Microwave-assisted heck synthesis of substituted 2,4-diaminopyrimidine- based antibiotics

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Organic Preparations and Procedures
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Microwave-assisted Heck Synthesis of
Substituted 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: 21 May 2012.
To cite this article: Baskar Nammalwar , Richard A. Bunce , K. Darrell Berlin , Christina R. Bourne ,
Philip C. Bourne , Esther W. Barrow & William W. Barrow (2012): Microwave-assisted Heck Synthesis
of Substituted 2,4-Diaminopyrimidine-based Antibiotics, Organic Preparations and Procedures
International: The New Journal for Organic Synthesis, 44:3, 281-287
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Organic Preparations and Procedures International, 44:281–287, 2012
Copyright © Taylor & Francis Group, LLC
ISSN: 0030-4948 print / 1945-5452 online
DOI: 10.1080/00304948.2012.676823
Microwave-assisted Heck Synthesis of Substituted
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
Microwave-assisted organic synthesis is an area of increasing interest for promoting clean,
reproducible, high-yielding reactions under mild conditions.1,2 This is evident from the large
number of papers and reviews that have appeared on this topic in the recent literature.3–8
In the current work, microwave irradiation was employed to facilitate the intermolecular
formation of C–C bonds using a palladium-catalyzed Heck coupling reaction. Microwave
conditions have previously been used to accelerate this type of reaction9,10 as well as other
metal-catalyzed processes such as the Suzuki, Sonogashira and Negishi couplings.11,12
However, the use of microwave irradiation to induce reactions of highly functionalized
molecules has not been studied in detail. We, therefore, wish to report our work on a
microwave-assisted Heck reaction to prepare a series of antibacterials bearing a variety of
functional groups.
The goal of the current project is the synthesis 2,4-diaminopyrimidine antibiotics 3a–h,
which have potential for the treatment of inhalation anthrax, a bioterror threat. The most im-
portant aspect of these drugs is that they selectively inhibit the activity of Bacillus anthracis
dihydrofolate reductase (DHFR) but not human DHFR.13,14 DHFR plays a critical role in
folate metabolism and is a good target for antibiotic drug candidates. Furthermore, since
our compounds incorporate several structural units common to drugs that inhibit DHFR, it
is less likely that bacteria exposed to these agents will readily develop a resistance to them.
The synthesis involves a Heck reaction of 2,4-diamino-5-(5-iodo-3,4-dimethoxy-
benzyl)pyrimidine (1) with a series of ( )-1-(1-substituted-1H-phthalazin-2-yl)prop-2-en-
1-ones 2, both of which are available by known methods.13,15 Earlier syntheses of certain
examples of 3 by conventional Heck procedures13,15 gave yields of 10%–37%. The prod-
ucts obtained by this method, however, were difficult to purify from the reaction mixture
Submitted December 14, 2011.
Address correspondence to Richard A. Bunce, Department of Chemistry, Oklahoma State Uni-
versity, Stillwater, OK 74078-3071, USA. E-mail: rab@okstate.edu
281

282
Bunce et al.
due to extensive side-product formation. We have successfully improved the synthesis by
employing microwave irradiation to assist the Heck coupling process.
The conventional reactions were carried out using 2.07 mmol each of 1 and 2, 2.27
mmol of N-ethylpiperidine and 0.026 mmol (1.24 mol % relative to substrates 1 and 2)
of bis(triphenylphosphine)palladium(II) dichloride catalyst in 8 mL of DMF under argon
at 140◦C–150◦C for 18 h.13,15 This procedure generally afforded the coupled product in
low yield (10%–37%) with substantial side-product formation. In an effort to improve
this outcome, substrate concentrations and temperatures were varied, but neither of these
changes resulted in significant improvement. Attempts to adjust the catalyst loading for
this transformation were also examined. An increase in catalyst loading to 2.00 mol %
decreased the yield of the product and added to the impurity profile, making isolation of
the product more difficult. A decrease in catalyst loading to 0.96 mol % led to incomplete
reaction and recovery of starting material along with the desired product. Thus, a catalyst
loading of 1.24 mol % proved optimum for the complete conversion to the product with
a minimum of side reactions. Finally, the use of other catalysts (e.g. Pd(OAc)2, PdCl2,
(Ph3P)4Pd, Pd/C and CuI)13 and bases (e.g. Et3N, DBU, K2CO3 and Cs2CO3)13 failed to
improve the conversion to product.
Reactions were also carried out on the same molar scale in sealed tubes. This resulted
in slightly improved yields (42%–65%), but side-reactions were still problematic. It is
conceivable that prolonged heating under conventional and sealed tube conditions caused
degradation of the substrates and the catalyst, leading to a more complex product mixture.
Thus, a method was sought to decrease the reaction time, which led us to the use of
microwave irradiation.
Microwave-assisted reactions were run on the same scale as above at 400 W and
150◦C under argon for 60–80 min and gave superior conversions to products with far
fewer impurities. A comparison of yields obtained using conventional, sealed tube and
microwave conditions is shown in Table 1. Microwave irradiation as an alternative source
of heating expedited the reaction, decreased the required catalyst loading by 20% (to
0.96 mol %) and reduced the amount of solvent needed by 25%. A series of reactions
was carried out with R = propyl, isobutyl, isobutenyl, phenyl, 4-fluorophenyl, benzyl,
4-methylbenzyl and 4-trifluoromethoxybenzyl to establish the generality of the method.
Products prepared in this manner were conveniently purified by placing the crude reaction
mixture directly onto a silica gel column and eluting with increasing concentrations of
methanol in dichloromethane. The target molecules were isolated as hydrates or solvates16
and were characterized by elemental and spectral analysis.

Synthesis of 2,4-Diaminopyrimidine-based Antibiotics
283
(Ph3P)2PdCl2
1 + 2a–h −−−−−−−−−−−−→ 3a–h
N-ethylpiperidine
DMF, ꢀ
Table 1
Yields of 3 Using Conventional, Sealed Tube and Microwave Conditions
Product
R
Yields
Sealed Tubea
Conventional
Microwaveb
3a
3b
3c
3d
3e
3f
n-C3H7
i-C4H9
i-C4H7
C6H5
4-FC6H4
C6H5CH2
37
30
36
26
28
22
18
10
42
65
65
60
55
56
48
25
74
76
70
78
72
72
68
58
3g
3h
4-CH3C6H4CH2
4-CF3OC6H4CH2
aSealed tube, 2.07 mmol each of 1 and 2, 2.27 mmol of N-ethylpiperidine, 0.026 mmol of
(Ph3P)2PdCl2, 8 mL DMF, 140◦C–150◦C, 18 h; bGreenchem Plus glass microwave tube, 2.07 mmol
each of 1 and 2, 2.27 mmol of N-ethylpiperidine, 0.020 mmol of (Ph3P)2PdCl2, 6 mL of DMF, 400
W, 150◦C, 60–80 min.
We have successfully developed a synthesis of 2,4-diaminopyrimidine-based antibi-
otics that utilizes a microwave-assisted Heck reaction on highly functionalized substrates
in the final step. The reaction is superior to reactions performed under conventional or
sealed tube conditions, requiring less solvent and catalyst. More importantly, the use of
microwave conditions reduced reaction times and provided higher coupling yields with
fewer side products.
Experimental Section
Commercial anhydrous N,N-dimethylformamide (DMF) was stored under dry nitrogen and
transferred by syringe into reactions where it was used. 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
chromatography in quartz columns using silica gel (grade 62, 60–200 mesh) mixed with
UV-active phosphor (Sorbent Technologies, No. UV-5) and band elution was followed us-
ing a hand-held UV lamp. Melting points were uncorrected. FT-IR spectra were run as thin
films on sodium chloride disks. 1H- and 13C-NMR spectra were measured in DMSO-d6 on
a Varian GEMINI 300 instrument at 300 MHz (1H) and 75 MHz (13C) or a Varian INOVA
400 instrument at 400 MHz and 100 MHz, respectively, and referenced to internal tetram-
ethylsilane. Elemental analyses were performed by Atlantic Microlab, Inc. (Norcross, GA).
General Procedure for the Synthesis of 3a–h.11
A solution of 2,4-diamino-5-(5-iodo-3,4-dimethoxybenzyl)pyrimidine (1) (800 mg, 2.07
mmol),11 the corresponding phthalazine derivative 2a–h (2.07 mmol),11 N-ethylpiperidine

284
Bunce et al.
(257 mg, 0.30 mL, 2.27 mmol) and bis(triphenylphosphine)palladium(II) dichloride
(14 mg, 0.020 mmol) in 6 mL of dry DMF was prepared in a 125 mm × 30 mm id
Greenchem Plus glass microwave reactor tube. The solution was purged with dry argon for
1 min, and the tube was closed. The sample was then placed inside a CEM (Mars Model
230/60) microwave unit and irradiated at 400 W and 150◦C for 1–1.3 h. 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
coupled product was eluted using 4% methanol in dichloromethane. Evaporation of the sol-
vent gave a pale yellow solid which was chromatographed a second time using a 15-cm ×
2-cm silica gel column, packed with 5% triethylamine in dichloromethane and eluted with
4% methanol in dichloromethane. This second chromatography removed traces of catalyst
as well as several other minor impurities. The products obtained were recrystallized from
methanol to give pure 3a–h.
( )-(E)-3-{5-[(2,4-Diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl}-1-
[1-propylphthalazin-2(1H)-yl]prop-2-en-1-one (3a)
This compound was obtained as described above using 472 mg (2.07 mmol) of 2a to give
745 mg (74%) of 3a as a white powder, mp. 121◦C–124◦C (shrinks to a glass-like bead).
IR: 3474, 3341, 3182, 1645 cm−1; 1H-NMR (300 MHz): δ 8.07 (d, 1 H, J = 16.1 Hz), 7.80
(s, 1 H), 7.66 (s, 1 H), 7.64 (d, 1 H, J = 16.1 Hz), 7.45 (td, 1 H, J = 7.3, 1.5 Hz), 7.36 (td,
1 H, J = 7.5, 1.3 Hz), 7.28 (dd, 1 H, J = 7.5, 1.5 Hz), 7.18 (dd, 1 H, J = 7.3, 1.5 Hz), 7.13
(d, 1 H, J = 1.9 Hz), 6.66 (d, 1 H, J = 1.9 Hz), 5.91 (t, 1 H, J = 6.8 Hz), 4.84 (br s, 2 H),
4.66 (br s, 2 H), 3.84 (s, 3 H), 3.80 (s, 3 H), 3.68 (s, 2 H), 1.64 (m, 2 H), 1.27 (m, 2 H),
0.87 (t, 3 H, J = 7.1 Hz); 13C-NMR (75 MHz): δ 166.5, 162.6, 162.3, 156.8, 153.5, 147.3,
142.3, 137.1, 134.2, 134.0, 131.4, 129.7, 128.0, 126.5, 125.6, 124.0, 118.7, 118.6, 112.9,
106.3, 61.4, 55.9, 51.3, 37.3, 34.4, 18.3, 13.8.
Anal. Calcd for C27H30N6O3·2.0 H2O·0.5 CH3OH: C, 61.32; H, 6.32; N, 15.92. Found:
C, 61.56; H, 6.12; N, 15.81.
( )-(E)-3-{5-[(2,4-Diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl}-1-
[1-isobutylphthalazin-2(1H)-yl]prop-2-en-1-one (3b)
This compound was obtained as described above using 501 mg (2.07 mmol) of 2b to give
790 mg (76%) of 3b as an off-white powder, mp. 127◦C–129◦C. IR: 3443, 3352, 3173,
1644 cm−1; 1H-NMR (300 MHz): δ 8.00 (s, 1 H), 7.86 (d, 1 H, J = 16.5 Hz), 7.58 (d, 1 H,
J = 16.5 Hz), 7.57 (s, 1 H), 7.55 (overlapping d and t, 2 H, J ≈ 7.7 Hz), 7.46 (t, 1 H, J =
7.4 Hz), 7.38 (d, 1 H, J = 7.1 Hz), 7.27 (s, 1 H), 7.02 (s, 1 H), 6.87 (br s, 2 H), 6.38 (br s,
2 H), 5.89 (t, 1 H, J = 6.6 Hz), 3.80 (s, 3 H), 3.74 (s, 3 H), 3.62 (s, 2 H), 1.38 (m, 3 H),
0.93 (d, 3 H, J = 4.9 Hz), 0.88 (d, 3 H, J = 4.9 Hz); 13C-NMR (75 MHz): δ 165.4, 162.8,
159.3, 152.5, 150.1, 146.1, 143.3, 136.6, 135.5, 134.0, 131.8, 128.3, 127.9, 126.2 (2 C),
123.6, 118.6, 117.9, 114.9, 106.9, 60.8, 55.8, 48.8, 43.3, 32.1, 23.5, 22.9, 22.2.
Anal. Calcd for C28H32N6O3·1.5 H2O: C, 63.85; H, 6.69; N, 15.93. Found: C, 63.85;
H, 6.44; N, 15.94.

Synthesis of 2,4-Diaminopyrimidine-based Antibiotics
285
( )-(E)-3-{5-[(2,4-Diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl}-
1-[1-isobutenylphthalazin-2(1H)-yl]prop-2-en-1-one (3c)
This compound was obtained as described above using 497 mg (2.07 mmol) of 2c to give
720 mg (70%) of 3c as an off-white powder, mp. 130◦C–132◦C. IR: 3474, 3339, 3172,
1642 cm−1; 1H-NMR (400 MHz): δ 7.91 (s, 1 H), 7.86 (d, 1 H, J = 16.0 Hz), 7.59 (d, 1 H,
J = 16.0 Hz), 7.57 (s, 1 H), 7.52 (m, 2 H), 7.42 (t, 1 H, J = 7.4 Hz), 7.31 (d, 1 H, J = 7.7
Hz), 7.25 (s, 1 H), 7.01 (s, 1 H), 6.72 (br s, 2 H), 6.50 (d, 1 H, J = 8.8 Hz), 6.24 (br s, 2 H),
5.24 (d, 1 H, J = 8.8 Hz), 3.80 (s, 3 H), 3.74 (s, 3 H), 3.61 (s, 2 H), 1.96 (s, 3 H), 1.60 (s, 3
H); 13C-NMR (100 MHz): δ 165.3, 162.7, 159.9, 155.9, 152.5, 151.2, 146.1, 142.0, 136.7,
135.7, 133.8, 133.5, 132.1, 128.2, 127.9, 126.1 (2 C), 123.0, 122.1, 118.5, 118.0, 114.8,
106.6, 60.8, 55.8, 49.2, 25.2, 18.4.
Anal. Calcd for C28H30N6O3·1.5 H2O: C, 64.32; H, 6.33; N, 15.99. Found: C, 64.67;
H, 6.35; N, 16.07.
( )-(E)-3-{5-[(2,4-Diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl}-1-
[1-phenylphthalazin-2(1H)-yl]prop-2-en-1-one (3d)
This compound was obtained as described above using 542 mg (2.07 mmol) of 2d to give
840 mg (78%) of 3d as a light pink powder, mp. 142◦C–144◦C. IR: 3478, 3340, 3178, 1653
cm−1; 1H-NMR (300 MHz): δ 7.98 (s, 1H), 7.87 (d, 1 H, J = 15.9 Hz), 7.70 (d, 1 H, J =
15.9 Hz), 7.64–7.50 (complex m, 3 H), 7.60 (s, 1 H), 7.45 (t, 1 H, J = 7.1 Hz), 7.33-7.18
(complex m, 7 H), 6.99 (s, 1 H), 6.19 (br s, 2 H), 5.74 (br s, 2 H), 3.78 (s, 3 H), 3.72 (s, 3
H), 3.59 (s, 2 H); 13C-NMR (75 MHz): δ 165.8, 162.3, 162.1, 155.8, 152.4, 146.0, 142.0,
141.7, 137.1, 136.6, 132.9, 132.2, 128.58, 128.51, 127.6, 127.5, 127.2, 126.4, 126.0, 122.9,
118.4, 117.6, 114.9, 105.7, 60.8, 55.7, 53.8, 32.4.
Anal. Calcd for C30H28N6O3·0.5 H2O: C, 68.31; H, 5.50; N, 15.87. Found: C, 68.41;
H, 5.49; N, 15.93.
( )-(E)-3-{5-[(2,4-Diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl}-1-
[1-(4-fluorophenyl)-phthalazin-2(1H)-yl]prop-2-en-1-one (3e)
This compound was obtained as described above using 582 mg (2.07 mmol) of 2e to give
800 mg (72%) of 3e as an off-white powder, mp. 143◦C–145◦C. IR: 3479, 3347, 3180,
1649 cm−1; 1H-NMR (300 MHz): δ 8.00 (s, 1 H), 7.88 (d, 1 H, J = 15.9 Hz), 7.69 (d, 1 H,
J = 15.9 Hz), 7.61-7.56 (complex m, 3 H), 7.60 (s, 1 H), 7.46 (m, 1 H), 7.27 (complex m,
3 H), 7.12 (t, 2 H, J = 8.8 Hz), 7.02 (s, 2 H), 6.19 (br s, 2 H), 5.75 (br s, 2 H), 3.79 (s, 3
H), 3.73 (s, 3 H), 3.59 (s, 2 H); 13C-NMR (75 MHz): δ 165.8, 162.3, 162.2, 161.4 (d, J =
243.9 Hz), 155.8, 152.5, 146.0, 142.1, 137.9 (d, J = 2.9 Hz), 137.3, 136.6, 132.7, 132.3,
128.7, 128.3 (d, J = 8.3 Hz), 127.6, 127.2, 126.5, 122.9, 118.4, 117.5, 115.4 (d, J = 21.5
Hz), 114.4, 105.7, 60.8, 55.7, 53.0, 32.4.
Anal. Calcd for C30H27FN6O3·0.5 H2O: C, 65.81; H, 5.12; N, 15.36. Found: C, 65.88;
H, 5.14; N, 15.24.

286
Bunce et al.
( )-(E)-1-(1-Benzylphthalazin-2(1H)-yl)-3-{5-[(2,4-diaminopyrimidin-5-yl)
methyl]-2,3-dimethoxyphenyl}prop-2-en-1-one (3f)
This compound was obtained as described above using 571 mg (2.07 mmol) of 2f to give
800 mg (72%) of 3f as an off-white powder, mp. 143◦C–145◦C. IR: 3479, 3336, 3179,
1658 cm−1; 1H-NMR (400 MHz): δ 7.83 (d, 1 H, J = 16.0 Hz), 7.78 (s, 1 H), 7.61 (s, 1 H),
7.60 (d, 1 H, J = 16.0 Hz), 7.47-7.37 (complex m, 3 H), 7.24 (s, 1 H), 7.17 (m, 3 H), 7.00
(d, 1 H, J = 1.2 Hz), 6.96 (m, 1 H), 6.86 (m, 2 H), 6.19 (br s, 2 H), 6.04 (t, 1 H, J = 6.4
Hz), 5.73 (br s, 2 H), 3.79 (s, 3 H), 3.74 (s, 3 H), 3.60 (s, 2 H), 2.90 (dd, 1 H, J = 13.0, 7.6
Hz), 2.83 (dd, 1 H, J = 13.0, 5.7 Hz); 13C-NMR (100 MHz): δ 165.6, 162.3, 162.2, 155.8,
152.5, 146.0, 142.3, 136.64, 136.57, 136.2, 132.4, 131.3, 129.6, 128.4, 127.9, 127.8, 126.6,
126.5, 125.9, 123.8, 118.3, 117.8, 114.7, 105.7, 60.8, 55.7, 52.3, 48.6, 32.4.
Anal. Calcd for C31H30N6O3·1.0 CH3OH: C, 67.96; H, 5.84; N, 14.86. Found: C,
68.13; H, 5.86; N, 15.12.
( )-(E)-3-{5-[(2,4-Diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl}-1-
[1-(4-methylbenzyl)phthalazin-2(1H)-yl]prop-2-en-1-one (3g)
This compound was obtained as described above using 571 mg (2.07 mmol) of 2g to give
770 mg (68%) of 3g as an off-white powder, mp. 135◦C–137◦C. IR: 3477, 3338, 3176,
1
1657 cm−1; H-NMR (400 MHz): δ 7.83 (d, 1 H, J = 16.1 Hz), 7.78 (s, 1 H), 7.61 (s, 1
H), 7.60 (d, 1 H J = 16.1 Hz), 7.44 (m, 1 H), 7.41 (dd, 2 H, J = 5.6, 3.4 Hz), 7.24 (d, 1 H
J = 1.6 Hz), 6.99 (s, 1 H), 6.98 (d, 2 H, J = 8.0 Hz), 6.96 (m, 1 H), 6.73 (d, 2 H, J = 8.0
Hz), 6.18 (br s, 2 H), 6.00 (t, 1 H, J = 6.4 Hz), 5.73 (br s, 2 H), 3.79 (s, 3 H), 3.74 (s, 3 H),
3.60 (s, 2 H), 2.85 (dd, 1 H, J = 13.2, 7.6 Hz), 2.78 (dd, 1 H, J = 13.2, 5.5 Hz), 2.23 (s, 3
H); 13C-NMR (100 MHz): δ 165.5, 162.3, 162.2, 155.8, 152.5, 146.0, 142.2, 136.6, 136.5,
135.4, 133.1, 132.5, 131.3, 129.5, 128.6, 128.3, 127.8, 126.7, 125.9, 123.8, 118.3, 117.8,
114.7, 105.7, 60.8, 55.7, 52.4, 48.6, 32.4, 20.7.
Anal. Calcd for C31H30N6O3·1.0 CH3OH: C, 68.26; H, 6.25; N, 14.47. Found: C,
68.27; H, 6.11; N, 14.78.
( )-(E)-3-{5-[(2,4-Diaminopyrimidin-5-yl)methyl]-2,3-dimethoxyphenyl}-1-
[1-(4-trifluoromethoxybenzyl)phthalazin-2(1H)-yl]prop-2-en-1-one (3h)
This compound was obtained as described above using 716 mg (2.07 mmol) of 2h to give
740 mg (58%) of 3h as an off-white powder, mp. 125◦C–127◦C. IR: 3481, 3335, 3183,
1657 cm−1; 1H-NMR (400 MHz): δ 7.81 (d, 1 H, J = 16.1 Hz), 7.80 (s, 1 H), 7.60 (s, 1 H),
7.58 (d, 1 H, J = 16.1 Hz), 7.44 (m, 3 H), 7.24 (s, 1 H), 7.17 (d, 2 H, J = 8.0 Hz), 7.08
(m, 1 H), 6.99 (s, 1 H), 6.98 (d, 2 H, J = 8.0 Hz), 6.18 (br s, 2 H), 6.08 (t, 1 H, J = 6.3
Hz), 5.73 (br s, 2 H), 3.79 (s 3 H), 3.73 (s, 3 H), 3.59 (s, 2 H), 2.95 (dd, 1 H, J = 13.2, 7.0
Hz), 2.85 (dd, 1 H, J = 13.2, 6.1 Hz); 13C-NMR (100 MHz): δ 165.6, 162.3, 162.2, 155.7,
152.5, 147.1, 146.0, 142.4, 136.6, 135.8, 132.3, 131.5, 131.4, 128.5, 127.7, 126.6, 126.0,
123.8, 120.5, 120.0 (q, J = 256.2 Hz), 118.8, 118.3, 117.7, 114.8, 105.7, 60.8, 55.7 (2 C),
52.0, 32.4.
Anal. Calcd for C32H29F3N6O4·2.5 H2O: C, 57.91; H, 4.86; N, 12.66. Found: C, 57.74;
H, 4.51; N, 12.37.

Synthesis of 2,4-Diaminopyrimidine-based Antibiotics
Acknowledgments
287
The authors gratefully acknowledge support of this work by the National Institutes of Al-
lergy and Infectious Diseases [1-R01-AI090685-01] of the NIH/NIAID to WWB. Funding
for the 300 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 also wish to thank
the OSU College of Arts and Sciences for funds to purchase the microwave apparatus and
to upgrade our departmental FT-IR instruments. Finally, B. N. thanks Dr. Loralee Ohrtman
for her help in using the microwave reactor.
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