapo-
ration of the solvents left highly purified product 27 from
each parallel reaction. This illustrates a simple, general,
and powerful purification protocol allowing the synthesis
to be performed in a high-speed parallel fashion.
Compounds 27 prepared by the synthesis described in
Scheme 6 are shown in Table 4. The anilines 26 used
were commercially available or retrieved from our in-
house compound archive. Compounds 27a -cc had a
multitude of substituents on the phenyl ring with a large
number containing a carbonyl functionality at the 3-posi-
tion. Compounds 27d d -h h were directed at analogs of
the lead 3 with various linking groups between the two
phenyl rings at the 3-position. Compounds 27ii,jj are
both regioisomers of the lead 3.
(12) The pyrazole acid chloride 25 was synthesized in the straight-
forward fashion shown in Scheme 5. Pinacolone (18) was added
dropwise to a solution of ethyl oxalate (19) and sodium ethoxide to
afford the ethyl ester of 5,5-dimethyl-2,4-dioxohexanoic acid (20).
Compound 20 was condensed with methylhydrazine to afford an 88:
12 ratio of regioisomers 3-(1,1-dimethylethyl)-1-methyl-1H-pyrazole-
5-carboxylic acid, ethyl ester (21) and 5-(1,1-dimethylethyl)-1-methyl-
1H-pyrazole-3-carboxylic acid, ethyl ester (22), respectively, which were
separated using silica gel. Compounds 21 and 22 were each separately
hydrolyzed to 3-(1,1-dimethylethyl)-1-methyl-1H-pyrazole-5-carboxylic
acid (23) and 5-(1,1-dimethylethyl)-1-methyl-1H-pyrazole-3-carboxylic
acid (24), respectively. The free acid 23 was converted to 3-(1,1-
dimethylethyl)-1-methyl-1H-pyrazole-5-carbonyl chloride (25) using
oxalyl chloride. Structural assignments of regioisomers 23 and 24 are
based on 13C NMR chemical shifts and comparisons with regiochemi-
cally known hydoxypyrazoles.13
Figure 1 shows the GC/MS profile of three compounds
prepared by the solution-phase CMR/R strategy of Scheme
6. Included is a GC/MS profile of 27s taken before the
addition of the CMR/R polymer 8, and the second is after
purification utilizing polymer 8. The latter GC/MS
tracing, with complete sequestrative removal of excess
acid chloride 11, indicates highly purified product 27s.
(13) Hamper, B. C.; Kurtzweil, M. L.; Beck, J . P. J . Org. Chem. 1992,
57, 5680.

CMR/R in Synthesis of Heterocyclic Carboxamides
J . Org. Chem., Vol. 62, No. 17, 1997 5913
Ta ble 4. P yr a zoleca r boxa m id es 27 P r ep a r ed by th e
Syn th esis in Sch em e 6
substituent, the Friedel-Crafts acylation reaction mix-
ture was stirred at room temperature for 4 h to avoid
dealkylation. Because of the large variety of substituents
in the nitrobenzophenones 33, a relatively selective
reducing agent was required. It was found that reduction
using iron gave excellent results and could be used in a
parallel fashion. The 3-nitrobenzophenones 33 were
reduced with powdered iron in acetic acid at 80 °C to
afford 3-aminobenzophenone 34 building blocks substi-
tuted with electron-donating substituents on the phenyl
ring. In some cases, the substituted 3-aminobenzophe-
nones 34 required purification which was accomplished
using preparative thin layer chromatography.
The second synthesis for preparing the 3-aminoben-
zophenone building blocks is shown in Scheme 7B. The
acid chlorides 35b of substituted 3-nitrobenzoic acids 35a
were prepared using excess oxalyl chloride in dichlo-
romethane. Oxalyl chloride was the reagent of choice due
to the low-boiling nature of the reagent, permitting the
use of excess and purification by straightforward evapo-
ration of volatiles. The solution was typically stirred at
room temperature for 4 h followed by evaporation of the
oxalyl chloride and solvent. In the same reaction vials,
a Friedel-Crafts acylation reaction was performed by the
addition of benzene followed by aluminum trichloride.
The solution was stirred at room temperature overnight
or for 4 h when alkoxy substituents were present. Upon
completion of the reaction, purification was accomplished
by an aqueous extraction, followed by addition of mag-
nesium sulfate and the CMR/R polymer 8 to afford the
pure substituted 3-nitrobenzophenones 36. Compounds
36 were reduced in a similar manner as stated above to
afford 3-aminobenzophenone 37 building blocks with
substituents present on the aniline ring.
compd
R2
R3
R4
R5
R6 % yieldb
27a
27b
27c
27d
27e
27f
27g
27h
27i
27j
27k
27l
27m
27n
27o
27p
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
NO2
Me
H
H
H
H
H
Me
Cl
H
H
H
H
H
H
H
H
H
H
H
100
100
62
100
88
92
82
88
96
75
79
43
100
100
98
COMe
COMe
COMe
COMe
COPr
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
-
COCH2CH2
-
CO(CH2)4
-
COOCH2
CONMeCO-
COCONH-
CO2Me
CO2Et
CONH2
CONEt2
H
H
H
H
H
COCH2CONH-
70
2-isothiazole
27q
27r
27s
27t
H
H
H
H
H
H
H
SiMe3
CF3
Cl
COCH2CO2Et
NHCO2t-Bu
OMe
OMe
OCH(Me)2
CF3
NO2
H
H
H
H
H
H
Ph
H
H
OMe
H
H
H
H
H
NO2
Cl
SO2Me
F
F
H
H
H
H
H
H
H
H
H
H
H
H
H
H
OMe
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
93
81
94
82
27u
27v
27w
27x
27ya
27z
100
100
99
96
68
96
86
100
80
87
75
100
81
69
82
27a a a Cl
27bb
27cc
27d d
27ee
27ff
27gg
27h h
27ii
Cl
F
H
H
H
H
H
COPh
H
The substituted 3-aminobenzophenones 34 and 37
were then reacted with the acid chloride 25 in an array
library format (Scheme 8), followed by purification with
the CMR/R polymer 8 to afford pure pyrazolecarboxam-
SO2Ph
OPh
NHCOPh
CONHPh
H
H
H
H
COPh
H
H
ides 38 substituted at R2
with electron-donating substit-
27jj
H
84
uents (R1 ) H; Table 5) and pyrazolecarboxamides 39
a
substituted at R1 (R2 ) H; Table 6).14
Prepared by reacting 25 with the aniline 26 in pyridine at
b
80°C. Yields are based on mass recovery.
After biological evaluation of the analogs from Tables
4-6, it was determined that compound 27o had a 4-fold
increase in herbicidal activity compared to the initial lead
3. Thus, lead refinement with the synthesis in Scheme
9 was carried out to prepare other amide analogs of
compound 27o. The pyrazole acid chloride 25 and ethyl
3-aminobenzoate (40) were reacted to yield 3-[[[3-(1,1-
dimethylethyl)-1-methyl-1H-pyrazol-5-yl]carbonyl]ami-
no]benzoic acid, ethyl ester (27m ). The ethyl ester 27m
was hydrolyzed to the 3-[[[3-(1,1-dimethylethyl)-1-meth-
yl-1H-pyrazol-5-yl]carbonyl]amino]benzoic acid (41) using
potassium carbonate in a mixture of methanol and water.
The acid 41 was then reacted with P-EDC (4) to form
the anhydride followed by addition of amine to afford the
crude product 42. The same purification protocol as
described for Scheme 3 was utilized to yield the pure
products 42. Compounds prepared by this route are
shown in Table 7.
These GC/MS chromatograms are representative and
demonstrate the purity obtained using the CMR/R poly-
mer 8.
A series of 3-aminobenzophenone building blocks were
required to prepare analogs of similar structure to the
lead compound 3. The CMR/R polymer 8 played a major
role in the preparation of new 3-aminobenzophenone
building blocks, permitting their synthesis in a high-
speed, solution-phase, parallel format. Two solution-
phase strategies were devised to prepare 3-aminoben-
zophenones. The first strategy is shown in Scheme 7A.
Friedel-Crafts acylation using 1.3 equiv of 3-nitrobenzoyl
chloride (31), with 1 equiv of an electron-rich substituted
benzene (32) was carried out in 1,2-dichloroethane with
aluminum trichloride. An excess of 31 was used to
assure total consumption of the substituted benzene 32.
Upon completion, an aqueous extraction was utilized to
remove the salts, leaving 3-nitrobenzophenone 33, excess
acid chloride 31, and trace amounts of water. Purifica-
tion at this point was accomplished by addition of
magnesium sulfate and the CMR/R polymer 8 together,
followed by stirring the slurry for 15 min. After the
polymer was filtered and rinsed, the solvent was removed
to afford the pure substituted 3-nitrobenzophenones 33.
In the cases where benzene 32 contained an alkoxy
Con clu sion
Use of our recently reported chemical library purifica-
tion strategy based on principles of molecular recognition
(14) The Friedel-Crafts acylation reactions (Scheme 7) afforded
regioisomers in several cases and were purified at some point in the
synthesis. The two exceptions are compounds 38j,k , in which each
contains a mixture of regioisomers.

5914 J . Org. Chem., Vol. 62, No. 17, 1997
Parlow et al.

CMR/R in Synthesis of Heterocyclic Carboxamides
J . Org. Chem., Vol. 62, No. 17, 1997 5915
Ta ble 5. P yr a zoleca r boxa m id es 38 P r ep a r ed by th e
Syn th esis in Sch em e 8
Sch em e 7
compd
R2
R3
R4
R5 R6 % yieldc
38a
38b
38c
38d
38e
38f
H
H
H
OMe
Cl
H
F
F
F
F
F
H
Me
H
Me
F
OMe
OMe
F
Cl
Cl
H
OH
OMe
H
cyclohexyl
Me
H
H
H
H
Me
H
Me
OH
H
H
Me
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
80
79
76
72
69
70
65
67
69
60
61
93
87
84
94
86
92
88
62
H
H
H
H
Cl
H
H
H
H
H
H
Me
H
H
H
H
H
38g
38h
38i
38ja
38k b
38l
38m
38n
38o
38p
38q
38r
H
pentyl
CH(Me)2
cyclohexyl
H
H
H
CH(Me)2
cyclohexyl
CH2(cyclohexyl)
OBu
38s
OMe OMe
a
b
A 61:39 mixture of regioisomers determined by 1H NMR.
A
70:30 mixture of regioisomers determined by 1H NMR. c Yields are
based on mass recovery.
Ta ble 6. P yr a zoleca r boxa m id es 39 P r ep a r ed by th e
Syn th esis in Sch em e 8
Sch em e 8
compd
R2
R4
Cl
H
H
H
H
H
H
H
H
H
OMe
H
R5
R6
% yielda
39a
39b
39c
39d
39e
39f
39g
39h
39i
H
H
H
H
H
H
H
H
Cl
75
91
35
88
100
80
95
81
79
95
CF3
H
Me
H
H
CF3
H
H
H
Me
allowed the solution-phase synthesis of individual het-
erocyclic carboxamides in a high-speed parallel fashion
(typically 10-30 mg each). Polymeric reagents were used
in the synthesis to generate reactive species involved in
product formation, and complementary molecular reac-
tivity/molecular recognition polymer 8 (CMR/R polymer
8) was used to remove unreacted or derivatized starting
materials from reaction mixtures to afford essentially
pure products, irrespective of the reaction yields. This
technique was utilized in the preparation of building
blocks and primary screening libraries, as well as lead
refinement libraries. Although not illustrated herein, the
strategy is not limited to the parallel synthesis of
individual compounds and is also applicable to compound
mixtures. The high-speed parallel synthesis allowed for
the preparation and screening of over 400 compounds in
a timely manner15 resulting in compound 27o with a
4-fold improvement in herbicidal activity over the lead
3.
CO2Me
H
H
H
H
H
CO2Me
H
H
H
H
H
OMe
CO2Me
H
N(CH2)5
SO2Me
39j
39k
39l
OMe
H
100
86
84
39m
H
H
a
Yields are based on mass recovery.
spectrometers. Elemental analyses were performed by Atlan-
tic Microlab Inc., Atlanta, GA. Sample purity was determined
by GLC analysis utilizing a capillary column (0.53 mm i.d.,
DB-1 bonded phase, 1.5 µm film thickness, 30 m). Normally,
a temperature program from 100 to 300 °C at 15 °C/min was
employed. Column chromatography was performed on a
preparative liquid chromatography instrument using silica gel
columns. Reported yields are unoptimized with emphasis on
purity of products rather than quantity.
Gen er a l P r oced u r e A. Am id e F or m a tion fr om Ca r -
boxylic Acid 5 To Affor d Heter ocyclic Ca r boxa m id es 7
(Ta bles 1-3 a n d Sch em e 3). The carboxylic acid 5 (0.30
mmol) completely dissolved in dichloromethane (2 mL) (or in
a dichloromethane/dimethyl formamide solution) was added
Exp er im en ta l Section
Gen er a l. Melting points were determined with a capillary
melting point apparatus and are uncorrected. 1H, 13C, and
19F NMR spectra were recorded using 360 and 400 MHz NMR
(15) It took an equivalent of one person working 7 months for both
validation and generation of the 400-membered library.

5916 J . Org. Chem., Vol. 62, No. 17, 1997
Parlow et al.
7d : general procedure A; 1H NMR (CDCl3) ppm 4.24 (s, 3H),
6.71 (d, 1H), 7.57 (m, 6H), 7.82 (m, 2H), 7.89 (s, 1H), 7.95 (s,
1H), 8.05 (dd, 1H).
Sch em e 9
7f: general procedure A; 1H NMR (CDCl3) ppm 1.42 (s, 9H),
6.20 (s, 2H), 7.50 (m, 10H), 7.81 (d, 2H), 8.12 (d, 1H), 8.21 (d,
1H), 9.17 (bs, 1H).
7j: general procedure A; 1H NMR (CDCl3) ppm 1.72 (s, 9H),
2.29 (s, 3H), 6.38 (s, 1H), 7.54 (m, 5H), 7.83 (m, 4H), 8.08 (d,
1H).
7k : general procedure A; 1H NMR (CDCl3) ppm 1.42 (s, 9H),
4.04 (s, 3H), 6.69 (s, 1H), 7.53 (m, 5H), 7.84 (m, 2H), 7.87 (d,
1H), 7.95 (s, 1H), 8.12 (dd, 1H), 8.78 (bs, 1H).
7o: general procedure A; 1H NMR (CDCl3) ppm 3.94 (s, 3H),
4.27 (s, 3H), 7.50 (m, 5H), 7.84 (d, 2H), 7.97 (d, 1H), 8.14 (dd,
1H), 8.80 (bs, 1H).
7p : general procedure A; 1H NMR (CDCl3) ppm 1.58 (s, 9H),
4.09 (s, 3H), 7.25 (s, 1H), 7.52 (m, 5H), 7.84 (m, 2H), 7.95 (s,
1H), 8.14 (d, 1H), 8.74 (bs, 1H).
Ta ble 7. 3-[[[3-(1,1-Dim eth yleth yl)-1-m eth yl-1H-p yr a zol-
5-yl]ca r bon yl]a m in o]ben za m id es 42a -l P r ep a r ed by th e
Syn th esis in Sch em e 8
7q: general procedure A; 1H NMR (CDCl3) ppm 4.13 (s, 3H),
7.52 (m, 5H), 7.84 (d, 2H), 7.91 (s, 1H), 8.20 (d, 1H), 8.74 (bs,
1H).
7A: general procedure A; 1H NMR (CDCl3) ppm 7.13 (m,
1H), 7.53 (m, 5H), 7.69 (m, 1H), 7.82 (m, 2H), 7.97 (m, 2H),
8.08 (d, 1H).
7C: general procedure A; 1H NMR (CDCl3) ppm 6.95 (d, 1H),
7.53 (m, 6H), 7.81 (d, 2H), 7.90 (s, 1H), 7.99 (s, 1H), 8.06 (s,
1H), 8.08 (d, 1H).
compd
R1
R2
% yielda
7M: general procedure A; 1H NMR (CDCl3) ppm 2.72 (s,
3H), 2.74 (s, 3H), 7.50 (m, 6H), 7.83 (m, 3H), 8.03 (d, 1H).
7P : general procedure A; 1H NMR (CDCl3) ppm 1.35 (d, 3H),
1.37 (d, 3H), 3.70 (sept, 1H), 7.54 (m, 6H), 7.84 (m, 3H), 8.02
(d, 1H).
42a
42b
42c
42d
42e
42f
42g
42h
42i
42j
42k
42l
Pr
H
H
H
Me
Ph
CH2CHCH2
CH2CCH
Et
78
69
82
99
63
58
77
98
65
72
71
68
Ph
Me
Me
Me
Me
Me
Et
1
7W: general procedure A; H NMR (CDCl3) ppm 7.39 (m,
3H), 7.57 (m, 7H), 7.77 (m, 2H), 7.79 (m, 2H).
7X: general procedure A; 1H NMR (CDCl3) ppm 1.51 (s, 9H),
7.52 (m, 4H), 7.63 (m, 2H), 7.82 (m, 3H), 7.98 (m, 2H).
7Z: general procedure A; 1H NMR (CDCl3) ppm 7.53 (m,
6H), 7.85 (m, 6H), 8.06 (m, 2H), 9.19 (bs, 1H).
CH2CHCH2
CH2CHCH2
-(CH2)2NMe(CH2)2-
-(CH2)2O(CH2)2-
-(CH2)5-
1
7a a : general procedure A; H NMR (CDCl3) ppm 7.13 (d,
1H), 7.38 (t, 1H), 7.66 (m, 11H), 8.22 (bs, 1H).
a
1
Yields were based on mass recovery.
7bb: general procedure A; H NMR (CDCl3) ppm 7.52 (m,
6H), 7.83 (m, 3H), 7.96 (s, 1H), 8.17 (m, 1H).
7ii: general procedure A; 1H NMR (CDCl3) ppm 7.55 (m,
5H), 7.85 (dd, 2H), 8.06 (s, 1H), 8.20 (dd, 1H), 8.62 (s, 1H),
8.85 (s, 1H), 9.54 (d, 1H), 9.82 (bs, 1H).
to a suspension of P-EDC9 (4), in dichloromethane (2 mL) at 0
°C. After the mixture stirred at room temperature for 30 min,
the aniline 2 (0.10 mmol) was added, and the suspension was
heated to 50 °C. The suspension was stirred at 50 °C for 1 h
to 7 days.
7jj: general procedure A; 1H NMR (CDCl3) ppm 2.76 (s, 3H),
7.55 (m, 5H), 7.66 (dd, 2H), 8.05 (s, 1H), 8.19 (d, 1H), 8.52 (s,
1H), 9.40 (s, 1H), 9.76 (bs, 1H).
When the aniline 2 had completely reacted, the CMR/R
polymer 8 (2.36 mmol/g) (200 mg, 0.472 mmol) was added and
stirred for 15 min. The solution was filtered, and the polymer
was rinsed with dichloromethane, tetrahydrofuran (BHT free),
and dichloromethane until no more UV activity was seen in
the dichloromethane washing. The solvent was removed to
afford the pure product 7.
7ll: general procedure A; 1H NMR (CDCl3) ppm 7.56 (m,
5H), 7.76 (s, 2H), 7.79 (m, 2H), 7.81 (m, 1H), 8.02 (m, 1H),
8.70 (s, 1H).
P r ep a r a tion of th e CMR/R P olya m in e P olym er 8.
Merrifield’s resin (14) (2% cross-linked, 1.07 mmol/g) (106.7
g, 0.114 mol) was added to diethylenetriamine (15) (0.382 g,
2.19 mol) and the mixture heated at 100 °C for 4 h. The
polymer was filtered and successively rinsed two times with
10% triethylamine in dimethylformamide, once with dimeth-
ylformamide, four times with 10% triethylamine in tetrahy-
drofuran, three times with tetrahydrofuran, and three times
with methanol. The CMR/R polymer 8 was then dried under
vacuum to a constant weight. Anal. Obsd: Cl, 0.0; N, 3.31;
this corresponds to 2.36 mmol/g, 64% monoalkylation, and 36%
dialkylation.
Bis(h exa flu or oisop r op yl) Oxa la te (11). The following
reaction utilized oven-dried glassware, and the reaction mix-
ture and product were maintained under a dry nitrogen
atmosphere at all times. Hexafluoro-2-propanol (9.00 mL, 85.5
mmol) was dissolved in anhydrous ether (200 mL), the mixture
was cooled in an ice bath, and oxalyl chloride (3.50 mL, 40.1
mmol) was added. An anhydrous ether solution (100 mL) of
triethylamine (10.95 mL, 80.3 mmol) was then added dropwise
with stirring over a 45 min period. White solids formed
immediately, and the mixture was stirred overnight allowing
the ice in the ice bath to melt. The mixture was carefully
filtered, rinsing with a minimum of anhydrous ether. The
filtrate was then distilled at atmospheric pressure to remove
If the aniline 2 had not completely reacted and some product
was seen, hexafluoroisopropyl oxalate (11) (0.050 g, 0.146
mmol) was added and the solution was stirred at 50 °C for
1-24 h. The CMR/R polymer 8 (2.36 mmol/g) (200 mg, 0.472
mmol) was then added and stirred for 15 min. The solution
was filtered, and the polymer was rinsed with dichlo-
romethane, tetrahydrofuran (BHT free), and dichloromethane
until no more UV activity was seen in the dichloromethane
washing. The solvent was removed to afford the pure product
7. All products were characterized by MS, and some were
1
characterized by H NMR as listed below.
7a : general procedure A; 1H NMR (CDCl3) ppm 1.00 (s, 9H),
2.72 (s, 2H), 4.43 (s, 3H), 7.51 (m, 7H), 7.80 (d, 2H), 8.18 (m,
1H), 8.23 (bs, 1H).
7b: general procedure A; 1H NMR (CDCl3) ppm 2.31 (s, 3H),
4.16 (s, 3H), 6.47 (s, 1H), 7.56 (m, 5H), 7.85 (m, 4H), 8.03 (d,
1H).
7c: general procedure A; 1H NMR (CDCl3) ppm 2.34 (s, 3H),
3.90 (s, 3H), 7.51 (m, 5H), 7.85 (m, 2H), 7.92 (s, 1H), 8.20 (d,
1H), 8.80 (bs, 1H).

CMR/R in Synthesis of Heterocyclic Carboxamides
J . Org. Chem., Vol. 62, No. 17, 1997 5917
the bulk of the ether. When the distillate temperature reached
43 °C, the pot remains were transferred to a smaller flask and
the distillation was continued. The product fraction was
collected at 126-127 °C to afford 10.33 g (66%) of a clear oil
of 11: 1H NMR (CDCl3) ppm 5.81 (heptet, J ) 5.5 Hz, 1H);
13C NMR (CDCl3) ppm 152.2 (s), 119.6 (q, J ) 282.9 Hz), 68.9
(heptet, J ) 35.8 Hz); 19F NMR (CDCl3) -74.144 (doublet, J
) 5.4 Hz).
(CDCl3) ppm 1.37 (s, 9H), 4.13 (s, 3H), 6.99 (s, 1H); 13C NMR
(CDCl3) ppm 30.2, 32.0, 39.8, 113.2, 135.0, 157.9, 160.8.
Gen er a l P r oced u r e B. Rea ction of 3-(1,1-Dim eth yl-
et h yl)-1-m et h yl-1H-p yr a zole-5-ca r b on yl Ch lor id e (25)
w ith An ilin es To Affor d th e P yr a zoleca r boxa m id es 27,
38, a n d 39 (Ta bles 4-6 a n d Sch em es 6, 8). Under condi-
tions of parallel reaction synthesis, pyridine (0.12 mmol) was
added to a solution of 25 (0.12 mmol) and aniline (0.10 mmol)
in dichloromethane, and the resulting solution was stirred at
room temperature for 2-24 h. The CMR/R polymer 8 (2.36
mmol/g) (200 mg, 0.472 mmol) was added and stirred for 15
min. The solution was filtered, and the polymer was rinsed
with dichloromethane, tetrahydrofuran (BHT free), and dichlo-
romethane until no more UV activity was seen in the dichlo-
romethane washing. The solvents were removed to afford the
pure product. Yields were in the range of 35-100%. All
products were characterized by MS, and a portion were further
characterized as listed below.
5,5-Dim eth yl-2,4-dioxoh exan oic Acid, Eth yl Ester (20).16
Sodium metal (74 g, 3.21 mol) was added in small portions to
ethanol (1.5 L) and stirred until all of the sodium had reacted.
Ethyl oxalate (19) (233.0 g, 1.6 mol) was added, followed by
dropwise addition of pinacolone (18) (160.2 g, 1.6 mol). The
solution was stirred at room temperature for 5 h and then
poured over ice/hydrochloric acid, followed by extraction with
ether. The organic layer was then washed with 4 N hydro-
chloric acid, water, and brine. The solution was dried over
magnesium sulfate and filtered, and the solvent was removed
to give the crude product. The product was purified by column
chromatography (5% ethyl acetate-hexane) to give 344 g (93%)
of an orange oil of 20: 1H NMR (CDCl3) ppm 1.25 (s, 9H), 1.40
(t, 3H), 4.37 (q, 3H), 6.56 (s, 1H).
3-(1,1-Dim eth yleth yl)-1-m eth yl-1H-p yr a zole-5-ca r box-
ylic Acid , Eth yl Ester (21). Methyl hydrazine (23.0 g, 0.50
mol) was added dropwise to a solution of compound 20 (100.0
g, 0.50 mol) in acetic acid (1.5 L). The resulting solution was
stirred at room temperature for 18 h. The solution was then
diluted with ether and brine, the organic layer was washed
with brine, dried over magnesium sulfate, and filtered, and
the solvent was removed to give the crude product. Fraction
1 of column chromatography (5% ethyl acetate-hexane) gave
72.4 g (69%) of a clear oil of 21: 1H NMR (CDCl3) ppm 1.35 (s,
9H), 1.42 (t, 3H), 4.17 (s, 3H), 4.37 (q, 2H), 6.72 (s, 1H); 13C
NMR (CDCl3) ppm 13.4, 29.6, 31.1, 38.3, 59.9, 106.4, 131.7,
159.2, 159.5. Anal. Calcd for C11H18O2N2: C, 62.83; H, 8.63;
N, 13.32. Found: C, 62.75; H, 8.69; N, 13.22.
5-(1,1-Dim eth yleth yl)-1-m eth yl-1H-p yr a zole-3-ca r box-
ylic Acid , Eth yl Ester (22). Following the same procedure
described for 21, fraction 2 of column chromatography (5%
ethyl acetate-hexane) gave 12.1 g (12%) of a yellow oil of 22:
1H NMR (CDCl3) ppm 1.39 (t, 3H), 1.40 (s, 9H), 4.05 (s, 3H),
4.39 (q, 2H), 6.60 (s, 1H); 13C NMR (CDCl3) ppm 13.5, 28.5,
30.3, 39.3, 59.8, 105.7, 140.5, 151.9, 161.6. Anal. Calcd for
C11H18O2N2: C, 62.83; H, 8.63; N, 13.32. Found: C, 62.56; H,
8.68; N, 13.11.
3-(1,1-Dim eth yleth yl)-1-m eth yl-1H-p yr a zole-5-ca r box-
ylic Acid (23). Aqueous sodium hydroxide (10%) (191 mL,
0.47 mol) was added to a solution of compound 21 (67.0 g, 0.319
mol) in ethanol (1.2 L), and the resulting solution stirred at
room temperature for 18 h. The solution was then poured over
ice/hydrochloric acid and extracted with ether. The organic
layer was washed with brine, dried over magnesium sulfate,
and filtered, and the solvent was removed to give 53.9 g (93%)
of a white solid of 23: mp 155-156 °C; 1H NMR (CDCl3) ppm
1.38 (s, 9H), 4.22 (s, 3H), 6.86 (s, 1H); 13C NMR (CDCl3) ppm
29.5, 31.0, 38.2, 107.8, 131.1, 159.8, 163.0. Anal. Calcd for
C9H14O2N2: C, 59.32; H, 7.74; N, 15.37. Found: C, 59.55; H,
7.78; N, 15.43.
27c: general procedure B; 1H NMR (CDCl3) ppm 1.36 (s,
9H), 2.59 (s, 3H), 4.18 (s, 3H), 6.56 (s, 1H), 7.70 (d, 1H), 7.86
(dd, 1H), 7.96 (bs, 1H), 8.20 (d, 1H).
27e: general procedure B; 1H NMR (CDCl3) ppm 1.45 (s,
9H), 2.67 (s, 3H), 4.37 (s, 3H), 6.62 (s, 1H), 7.56 (d, 1H), 7.76
(dd, 1H), 8.19 (bs, 1H), 9.01 (m, 1H).
27g: general procedure B; 1H NMR (CDCl3) ppm 1.36 (s,
9H), 2.75 (m, 2H), 3.15 (m, 2H), 4.18 (s, 3H), 6.65 (s, 1H), 7.53
(dd, 1H), 7.80 (d, 1H), 8.11 (bs, 1H), 9.11 (m, 1H).
1
27h : general procedure B; H NMR (CDCl3) ppm 1.35 (s,
9H), 1.87 (m, 4H), 2.77 (m, 2H), 2.95 (m, 2H), 4.17 (s, 3H),
6.51 (s, 1H), 7.27 (m, 1H), 7.65 (d, 1H), 7.80 (bs, 1H), 8.00 (dd,
1H).
27m : general procedure B yielded a white solid, mp 114-
1
115 °C; H NMR (CDCl3) ppm 1.45 (s, 9H), 4.12 (s, 3H), 6.71
(s, 1H). Anal. Calcd for C18H14O2N2: C, 59.32; H, 7.74; N,
15.37. Found: C, 59.40; H, 7.76; N, 15.35.
27o: general procedure B yielded a white solid, mp 141-
142 °C; 1H NMR (CDCl3) ppm 1.16 (bt, 3H), 1.29 (bt, 3H), 1.39
(s, 9H), 3.31 (bq, 2H), 3.59 (bq, 2H), 4.18 (s, 3H), 6.76 (s, 1H),
7.06 (bd, 1H), 7.37 (t, 1H), 7.39 (bs, 1H), 7.74 (bd, 1H), 8.81
(bs, 1H). Anal. Calcd for C20H28O2N4: C, 67.39; H, 7.92; N,
15.72. Found: C, 67.48; H, 7.93; N, 15.67.
27q: general procedure B; 1H NMR (CDCl3) ppm 1.26 (t,
3H), 1.30 (s, 9H), 4.02 (s, 2H), 4.17 (s, 3H), 4.25 (q, 2H), 6.56
(s, 1H), 7.50 (m, 2H), 7.74 (d, 1H), 7.98 (m, 2H), 8.08 (s, 1H).
27t: general procedure B; 1H NMR (CDCl3) ppm 1.35 (s,
9H), 3.85 (s, 3H), 4.17 (s, 3H), 6.48 (s, 1H), 6.73 (dd, 1H), 7.06
(d, 1H), 7.28 (m, 2H), 7.62 (bs, 1H).
27u : general procedure B yielded a white solid, mp 94-95
°C; 1H NMR (CDCl3) ppm 1.36 (s, 9H), 4.20 (s, 3H), 4.59 (sept,
1H), 6.51 (s, 1H), 6.72 (dd, 1H), 7.04 (d, 1H), 7.25 (m, 1H),
7.33 (s, 1H), 7.70 (bs, 1H). Anal. Calcd for C18H25O2N3: C,
68.54; H, 7.99; N, 27.32. Found: C, 68.29; H, 7.93; N, 13.15.
27v: general procedure B; 1H NMR (CDCl3) ppm 1.35 (s,
9H), 4.18 (s, 3H), 6.53 (s, 1H), 7.45 (m, 1H), 7.51 (m, 1H), 7.82
(m, 2H), 7.91 (bs, 1H).
1
27w : general procedure B; H NMR (CDCl3) ppm 1.36 (s,
9H), 4.19 (s, 3H), 6.57 (s, 1H), 7.57 (t, 1H), 7.91 (bs, 1H), 8.05
(dd, 2H), 8.49 (m, 1H).
5-(1,1-Dim eth yleth yl)-1-m eth yl-1H-p yr a zole-3-ca r box-
ylic Acid (24). Following the same procedure described for
compound 23, compound 22 (12.0 g, 0.057 mol) and aqueous
sodium hydroxide (10%) (29.0 mL, 0.073 mol) were used to give
7.29 g (70%) of a white solid of 24: mp 168-169 °C; 1H NMR
(CDCl3) ppm 1.45 (s, 9H), 4.12 (s, 3H), 6.71 (s, 1H); 13C NMR
(CDCl3) ppm 28.2, 31.1, 39.1, 105.8, 138.6, 152.3, 166.0. Anal.
Calcd for C9H14O2N2: C, 59.32; H, 7.74; N, 15.37. Found: C,
59.40; H, 7.76; N, 15.35.
3-(1,1-Dim et h ylet h yl)-1-m et h yl-1H -p yr a zole-5-ca r b o-
n yl Ch lor id e (25). To a solution of compound 23 (25.0 g,
137.2 mmol) in dichloromethane was added oxalyl chloride
(87.0 g, 685.4 mmol) followed by 1 drop of dimethyl formamide.
After stirring at room temperature for 16 h the solvent was
removed to give 26.58 g (97%) of a clear oil of 25: 1H NMR
1
27cc: general procedure B; H NMR (CDCl3) ppm 1.35 (s,
9H), 4.17 (s, 3H), 6.51 (s, 1H), 6.94 (m, 2H), 7.72 (bs, 1H), 8.28
(m, 1H).
1
27d d : general procedure B; H NMR (CDCl3) ppm 1.36 (s,
9H), 4.19 (s, 3H), 7.42 (m, 5H), 7.58 (m, 3H), 7.74 (bs, 1H),
7.84 (s, 1H).
1
27ee: general procedure B; H NMR (CDCl3) ppm 1.35 (s,
9H), 4.16 (s, 3H), 6.54 (s, 1H), 7.56 (m, 4H), 7.73 (dd, 1H), 7.83
(bs, 1H), 7.99 (m, 4H).
1
27ff: general procedure B; H NMR (CDCl3) ppm 1.34 (s,
9H), 4.15 (s, 3H), 6.47 (s, 1H), 6.82 (m, 1H), 7.17 (m, 3H), 7.30
(m, 5H), 7.64 (bs, 1H).
1
27ii: general procedure B; H NMR (CDCl3) ppm 1.37 (s,
9H), 4.22 (s, 3H), 6.76 (s, 1H), 7.15 (t, 1H), 7.50 (m, 2H), 7.63
(m, 3H), 7.75 (m, 2H), 8.76 (dd, 1H).
1
27jj: general procedure B; H NMR (CDCl3) ppm 1.36 (s,
(16) Seki, S.; Yamaguchi, H.; Nakamura, Y.; Kubo, H. J apanese
Patent SHO 57-106665, 1982.
9H), 4.19 (s, 3H), 6.55 (s, 1H), 7.54 (t, 2H), 7.82 (m, 6H).

5918 J . Org. Chem., Vol. 62, No. 17, 1997
Parlow et al.
1
38b: general procedure B; H NMR (CDCl3) ppm 1.46 (s,
mmol) was added to a solution of 3-nitrobenzoyl chloride (31)
(0.16 g, 1.10 mmol) and substituted benzene derivative 32 (1.0
mmol) in 1,2-dichloroethane (4 mL). The solution was stirred
at room temperature for 4 h when alkoxy substituents were
used and overnight for all other aromatic compounds. The
mixture was poured into water and extracted with dichlo-
romethane. The resultant organic layer was washed with
water and brine. The solution was dried over magnesium
sulfate followed by addition of the CMR/R polymer 8 (2.36
mmol/g) (200 mg, 0.472 mmol) and then stirred for 15 min.
The solution was filtered, and the polymer was rinsed with
dichloromethane, tetrahydrofuran (BHT free), and dichlo-
romethane until no more UV activity was seen in the eluant.
The solvent was removed to afford the substituted nitroben-
zophenone 33. The purity of products was determined by GC,
and some products were characterized by MS.
9H), 4.46 (s, 3H), 7.21 (m, 3H), 7.54 (m, 2H), 7.87 (m, 2H),
8.10 (m, 2H), 9.68 (bs, 1H).
38e: general procedure B; 1H NMR (CDCl3) ppm 1.51 (s,
9H), 2.31 (s, 3H), 4.57 (s, 3H), 7.16 (d, 1H), 7.25 (s, 1H), 7.29
(m, 1H), 7.41 (m, 1H), 7.49 (m, 1H), 8.21 (m, 1H), 8.27 (bs,
1H).
38f: general procedure B; 1H NMR (CDCl3) ppm 1.46 (s,
9H), 4.49 (s, 3H), 7.31 (s, 1H), 7.52 (m, 4H), 7.90 (s, 1H), 8.20
(d, 1H), 8.25 (s, 1H), 10.01 (bs, 1H).
38g: general procedure B; 1H NMR (CDCl3) ppm 1.33 (s,
9H), 2.41 (s, 3H), 4.17 (s, 3H), 6.53 (s, 1H), 7.22 (d, 1H), 7.48
(m, 3H), 7.80 (bs, 1H), 7.89 (s, 1H), 8.07 (dd, 1H).
38i: general procedure B; 1H NMR (CDCl3) ppm 1.49 (s,
9H), 4.52 (s, 3H), 6.63 (m, 1H), 6.75 (dd, 1H), 7.49 (m, 3H),
7.69 (m, 1H), 8.18 (m, 1H), 8.19 (m, 1H).
38n : general procedure B; 1H NMR (CDCl3) ppm 0.91 (t,
3H), 1.32 (m, 4H), 1.45 (s, 9H), 1.65 (m, 2H), 2.68 (t, 2H), 4.49
(s, 3H), 7.28 (m, 2H), 7.49 (m, 3H), 7.72 (m, 2H), 8.17 (m, 2H).
Gen er a l P r oced u r e D. Red u ction of th e 3-Nitr oben -
zop h en on es 33 a n d 36 w ith Ir on To Affor d th e 3-Am i-
n oben zop h en on es 34 a n d 37 (Sch em e 7). The substituted
nitrobenzophenone 33 or 36 (1.0 mmol) was stirred in glacial
acetic acid (4 mL). The solution was heated to 80 °C, and
powdered iron (0.28 g, 5.0 mmol) was added with vigorous
stirring. The solution was stirred at 80 °C for 15-60 min at
which point the iron had turned gray. The reaction mixture
was filtered through Celite, and the solid was washed with
dichloromethane. The resultant organic layer was washed
with water, stirred with saturated sodium bicarbonate, and
washed with water again. The solution was dried over
magnesium sulfate and filtered, and the solvent was removed
to afford the substituted aminobenzophenone product 34 or
37. When necessary, the product was purified by preparative
thin layer chromatography. All products were characterized
1
38o: general procedure B; H NMR (CDCl3) ppm 1.20 (m,
12H), 1.49 (s, 9H), 2.92 (m, 2H), 4.55 (s, 3H), 7.05 (s, 1H), 7.36
(m, 6H), 8.11 (m, 1H), 8.33 (bs, 1H).
1
38q: general procedure B; H NMR (CDCl3) ppm 1.18 (m,
7H), 1.47 (s, 9H), 1.70 (m, 2H), 2.57 (d, 2H), 4.51 (s, 3H), 7.27
(m, 2H), 7.54 (m, 4H), 7.73 (m, 2H), 8.19 (m, 2H).
39a : general procedure B; 1H NMR (CDCl3) ppm 1.44 (s,
9H), 4.48 (s, 3H), 6.83 (s, 1H), 7.43 (m, 4H), 7.60 (m, 1H), 7.79
(m, 2H), 8.00 (s, 1H), 8.12 (dd, 1H).
1
39b: general procedure B; H NMR (CDCl3) ppm 1.32 (s,
9H), 4.16 (s, 3H), 6.54 (s, 1H), 7.55 (m, 5H), 7.85 (dd, 1H), 8.23
(bs, 1H), 8.85 (s, 1H).
1
39d : general procedure B; H NMR (CDCl3) ppm 1.50 (s,
1
by MS, and a portion were characterized by H NMR.
9H), 2.25 (s, 3H), 4.45 (s, 3H), 7.28 (m, 3H), 7.48 (m, 2H), 7.67
(m, 2H), 7.82 (d, 2H), 9.63 (bs, 1H).
39e: general procedure B; 1H NMR (CDCl3) ppm 1.47 (s,
9H), 4.51 (s, 3H), 7.28 (m, 2H), 7.53 (m, 3H), 7.81 (m, 3H),
8.60 (s, 2H).
Gen er a l P r oced u r e E. Acid Ch lor id e F or m a tion fr om
th e Su bstitu ted 3-Nitr oben zoic Acid 35a (Sch em e 7). To
a solution of substituted 3-nitrobenzoic acid 35a (1.0 mmol)
in dichloromethane was added oxalyl chloride (0.64 g, 5.0
mmol) followed by 1 drop of dimethylformamide. After stirring
at room temperature for 1-24 h, the solvent was removed to
afford the substituted 3-nitrobenzoyl chloride 35b. The crude
products were carried on to the next step without character-
ization.
39f: general procedure B; 1H NMR (CDCl3) ppm 1.35 (s,
9H), 2.43 (s, 3H), 4.16 (s, 3H), 6.52 (s, 1H), 7.39 (d, 1H), 7.53
(m, 2H), 7.62 (m, 3H), 7.84 (d, 2H), 8.17 (d, 1H).
39g: general procedure B; 1H NMR (CDCl3) ppm 1.40 (s,
9H), 3.51 (s, 3H), 4.30 (s, 3H), 6.70 (s, 1H), 7.18 (dd, 1H), 7.60
(m, 6H), 7.79 (m, 1H), 8.85 (d, 1H).
Gen er a l P r oced u r e F . F r ied el-Cr a fts Acyla tion w ith
Su bstitu ted 3-Nitr oben zoyl Ch lor id e 35b a n d Ben zen e
To Affor d t h e Su b st it u t ed 3-Nit r ob en zop h en on e 36
(Sch em e 7). To a solution of the substituted 3-nitrobenzoyl
chloride 35b (1.0 mmol) in benzene was added aluminum
trichloride (0.17 g, 1.3 mmol). The solution was stirred at room
temperature for 4 h for alkoxy substituents and overnight for
other aromatic compounds. The mixture was poured into
water and extracted with dichloromethane, and the resultant
organic layer was washed with water and brine. The solution
was dried over magnesium sulfate followed by addition of the
polymer 8 (2.36 mmol/g) (423 mg, 1.0 mmol) and stirred for
15 min. The solution was filtered, and the polymer was rinsed
with dichloromethane, tetrahydrofuran (BHT free), and dichlo-
romethane until no more UV activity was seen in the eluant.
The solvent was removed to afford the substituted nitroben-
zophenone 36. The purity of products was determined by GC,
and some products were characterized by MS.
1
39h : general procedure B; H NMR (CDCl3) ppm 1.34 (s,
9H), 3.96 (s, 3H), 4.17 (s, 3H), 6.61 (s, 1H), 7.53 (m, 2H), 7.65
(m, 1H), 7.85 (d, 2H), 8.19 (d, 2H), 8.23 (d, 1H), 8.56 (s, 1H).
39i: general procedure B; 1H NMR (CDCl3) ppm 1.44 (s,
9H), 4.05 (s, 3H), 4.33 (s, 3H), 6.57 (s, 1H), 7.05 (d, 1H), 7.58
(m, 4H), 7.83 (dd, 2H), 8.37 (bs, 1H), 8.84 (s, 1H).
39j: general procedure B; 1H NMR (CDCl3) ppm 1.38 (s,
9H), 4.04 (s, 3H), 4.17 (s, 3H), 6.73 (s, 1H), 7.52 (m, 5H), 7.87
(d, 2H), 8.20 (d, 1H), 9.15 (s, 1H).
1
39k : general procedure B; H NMR (CDCl3) ppm 1.33 (s,
9H), 3.73 (s, 3H), 3.74 (s, 3H), 4.19 (s, 3H), 6.43 (s, 1H), 6.80
(m, 2H), 7.48 (m, 2H), 7.61 (m, 1H), 7.87 (m, 2H), 8.08 (bs,
1H), 8.38 (d, 1H).
1
39m : general procedure B; H NMR (CDCl3) ppm 1.50 (s,
9H), 3.22 (s, 3H), 4.50 (s, 3H), 6.75 (s, 1H), 7.57 (m, 2H), 7.74
(m, 2H), 7.89 (m, 2H), 8.13 (d, 1H), 8.97 (s, 1H).
Com p ou n d s 27y,a a . Compound 25 (0.12 mmol) was added
dropwise to a solution of the aniline (0.010 mmol) in pyridine
(5 mL). The solution was stirred at 80 °C overnight. The
mixture was poured into ice water and extracted with ether,
and the resultant organic layer was washed with 2 N hydro-
chloric acid, water, and brine. The solution was dried over
magnesium sulfate and filtered, and the solvent was removed
to give the crude product. The product was purified by
preparative thin layer chromatography. Compound 27y: EI-
MS m/ e 370 (M+), 355 (M+ - Me), 165 (pyrazoleCO+).
Compound 27a a : EI-MS m/ e 369 (M+), 354 (M+ - Me), 165
(pyrazoleCO+).
3-[[[3-(1,1-Dim et h ylet h yl)-1-m et h yl-1H -p yr a zol-5-yl-
]ca r bon yl]a m in o]ben zoic Acid , Eth yl Ester (27m ). Com-
pound 25 (2.0 g, 1.0 mmol) was added to a solution of ethyl
3-aminobenzoate (40) (1.65 g, 1.0 mmol) and triethylamine
(0.11 g, 1.0 mmol) in dichloromethane (30 mL). After stirring
at room temperature for 16 h, the mixture was washed with
water and brine, dried over magnesium sulfate, and filtered,
and the solvent was removed to give the crude product 27m .
The product was purified by column chromatography (20%
ethyl acetate-hexane) to give 2.02 g (61%) of a white solid of
27m : mp 114-115 °C; 1H NMR (CDCl3) ppm 1.37 (s, 9H), 1.44
(t, 3H), 4.20 (s, 3H), 4.43 (q, 2H), 6.59 (s, 1H), 7.49 (t, 1H),
7.88 (m, 1H), 7.96 (bs, 1H), 8.07 (m, 2H). Anal. Calcd for
C18H23O3N3: C, 65.63; H, 7.04; N, 12.76. Found: C, 65.63; H,
7.05; N, 12.68.
Gen er a l P r oced u r e C. F r ied el-Cr a fts Acyla tion w ith
3-Nitr oben zoyl Ch lor id e (31) To Affor d th e Su bstitu ted
3-Nitr oben zop h en on e 33 (Sch em e 7). Under conditions of
parallel reaction synthesis, aluminum trichloride (0.17 g, 1.3

CMR/R in Synthesis of Heterocyclic Carboxamides
J . Org. Chem., Vol. 62, No. 17, 1997 5919
3-[[[3-(1,1-Dim et h ylet h yl)-1-m et h yl-1H -p yr a zol-5-yl-
]ca r bon yl]a m in o]ben zoic Acid (41). Potassium carbonate
(6.0 g, 43.4 mmol) was added to a solution of compound 27m
(1.82 g, 5.5 mmol) in a 2:1 mixture of methanol/water. The
solution was stirred at room temperature for 18 h. The
solution was poured over ice/hydrochloric acid and extracted
with ether. The organic layer was washed with brine, dried
over magnesium sulfate, and filtered, and the solvent was
removed to give 1.5 g (91%) of a white solid of 41: mp 245 °C
3-(1,1-Dim eth yleth yl)-1-m eth yl-N-[3-[(m eth yl-2-p r op y-
n yla m in o)ca r b on yl]p h en yl]-1H -p yr a zole-4-ca r b oxa m -
id e (42g): 1H NMR (CDCl3) ppm 1.38 (s, 9H), 1.67 (bs, 2H),
2.37 (bs, 1H), 3.10 (bs, 3H), 4.18 (s, 3H), 6.56 (s, 1H), 7.18 (bm,
1H), 7.37 (t, 1H), 7.57 (bs, 1H), 7.76 (bm, 1H), 8.29 (bs, 1H).
3-(1,1-Dim eth yleth yl)-1-m eth yl-N-[3-(m or p h olin oca r -
bon yl)ph en yl]-1H-pyr azole-4-car boxam ide (42l): 1H NMR
(CDCl3) ppm 1.39 (s, 9H), 1.59 (m, 6H), 3.40 (bt, 2H), 3.75 (bt,
2H), 4.19 (s, 3H), 6.70 (s, 1H), 7.10 (bm, 1H), 7.37 (t, 1H), 7.49
(bs, 1H), 7.78 (m, 1H), 8.29 (bs, 1H).
1
dec; H NMR (CDCl3) ppm 1.27 (s, 9H), 4.02 (s, 3H), 6.98 (s,
1H), 7.46 (t, 1H), 7.67 (d, 1H), 7.98 (bd, 1H), 8.36 (s, 1H), 10.24
(s, 1H), 12.95 (bs, 1H).
Su p p or tin g In for m a tion Ava ila ble: GC/MS data avail-
able in tables for compounds 7, 27, 38, 39, and 42; H NMR
1
available for a random 60% of these compounds; GC/MS data
available in tables for building blocks 33, 34, 36, and 37 (70
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; see any current
masthead page for ordering information.
3-[[[3-(1,1-Dim et h ylet h yl)-1-m et h yl-1H -p yr a zol-5-yl-
]ca r bon yl]a m in o]ben za m id es 42 (Ta ble 7). These com-
pounds were prepared according to the general procedure given
above for Scheme 3 using 3-[[[3-(1,1-dimethylethyl)-1-methyl-
1H-pyrazol-5-yl]carbonyl]amino]benzoic acid (41). All products
were characterized by MS, and a portion were characterized
1
by H NMR as listed below.
J O970571I