N-formamido-containing mono- and diheterocyclic pyrrole-and imidazole-2-carboxylic acids as building blocks for polyamide synthesis

Article abstract of DOI:10.1080/00397910701648785

Four N-formamido-containing mono-and diheterocyclic pyrrole- and imidazole-2-containing acids 1-4 were synthesized as intermediates for the preparation of polyamide molecules. The N-formamido-moiety forces the compounds to bind strongly as a stacked dimer, and in a staggered fashion, at specific sequences in the minor-groove of DNA. The acid moiety at the C-terminus of compounds enables these molecules to be coupled to amine-containing intermediates to form the amide linkages of the target polyamide. This convergent approach increases the synthetic diversity in polyamide chemistry by enabling one acid to be used with a variety of different C-terminus- functionalized intermediates. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910701648785

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N ‐Formamido‐Containing Mono‐
and Diheterocyclic Pyrrole‐and
Imidazole‐2‐carboxylic Acids as Building
Blocks for Polyamide Synthesis
Keith Mulder a , Jim Sexton b , Zarmeen Taherbhai b , Justin Jones b , Peter
Uthe b , Toni Brown a b & Moses Lee a b
a Division of Natural and Applied Sciences and Department of Chemistry ,
Hope College , Holland, Michigan, USA
b Department of Chemistry , Furman University , Greenville, South Carolina,
USA
Published online: 25 Jan 2008.
To cite this article: Keith Mulder , Jim Sexton , Zarmeen Taherbhai , Justin Jones , Peter Uthe , Toni Brown &
Moses Lee (2007) N ‐Formamido‐Containing Mono‐ and Diheterocyclic Pyrrole‐and Imidazole‐2‐carboxylic Acids
as Building Blocks for Polyamide Synthesis , Synthetic Communications: An International Journal for Rapid
Communication of Synthetic Organic Chemistry, 38:1, 33-44, DOI: 10.1080/00397910701648785
To link to this article: http://dx.doi.org/10.1080/00397910701648785
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Synthetic Communicationsw, 38: 33–44, 2008
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910701648785
N-Formamido-Containing Mono- and
Diheterocyclic Pyrrole-and Imidazole-2-
carboxylic Acids as Building Blocks for
Polyamide Synthesis
Keith Mulder,1 Jim Sexton,2 Zarmeen Taherbhai,2
Justin Jones,2 Peter Uthe,2 Toni Brown,1,2 and Moses Lee1,2
1Division of Natural and Applied Sciences and Department of Chemistry,
Hope College, Holland, Michigan, USA
2Department of Chemistry, Furman University, Greenville, South
Carolina, USA
Abstract: Four N-formamido-containing mono-and diheterocyclic pyrrole- and
imidazole-2-containing acids 1–4 were synthesized as intermediates for the prep-
aration of polyamide molecules. The N-formamido-moiety forces the compounds to
bind strongly as a stacked dimer, and in a staggered fashion, at specific sequences in
the minor-groove of DNA. The acid moiety at the C-terminus of compounds enables
these molecules to be coupled to amine-containing intermediates to form the amide
linkages of the target polyamide. This convergent approach increases the synthetic
diversity in polyamide chemistry by enabling one acid to be used with a variety of
different C-terminus-functionalized intermediates.
Keywords: acid, distamycin, DNA, formamido, polyamide
INTRODUCTION
The formamido (f-) group, Fig. 1 found at the N-terminus of the naturally
occurring polyamide distamycin, is known to contribute significantly to its
binding affinity, specificity, and orientation.[1] The f-group has been shown
Received November 30, 2006
Address correspondence to Moses Lee, Division of Natural and Applied Sciences
and Department of Chemistry, Hope College, Holland, Michigan 49423, USA.
E-mail: lee@hope.edu
33

34
K. Mulder et al.
Figure 1. Structure of possible N-terminus groups found on polyamides: (a) the
formamido-group (f-) and (b) the acetyl-group (CH3-).
to affect the stacking of two polyamide molecules in the minor groove of
DNA.[2,3] When the f-group is present, the compounds tend to favor a
staggered motif;[3] conversely, when the f-moiety is absent, a fully overlapped
conformation is adopted by the two polyamide compounds[4] (Fig. 2).
The f-group is not found abundantly in natural molecules in comparison
to other acyl groups, such as the acetyl group (Ac-) (Fig. 1), which is much
more prevalent in nature.[5] DNA binding studies have been performed with
compounds that replaced the f- with the Ac-, and previous results showed
that this substitution had consequences on binding orientation.[6] The
authors showed that when an f-group is present, the polyamide binds to the
minor groove in a 50 to 30 orientation (N-terminus to C-terminus), but when
the Ac-group is present, the polyamide binds backward, in the 30 to 50
direction.[6] In addition, the formamido group has been shown to have a
positive effect on the binding affinity of polyamide molecules.[3,7] When
directly comparing f- and nonformamido (nf-) derivatives of the same hetero-
cyclic order, the f-containing polyamide generally binds with significantly
stronger affinity than its nf- counterpart.[3]
Because the formamido group is of such scientific interest, this article
describes the synthesis of four N-formamido heterocyclic acids (1–4,
Fig. 3). These compounds contain a one- or two-heterocycle core, with
the formamido group on the N-terminus and an acid functional group at the
C-terminus of the molecule. The acid group is present to enable the
molecule to be coupled to any amino-containing intermediate, allowing
amide bonds to be formed and a range of polyamides to be produced from
Figure 2. Two possible stacking modes found for polyamides binding to DNA in a
2:1 complex: (a) the staggered mode (observed when compounds possess the
f-group) and (b) the overlapped mode (observed in compounds with no f-group).

Building Blocks for Polyamide Synthesis
35
Figure 3. Structures of the four-heterocyclic formamido-acids 1–4.
one batch of the acid compound.[8] This convergent synthesis increases the
synthetic diversity of producing polyamide compounds.
RESULTS AND DISCUSSION
The syntheses of compounds 1, 2, and 3 (Fig. 1) begin with the common
building block, compound 5.[9] The synthesis of compounds 1 and 2 was
achieved by reducing the nitro-group on 5 to an amine using palladium-on-
carbon catalytic hydrogenation under atmospheric pressure (Scheme 1).[8] The
Scheme 1. (i) 10% Pd/C, cold MeOH, H2, 24 h; (ii) 1-methyl-4-nitroimidazole-2-
acid chloride, triethylamine, dry CH2Cl2, 08C-rt, 24 h; (iii) formic acetic anhydride,
THF, 08C-rt; (iv) THF/MeOH, NaOH, reflux, 3–5 h; (v) 1 M HCl; (vi) 10% Pd/C,
MeOH/THF, H2, 24 h.

36
K. Mulder et al.
resulting amine was coupled directly to either 1-methyl-4-nitroimidazole-2-acid
chloride or 1-methyl-4-nitropyrrole-2-acid chloride using Schotten–Bauman
conditions[10] to produce amides 6 and 7 in yields of 76 and 73%, respectively.
Further reduction of these nitro-groups to the amines, using the same conditions
as already described,[8] followed by formylation with acetic formic anhydride
(formed in situ by reaction of formic acid with acetic anhydride[3]) produced
8 and 9 in yields of 80 and 95%, respectively. The formylated compounds
were hydrolyzed by refluxing in THF, MeOH, and aqueous NaOH. Acidification
with aqueous HCl formed pure compounds 1 and 2 in 65 and 50% yields,
respectively. The overall yields of these compounds were good (40 and 35%
for 1 and 2, respectively) considering flash-column purification was
required at the first two steps. The monopyrrole compound, 3, was performed
in a similar manner (Scheme 1). Thus 5 was formylated directly (using the
same nitro-to-amine reduction as previously described) to produce 1 in
overall 55% yield. The lower yield could be attributed to a drop in solubility
when working with the monoheterocycle compared to the diheterocyclic
compounds.
Synthesis of the imidazole compound 4 was more challenging. The first
attempt at producing compound 4 was unsuccessful and employed similar
chemistry as described in the synthesis of compound 3, except that ethyl
1-methyl-4-nitroimidazole-2-carboxylate was used (Scheme 2i). The formyla-
tion step to produce compound 10 was successful; however, isolating the acid
product from the aqueous phase following hydrolysis of the ester was unsuc-
cessful because it was fully water soluble. Removal of sodium chloride from
the mixture was difficult.
A second, successful route employed the benzyl-protected-nitro-
imidazole starting material (11, Scheme 2ii). The first step employed a
reduction and formylation (as described previously) to form compound 12
in good yield (77%). The benzyl protecting group was removed by catalytic
hydrogenation using a 10% palladium-on-carbon catalyst (50 psi). The sus-
pension was vacuum filtered over Celitew, and the residue was vigorously
washed with copious amounts of N,N-dimethylformamide (DMF). Concen-
tration of the DMF solution under vacuum gave the desired compound 4 in
22% yield. The insolubility of this product accounts for the low yield, as
repeated washings were needed to extract the product from the residue.
A shorter, more efficient synthetic pathway to forming compound 4 was
discovered when the aforementioned synthesis was reattempted (Scheme 2iii).
In this case, CHCl3 was used instead of MeOH in the catalytic hydrogenation
of benzyl ester 12. Upon workup of the reaction, it was discovered that the for-
mamidogroup had been removed and the amine 13 had been isolated. This
intermediate was treated directly with acetic formic anhydride, and during
the workup the reaction was quenched with H2O instead of MeOH to
remove any C-terminus adducts. The target molecule 4 was obtained via
filtration of the precipitate. This serendipitous finding was interesting for
two reasons: (a) a step in the synthesis could potentially be eliminated, and

Building Blocks for Polyamide Synthesis
37
Scheme 2. (i) 10% Pd/C, cold MeOH, H2, 24 h; (ii) formic acetic anhydride, THF,
08C-RT; (iii) THF/MeOH, NaOH, reflux; (iv) 1 M HCl; (v) 10% Pd/C, MeOH/
THF, H2, 24 h; (vi) 10% Pd/C, CHCl3, H2, 24 h.
(b) the product could be obtained by filtration, rather than extraction with
DMF, which was tedious to remove.
A fourth reaction was attempted to determine if compound 4 could be
obtained from the shortened synthesis, mentioned previously. Compound 11
(Scheme 2ii) was reduced directly in CHCl3 with 10% Pd/C to determine if
the nitrogroup and the benzyl protecting group could be removed in onestep.
The isolated intermediate was then treated with acetic formic anhydride,
quenched with water, and filtered, and the target compound (4) was obtained in
51% yield. This yield represented a significant improvement over the previous
method (Scheme 2ii). One step in the synthesis was eliminated, and the product
was obtained directly without the need for a lengthy extraction procedure.
CONCLUSION
This article describes the synthesis of four N-formamido-containing mono-
and diheterocyclic carboxylic acid intermediates 1–4 with potential

38
K. Mulder et al.
application in the field of polyamide chemistry. The syntheses described are
versatile, and the products can be obtained in good yields without the need
for difficult isolation or purification techniques. All compounds provided
1
satisfactory .96% purity by 500-MHz H NMR as well as by thin-layer
chromatography (TLC) analysis. Finally, compound 4 can be obtained via a
shortened route that improves on yield and ease of isolation of the compound.
EXPERIMENTAL
Compound 7
Methyl-1-methyl-4-nitropyrrole-2-carboxylate (5)[9] (1.51 g, 8.22 mmol) was
reduced under H2 at atmospheric pressure with 5% Pd/C (50% by weight) in
cold MeOH. The reaction mixture was stirred for ꢀ24 h, and the catalyst was
removed by filtration through Celitew, washed thoroughly with MeOH, and
evaporated to dryness. Residual MeOH was removed by co-evaporation
with dry CH2Cl2 (3 ꢀ 2 mL). The resulting amine was dissolved in triethyl-
amine (1.20 mL, 8.5 mmol) and dry CH2Cl2 (20 mL) and cooled to 08C
(ice/H2O). 1-Methyl-4-nitropyrrole-2-carbonyl chloride[10] (9.04 mmol) was
dissolved in CH2Cl2 and added dropwise to the amine solution with stirring.
The reaction was stirred at Rt for ꢀ24 h, and the solvent was removed by
evaporation. The resulting yellow solid was suspended in water (10 mL),
filtered, washed with hexanes (10 mL) and isopropanol (IPA) (10 mL), and
dried under vacuum over P2O5 to yield 7 as a yellow solid (1.84 g, 73%),
1
mp 257–2618C. Rf: 0.31 (98:2% v/v CHCl3/MeOH); H NMR (CDCl3) d
7.60 (d, 1H, J 1.5 Hz); 7.53 (s, br, 1H); 7.38 (d, 1H, J 1.5 Hz); 7.17 (d, 1H,
J 1.5 Hz); 6.79 (d, 1H, J 1.5 Hz); 4.03 (s, 3H); 3.93 (s, 3H), 3.83 (s, 3H);
IR (neat) 2947, 2906, 2841, 1694, 1667, 1652, 1645, 1574, 1568, 1558,
1538, 1505, 1447, 1393, 1317, 1250, 1108, 750 cm21; MS (direct probe)
m/z (rel. intensity) 306 ([M] 80%), 153 (100%).
Compound 2
Compound 7 (104 mg, 0.34 mmol) was reduced for ꢀ18 h in the presence of
H2 using 5% Pd/C (50% by weight) in MeOH. The amine was isolated as
described for compound 7. Acetic anhydride (4 mL) was cooled to 08C
(ice/H2O) with stirring, and formic acid (2 mL) was added dropwise. The
solution was heated to 508C for ꢀ20 min and then cooled to 08C. N,N-
dimethylaminopyridine (DMAP) (10 mg, 0.082 mmol) were dissolved in
dry THF (30 mL), and the formic acetic anhydride was added dropwise at
08C (ice/H20 bath).
The reaction was stirred at 08C for a further ꢀ4 h and was then quenched
by the dropwise addition of MeOH (50 mL). The reaction stirred for ꢀ1 h at

Building Blocks for Polyamide Synthesis
39
this temperature. The solvent was removed, and the resulting orange oil was
dissolved in CHCl3 (50 mL) and water (50 mL). The pH of the aqueous
layer was adjusted using aq. NaOH (1 M, pH ꢀ11), and the aqueous layer
was back-extracted with CHCl3 (ꢀ3). The organic layers were combined
and dried (Na2SO4). Following evaporation, the crude orange product was
purified via silica gel (70–230 mesh) column chromatography (100:0–
90:10% v/v, CHCl3/MeOH) to yield 9 as an orange solid (98.2 mg, 95%):
1
Rf: 0.14 (98:2% v/v, CHCl3/MeOH); H NMR (CDCl3) d 8.29 (s, 1H);
7.41 (d, 1H, J 1.5 Hz); 7.11 (d, 1H, J 1.5 Hz); 6.74 (d, 1H, J 1.5 Hz); 6.66
(d, 1H, J 1.5 Hz); 3.94 (s, 3H); 3.92 (s, 3H), 3.82 (s, 3H). Compound 9
(330 mg, 1.08 mmol) was suspended in aq. NaOH (0.22 M) and refluxed for
ꢀ1 h. The solid was then dissolved with MeOH to make an orange
solution, which was cooled to 08C, and cold 1 M HCl was added dropwise.
A precipitate formed, which was filtered, washed with H2O, and dried over
P2O5 under vacuum to yield an orange solid (155.1 mg, 50%), mp 154–
1
1608C. H NMR (CD3OD) d 8.21 (s, 1H); 7.34 (d, 1H, J 1.5 Hz); 7.19
(d, 1H, J 1.5 Hz); 6.94 (d, 1H, J 1.5 Hz); 6.85 (d, 1H, J 1.5 Hz); 3.90
(s, 3H); 3.89 (s, 3H); IR (neat) 3288 (br), 3134, 2958, 1646, 1576, 1436,
1265 cm21; MS (ES þ ) m/z (rel. intensity) 145 (40%), 291 ([M þ H]
100%), 305 (50%), 305 (50%), 313 (20%), 397 (20%).
Compound 14
Compound 5[9] (200 mg, 1.09 mmol) was dissolved in chilled MeOH
(10 mL) and reduced in the presence of H2 using 5% Pd/C (120 mg, 50%
by weight) at rt for ꢀ18 h. The amine was isolated using the same
procedure as described for compound 7. Acetic anhydride (6.7 mL) was
stirred at 08C (ice/H2O), and formic acid (3.3 mL) was added dropwise.
The reaction was stirred at 508C for ꢀ15 min and then stored at 08C (ice/
H2O). THF (10 mL) was added to the amine, and the mixture was cooled
to 08C (ice/H2O) with stirring. The formic acetic anhydride mixture was
added dropwise to the amine solution and stirred overnight while warming
to rt. The reaction was cooled to 08C (ice/H2O) and quenched with
MeOH (10 mL), followed by removal of the solvent. The obtained product
was dissolved in CH2Cl2 and washed with H2O (2 ꢀ 15 mL), followed by
back-extraction with CH2Cl2 (2 ꢀ 10 mL). The organic layers were
collected, dried (Na2SO4), and evaporated to dryness to yield compound
14 as a yellow solid (106 mg, 54%), mp dec. 2508C. Rf 0.9 (70:30%v/v
1
CHCl3/MeOH); H NMR (CDCl3) d 8.27 (s, 1H); 7.375 (d, 1H, J 1.5 Hz);
7.14 (s, 1H); 6.70 (d, 1H, J 3 Hz); 5.26 (s, 3H); 3.94 (s, 3H); IR (neat)
3299, 3150, 3122, 2921, 2858, 1690, 1586, 1457, 1410, 1457, 1385, 1354,
1293, 1277, 1222, 1134, 1096 cm21; MS (direct probe) m/z (rel. intensity)
182 ([M] 100%), 153 (35%).

40
K. Mulder et al.
Compound 3[8]
Compound 14 (1.1 g, 6.04 mmol) was dissolved in dry THF (17 mL) and
MeOH (17 mL). The mixture was stirred under reflux for ꢀ2.5 h following
the addition of aq. NaOH (2 M, 4.5 mL). The solvents were removed, and
CH2Cl2 (3 mL) was added. The solution was stirred for 15 min. The organic
solvent was removed, and the aqueous layer was cooled to 08C (ice/H2O)
and acidified by the dropwise addition of aq. HCl (1 M). Ice chips were
added to facilitate the precipitation of the product. Filtration afforded a
solid that was dried under vacuum for ꢀ2 h to yield compound 3 as an
1
orange solid (573 mg, 56%), mp dec. 2008C. H NMR (DMSO-d6) d 9.98
(s, 1H); 8.08 (s, 1H); 7.92 (s, 1H); 7.21 (d, 1H, J 1 Hz); 6.641 (d, 1H, J
1 Hz); 3.79 (s, 3H); IR (neat) 3309 (br), 2961, 2890, 1713, 1635, 1457,
1442, 1368, 1345, 1322, 1191, 1121, 1066, 1037, 966 cm21; MS (direct
probe) m/z (rel. intensity) 168 ([M] 100%), 139 (35%); HRMS for
C7H8N2O3 calcd. 168.0535, obsvd. 168.0532.
Compound 6
Compound 5 (247 mg, 1.34 mmol) was dissolved in MeOH (10 mL) and
reduced in the presence of H2 using Pd/C (5%, 124 mg) at rt for ꢀ4 h. The
amine was isolated as described for compound 7. 1-Methyl-4-nitroimidazole
carbonyl chloride[10] (1.60 mmol) in dry CH2Cl2 (10 mL) was added
dropwise to a mixture of the isolated amine in THF (15 mL) and triethylamine
(0.188 mL ¼ 136.5 mg, 1.35 mmol) at 08C (ice/H2O) with stirring. The
reaction was allowed to stir at rt for ꢀ18 h. The compound was isolated in
a similar manner as compound 7. The crude product was dried under
vacuum to yield compound 6 as a yellow residue (313 mg, 76%): Rf: 0.41
1
(98:2% v/v CHCl3/MeOH) H NMR (CDCl3) d 8.96 (s, 1H); 7.83 (s, 1H);
7.39 (d, 1H, J 1.5 Hz); 7.38 (d, 1H, J 2 Hz); 4.21 (s, 3H); 3.93 (s, 3H), 3.83
(s, 3H); IR (neat) 2955, 2918, 2849, 1705, 1652, 1557, 1463, 1455,
1309 cm21; MS (ES þ ) m/z (rel. intensity) 308 ([M þ H] 20%), 242
(25%), 226 (30%), 152 (45%).
Compound 8
Compound 7 (1.83 g, 5.9 mmol) was dissolved in cold MeOH (10 mL) and
THF (5 mL) and reduced in the presence of H2 using Pd/C (5%, 0.60 g) at
rt for ꢀ4 h. The amine was isolated as described for compound 7. Acetic
anhydride (15 mL) was stirred at 08C (ice/H2O), and formic acid (7.5 mL)
was added dropwise. The mixture was heated at 508C with stirring for
ꢀ20 min followed by cooling to 08C (ice/H2O). The resulting formic acetic
anhydride was added dropwise to a solution of the amine in THF (15 mL)

Building Blocks for Polyamide Synthesis
41
and DMAP (20 mg), followed by stirring for ꢀ4 h. The reaction was quenched
by the addition of MeOH (10 mL), followed by stirring for 15 min. The
solvent was removed, followed by addition of H2O (10 mL) and aqueous
NaOH (1 M, pHꢀ11). The aqueous layer was washed with CHCl3
(3 ꢀ 15 mL), and then the organic layer was dried (Na2SO4) and evaporated
to dryness to yield compound 8 as a yellow solid (1.46 g, 80%), mp 215–
2198C. Rf 0.3 (95:5% v/v CHCl3/MeOH); 1H NMR (CDCl3) d 9.88
(s, 1H); 8.26 (s, 1H); 7.64 (s, 1H); 7.39 (s, 1H); 7.38 (d, 1H, J 2 Hz); 6.81
(d, 1H, J 1.5 Hz); 4.02 (s, 3H); 3.88 (s, 3H); 3.78 (s, 3H); IR (neat) 2950,
2913, 2844, 1694, 1652, 1567, 1557, 1471, 1447, 1259, 1199, 1120, 1098,
1062 cm21; MS (direct probe) m/z (rel. intensity) 305 ([M] 100%).
Compound 1
Compound 8 (293 mg, 0.961 mmol) was stirred in aq. NaOH (0.5 mL, 2 M)
and H2O (4.3 mL) at reflux for ꢀ1 h. An additional aliquot of NaOH
solution (0.1 mL) was added, and the reaction was stirred at reflux for an
additional 30 min. The orange reaction mixture was cooled to 08C (ice/
H2O), and aq. HCl (1 M) was added until a solid precipitated. The solid
was filtered, washed with H2O, and dried under vacuum over P2O5 to
produce the product 1 as a yellow/brown solid (181 mg, 65%), mp 188–
1
1948C. H NMR (CDCl3) d 8.31 (s, 1H); 7.44 (d, 1H, J 2 Hz); 7.25 (s, 1H);
6.85 (d, 1H, J 2 Hz); 4.05 (s, 3H); 3.89 (s, 3H); MS (ES þ ) m/z (rel.
intensity) (292 [M þ H] 100%).
Compound 11
1-Methyl-4-nitroimidazole carbonyl chloride[10] (8.89 mmol) was dissolved in
dry CH2Cl2 (20 mL) and added dropwise to a cooled solution (ice/H2O) of
benzyl alcohol (2.0 mL ; 2.09 g, 19.33 mmol) and triethylamine
(1.5 mL ; 1.09 g, 10.78 mmol) in CH2Cl2 (20 mL). Following the complete
addition, the reaction was stirred at rt for 12–18 h. The crude material was
isolated in a similar manner as described for compound 14, except the
reaction was not quenched with MeOH. The organic layers were combined
and dried (Na2SO4), evaporated to dryness, and residual benzyl alcohol
removed via Ku¨gelrohr distillation (5 mmHg, 1008C). The obtained white
solid was purified by precipitation using petroleum ether 60:80 and diethyl
ether to yield a cream/white powder (2.22 g, 96%), mp 168.4–170.28C. Rf
1
0.42 (98:2% v/v CHCl3/MeOH); H NMR (CDCl3) d 7.83 (s, 1H); 7.38
(m, 5H); 5.42 (s, 2H); 4.10 (s, 3H); IR (neat) 1726, 1542, 1496, 1382, 1311,
1261, 1122 cm21; MS (direct probe) m/z (rel. intensity) 261 ([M] 10%),
244 (20%), 155 (35%), 127 (100%), 91 (75%).

42
K. Mulder et al.
Compound 12
Compound 11 (2.43 g, 0.0093 mol) and Pt/O2 (1.22 g) were dissolved in
MeOH (15 ml) and THF (15 mL). The solution was placed under H2 at
55 lbs. of pressure. Upon complete reduction, the Pt/O2 was filtered off
through Celitew. The filtrate was concentrated to dryness, and the amine
was coevaporated three times with dry CH2Cl2 (5 ml each). Acetic
anhydride (15 mL) was added to formic acid (7.5 mL) dropwise while
stirring at 08C. Upon complete addition, the mixture was heated to 508C,
stirred at reflux for ꢀ20 min, and then cooled to 08C. The amine was redis-
solved in dry CH2Cl2 (30 mL), and the formic acetic anhydride was added
dropwise at 58C. The reaction mixture was brought to rt and left stirring
overnight. The reaction was quenched with MeOH (20 mL), and concentrated
to dryness. Water was then added to the reaction mixture (and made alkaline
with aq. NaOH), and the aqueous layer was then extracted three times with
CHCl3 (50 ml each) and once with ethyl acetate (30 mL). The organic
layers were combined and dried (NaSO4) and then concentrated to dryness.
The product was then purified by column chromatography (80:20% v/v
CHCl3/MeOH) to yield compound 12 as a pale yellow solid (1.86 g, 77%),
1
mp 172–1768C. Rf 0.26 (95:5% v/v CHCl3/MeOH); H NMR (CDCl3) d
8.34 (s, 1H); 8.33 (s, 1H); 7.53 (s, 1H); 7.39–7.32 (m, 5H); 5.39 (s, 2H);
3.99 (s, 3H); IR (neat) 3210, 3161, 2919, 1714, 1686, 1436, 1269, 1210,
1118, 1060, 1012 cm21; MS (direct probe) m/z (rel. intensity) 259 ([M]
30%), 125 (70%), 91 (100%).
Method 1, Compound 4[8]
Compound 12 (1.86 g, 0.0072 mol) and 10% Pd/C (0.186 g) were dissolved in
MeOH (15 mL) and THF (15 mL) and reduced in the presence of H2 at atmos-
pheric pressure with stirring for ꢀ18 h. The amine was filtered, and compound
4 was extracted from the Pd/C catalyst DMF (3 ꢀ 5 mL each). The DMF was
removed via Ku¨gelrohr distillation (608C, 0.005 atm) and was washed with
acetone (2 ꢀ 10 mL) to yield compound 4 as a grey powder (0.27 g, 22%).
Method 2, Compound 4[8]
Compound 11 (1.01 g, 3.85 mmol) was dissolved in CHCl3 (10 mL) and
reduced for ꢀ18 h in the presence of H2 using Pd/C (10%, 0.2 g, 50 psi).
The amine was isolated as described for compound 7. Acetic anhydride
(7 mL) was stirred at 08C (ice/H2O), and formic acid (3.5 mL) was added.
The reaction was heated at 508C for ꢀ20 min and then stored at 08C (ice/
H2O) until required. The reduced compound was dissolved in dry THF
(30 mL) and cooled to 08C (ice/H2O), and the formic acetic anhydride

Building Blocks for Polyamide Synthesis
43
mixture was added dropwise and stirred overnight while warming to rt. The
reaction was cooled to 08C (ice/H2O) and quenched with H2O/ice (20 mL)
followed by removal of the solvent by evaporation. The suspension was
filtered, washed with H2O, and dried under vacuum (5 mmHg and 1008C)
1
to yield compound 4 a grey solid (331 mg, 51%), mp dec. 2008C. H NMR
(DMSO-d6) d 10.6 (s, 1H); 8.19 (s, 1H); 7.49 (s, 1H); 3.89 (s, 3H); IR
(neat) 3298 (br), 2962, 2888, 1706, 1622, 1569, 1476, 1383, 1368, 1278,
1191, 1121, 1064, 1037, 966, 926 cm21; MS (ES-) m/z (rel. intensity) 168
([M-H] 100%), 124 (100%), 97 (60%). HRMS for C6H7N3O3 calcd.
168.0409, obsvd. 168.0412.
ACKNOWLEDGMENT
The authors thank the National Science Foundation for support of this project.
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