Comparative study of the frech catalyst with two conventional catalysts in the heck synthesis of 2,4-diaminopyrimidine-based antibiotics

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Comparative Study of the Frech
Catalyst with Two Conventional
Catalysts in the Heck Synthesis of 2,4-
Diaminopyrimidine-based Antibiotics
Baskar Nammalwar a , Richard A. Bunce a , K. Darrell Berlin a ,
Christina R. Bourne b , Philip C. Bourne b , Esther W. Barrow b &
William W. Barrow b
a Department of Chemistry, Oklahoma State University, Stillwater,
OK, USA
b Department of Veterinary Pathobiology, Oklahoma State University,
Stillwater, OK, USA
Version of record first published: 16 Jan 2013.
To cite this article: Baskar Nammalwar , Richard A. Bunce , K. Darrell Berlin , Christina R. Bourne ,
Philip C. Bourne , Esther W. Barrow & William W. Barrow (2013): Comparative Study of the Frech
Catalyst with Two Conventional Catalysts in the Heck Synthesis of 2,4-Diaminopyrimidine-based
Antibiotics, Organic Preparations and Procedures International: The New Journal for Organic
Synthesis, 45:1, 66-71
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Organic Preparations and Procedures International, 45:66–71, 2013
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5453 online
DOI: 10.1080/00304948.2013.743755
OPPI BRIEF
Comparative Study of the Frech Catalyst with Two
Conventional Catalysts in the Heck Synthesis of
2,4-Diaminopyrimidine-based Antibiotics
Baskar Nammalwar,1 Richard A. Bunce,1 K. Darrell Berlin,1
Christina R. Bourne,2 Philip C. Bourne,2 Esther W. Barrow,2
and William W. Barrow2
1Department of Chemistry, Oklahoma State University, Stillwater, OK, USA
2Department of Veterinary Pathobiology, Oklahoma State University, Stillwater,
OK, USA
Nano palladium coordination complexes, incorporating pincer ligands are reported to be
highly efficient catalysts for C–C coupling reactions, giving excellent yields with low cat-
alyst loading.1–8 A relatively new amino pincer palladium complex has been reported by
Frech for C–C bond formation via the Heck, Sonogashira, Stille, Hiyama and Suzuki-
Miyaura reactions.3–7 A myriad of palladium complexes exist to promote these C–C bond
forming processes.9 However, a serious limitation to the use of these reactions for the syn-
thesis of bioactive molecules stems from the lack of thermal stability and functional group
tolerance of many palladium complexes as well as the requirement for relatively high cata-
lyst loadings.4 Decomposition of catalysts at normal reaction temperatures (140–150◦C) can
result in highly contaminated products that require extensive purification, which markedly
decreases the yields.8,10 Conventional catalysts also give modest results with heterocyclic
substrates.11,12 In contrast, the Frech catalyst exhibits robust thermal stability due, in large
part, to the P-Pd-P (PCP) moiety of the pincer ligand.5,13 This thermal stability, together
with its inertness to oxygen and water, are unique qualities of the Frech catalyst and allow
it to maintain high activity under a variety of reaction conditions.13 In the present work, we
have evaluated the Frech catalyst and compared it with two conventional palladium catalysts
for coupling highly-substituted, heterocyclic substrates in the final step of a synthesis of
2,4-diaminopyrimidine-based antibiotics, which have demonstrated activity against inhala-
tion anthrax14–16 and multi-drug resistant staph.17 We now report results which validate the
potential of this new catalyst in reactions involving multi-functional heterocyclic substrates.
Submitted by June 22, 2012
Address correspondence to Richard A. Bunce, Department of Chemistry, Oklahoma State Uni-
versity, Stillwater, OK, 74078-3071, USA. E-mail: rab@okstate.edu
66

Heck Synthesis of 2,4-Diaminopyrimidine-based Antibiotics
67
Initially, an evaluation was made of the catalyst, base, and solvent required for the
Heck reaction of 2,4-diamino-5-(5-iodo-3,4-dimethoxybenzyl)pyrimidine (1) with ( )-1-
(1-propyl-2(1H)-phthalazinyl)-2-propen-1-one (2a) to generate 3a (Scheme 1).14,15,18 Two
Pr
NH2
N
O
I
N
N
N
+
H2N
OCH3
OCH3
2a
1
NH2
N
O
Pr
catalyst
N
N
N
N-ethylpiperidine
H2N
OCH3
DMF, heat
OCH3
3a
Scheme 1
Preparation of 3a by Heck Coupling.
conventional catalysts, (Ph3P)2PdCl2 and Pd(OAc)2,18 as well as the Frech complex, were
examined and compared. The use of (Ph3P)2PdCl2 under standard conditions (round-
bottomed flask, 1.25 mol% catalyst relative to substrates 1 and 2a, 1.10 equivalents of
N-ethylpiperidine, DMF, argon atmosphere, 140–150◦C, 18 h) gave a low yield (37%) of
the coupled product 3a with a significant number of impurities. An improved return (42%)
was realized in a sealed tube under the same conditions, but impurities still persisted. The
use of Pd(OAc)2 (1.25 mol%) provided the products in similar yields (50–52%) under both
standard and sealed tube conditions, but with only a slightly improved impurity profile.
By comparison, the Frech catalyst afforded consistently high yields (80%) with far fewer
contaminants at a loading of just 0.12 mol%. Moreover, the Frech catalyst allowed the
reaction to be performed on a larger scale (see below).
Heck reactions using pincer catalysts are often critically influenced by the solvent and
base employed for the coupling process.19,20 To determine the optimum protocol, several
solvents, including DMF, THF, and PhCH3, were studied. For the current application,
DMF afforded the best results due to its superior solvating properties for the substrates
and high boiling point. A series of bases, which included K2CO3, Cs2CO3, Et3N, DBU
and N-ethylpiperidine, was also evaluated. In DMF, N-ethylpiperidine provided the highest
yields of coupled products.
Reaction temperatures were also varied to optimize the conditions. Using DMF and
N-ethylpiperidine, maximum conversions were realized at 140–150◦C. Reactions at lower
temperatures (110–120◦C) were slow and gave low yields even after prolonged heating
(36 h). At more elevated temperatures (≥160◦C), complex mixtures were formed which
hindered purification of the desired products. For catalyst comparison studies, reactions
using (Ph3P)2PdCl2, Pd(OAc)2, and the Frech complex were run at 140–150◦C for 16–20 h,
although 3h–3j required only 8–12 h. Without exception, the Frech catalyst gave higher
yields and cleaner products that were more easily purified.

68
Nammalwar et al.
Finally, catalytic loading for each catalyst was investigated. Our optimization studies
indicated that 1.25 mol% of (Ph3P)2PdCl2 and Pd(OAc)2 was required to achieve complete
conversions. Greater amounts of catalyst slightly decreased the yields and increased the
number of impurities, while less catalyst resulted in incomplete reactions. In sharp contrast,
the Frech complex afforded essentially complete conversions to products at a catalytic
loading of only 0.12 mol%. For the class of compounds examined, isolated yields of
products were highly reproducible with this quantity of catalyst.
Under optimized conventional conditions, the reactions of 1.30 mmol each of 1 with
2a–j were carried out using 1.42 mmol of N-ethylpiperidine and 1.55 × 10−3 mmol
(0.12 mol%) of the Frech catalyst in 4 mL of DMF under argon at 140–150◦C for
16–20 h. The R groups [propyl (3a), isobutyl (3b), isobutenyl (3c), cyclohexyl (3d), phenyl
(3e), 4-methylphenyl (3f), 4-fluorophenyl (3g), benzyl (3h), 4-methylbenzyl (3i) and 4-
trifluoromethoxybenzyl (3j)] were carefully chosen to provide a range of agents with
potential activity as antibiotics and also to ascertain the structural diversity tolerated by the
catalyst. The results are summarized in Table 1. Products 3a–j were highly polar and re-
tained water (from chromatography) or methanol (from recrystallizations) despite extensive
Table 1
Yields of 3a–j using Three Catalysts
O
NH2
R
NH2
N
R
O
I
catalyst
N
N
N
N
N
N
+
N-ethylpiperidine
DMF, heat
H2N
H2N
OCH3
N
OCH3
OCH3
OCH3
1
2a-j
3a-j
Product
R
Yield (%)
(Ph3P)2PdCl2 Pd(OAc)2
Catalyst:
Method:
Frech
A
B
A
B
C
D
3a
3b
3c
3d
3e
3f
3g
3h
3i
n-C3H7
i-C4H9
i-C4H7
c-C6H11
C6H5
4-CH3C6H4
4-FC6H4
C6H5CH2
37
30
36
32
26
38
28
22
18
10
42
65
56
47
60
67
55
56
48
25
50
67
65
54
58
66
62
68
56
38
52
67
63
57
55
64
63
68
45
40
80
82
75
82
78
76
79
83
75
74
80
81
76
82
80
74
77
80
71
77
4-CH3C6H4CH2
4-CF3OC6H4CH2
3j
Method A: Round-bottomed flask, 1.30 mmol each of 1 and 2, 1.42 mmol of N-ethylpiperidine,
1.63 × 10−2 mmol of catalyst, 4 mL of DMF, 140◦C, 18 h; Method B: Sealed tube, 1.30 mmol of 1
and 2, 1.42 mmol of N-ethylpiperidine, 1.63 × 10−2 mmol of catalyst, 4 mL of DMF, 140◦C, 18 h;
Method C: Round-bottomed flask, 1.30 mmol of 1 and 2, 1.42 mmol of N-ethylpiperidine, 1.55 ×
10−3 mmol of catalyst, 4 mL of DMF, 140◦C, 18 h; Method D: Sealed tube, 1.30 mmol of 1 and
2, 1.42 mmol of N-ethylpiperidine, 1.55 × 10−3 mmol of catalyst, 4 mL of DMF, 140◦C, 18 h. All
reactions were performed under argon.

Heck Synthesis of 2,4-Diaminopyrimidine-based Antibiotics
69
efforts to remove them.21 Finally, though our study compared reactions run on a 1.30-mmol
scale, the Frech catalyst (at a loading of 0.17 mol%) allowed us to run 20.0-mmol prepar-
ative scale reactions to generate lead compounds 3a and 3c in essentially undiminished
yields of 78% and 74%, respectively.
Coupling of substrates incorporating such wide functional diversity–a diaminopyrim-
idine ring, two ethers, a tertiary amide, an imine and (in some cases) fluorine–is rare. The
closest analogy to our work involved the use of the Frech catalyst to couple a variety of aryl
halides to N,N-dimethylacrylamide.13 In this investigation, the reported transformations
were assessed to be nearly quantitative by GC/MS analysis. Table 1 reports of products
isolated in our current study. Although our optimized catalyst loading was 0.12 mol%,
compared to 0.01 mol% for the acrylamide,13 this parameter would be expected to vary for
different compounds. Nevertheless, the marked flexibility of the Frech catalyst to operate
effectively on systems bearing such a large range of functional groups is remarkable and of
great significance in organic synthesis.
In summary, we have used the Frech pincer catalyst to efficiently prepare a series of
highly functionalized 2,4-diaminopyrimidine-based antibacterials for biological evaluation.
The Frech catalyst proved superior to conventional palladium-based Heck catalysts, giving
the desired products in higher yields and with fewer contaminants. The Frech catalyst also
exhibited superior activity and thermal stability and reduced the required catalytic loading
by a factor greater than ten compared to the other catalysts examined. Such remarkable
utility, broad scope of action, and multi-functional group tolerance by the Frech catalyst
mandates further exploration in organic synthesis.
Experimental Section
Commercial anhydrous N,N-dimethylformamide (DMF) was stored under dry argon and
transferred by syringe into reactions where required. All other commercial reagents were
used as received. Unless otherwise specified, all reactions were run under dry argon in
oven-dried glassware. Reactions were monitored by thin layer chromatography on silica
gel GF plates (Analtech No. 21521). Preparative separations were performed by column
ꢀR
chromatography in quartz columns using silica gel (Davisil , grade 62, 60–200 mesh)
mixed with UV-active phosphor (Sorbent Technologies, No. UV-05). Band elution for
all chromatographies was monitored using a hand-held UV lamp. Melting points were
uncorrected. FT-IR spectra were run as thin films on NaCl disks. Both 1H-NMR and 13C-
NMR spectra were measured in DMSO-d6 on a Varian GEMINI 300 instrument at 300 MHz
(1H) and 75 MHz (13C) or on a Varian INOVA 400 instrument at 400 MHz and 100 MHz,
respectively, and referenced to internal tetramethylsilane.
Representative Procedure for Heck Coupling using the Frech Catalyst to Prepare
( )-(E)-3-{5-[(2,4-Diamino-5-pyrimidinyl)methyl]-2,3-dimethoxyphenyl}-1-
(1-propyl-2(1H)-phthalazinyl)-2-propen-1-one (3a)
Note: Methods A and B [for (Ph3P)2PdCl2 and Pd(OAc)2] differ from C and D [for the
Frech catalyst] only in the mol% of catalyst used.
Conventional Conditions (Method C). A solution of 500 mg (1.30 mmol) of 1,14,15 the
corresponding phthalazine derivative (2a–j) (1.30 mmol),14,15 N-ethylpiperidine (161 mg,
0.195 mL, 1.42 mmol) and the Frech catalyst (1.00 mg, 1.55 × 10−3 mmol, 0.12 mol%) in

70
Nammalwar et al.
4 mL of anhydrous DMF was prepared in a 50-mL, round-bottomed flask equipped with
magnetic stirring. The solution was heated at 140–150◦C for a period of 18 h. During this
time, the reaction mixture turned from brown to bright red in color. After cooling, the crude
reaction mixture was transferred directly to a 30 cm × 2 cm silica gel column slurry packed
in dichloromethane. Impurities were eluted using dichloromethane, and the final product
was collected using 4% methanol in dichloromethane as the eluent. Evaporation of the
solvent gave a pale yellow solid which was further purified using a 15-cm × 2-cm silica gel
column, packed with 5% triethylamine-dichloromethane and eluted with 4% methanol in
dichloromethane. The second chromatography removed yellow-colored impurities as well
as several other minor contaminants. The products were recrystallized from methanol to
give pure 3a–j. Using this procedure, 503 mg (80%) of 3a was isolated as a white powder,
mp 121–124◦C (shrinks to glass-like bead). The IR, 1H-NMR, and 13C-NMR data for 3a,
as well as 3b–3j, matched those reported previously.14
Sealed Tube (Method D). Sealed tube reactions were run using the same reactant,
base, catalyst and solvent quantities given above. The reaction mixture was prepared in a
15-mL, screw-top Pyrex pressure vessel (Chemglass CG-1880–01 with O-ring CG-309-
210), purged with argon for 1 min, sealed, and heated in an oil bath at 140–150◦C for 18 h.
This procedure also produced 3a in 80% yield.
Large-Scale Preparation of 3a. This procedure followed Method C above using 8.00 g
(20.0 mmol) of 1, 5.20 g (22.0 mmol, 1.10 equiv) of 2, 2.58 g (3.12 mL, 22.0 mol, 1.10 equiv)
of N-ethylpiperidine, and 22 mg of the Frech catalyst (3.41 × 10−2 mmol, 0.17 mol%) in
20 mL of DMF. The reaction was heated at 140–150◦C for 18 h, and the product purified
as above to give 7.86 g (78%) of 3a as a white powder.
Acknowledgments
We are very grateful to Dr. Ronaldo Mariez (Sigma-Aldrich) for a generous sample of
the Frech catalyst used in this study. We gratefully acknowledge support of this work by
the National Institutes of Allergy and Infectious Diseases [1-R01-AI090685-01] of the
NIH/NIAID to WWB. Funding for the 300 MHz and 400 MHz NMR spectrometers of
the Oklahoma Statewide Shared NMR Facility was provided by NSF (BIR-9512269), the
Oklahoma State Regents for Higher Education, the W. M. Keck Foundation, and Conoco,
Inc. The authors thank the OSU College of Arts and Sciences for funds to upgrade the
Departmental FT-IR instruments.
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