Synthesis of N-methylpyrrole and N-methylimidazole amino acids suitable for solid-phase synthesis

Article abstract of DOI:10.1021/jo048686r

New and higher yielding synthetic routes to N-protected N-methylpyrrole and N-methylimidazole amino acids are introduced to circumvent difficulties associated with established schemes. Key steps in each synthesis include copper-mediated cross-coupling reaction to directly install a carbamate-protected 4-amine in the N-methylpyrrole derivative and effective nitration followed by a one-pot reduction/Boc protection of the amine in the synthesis of the N-Me-imidazole amino acid.

Full text of DOI:10.1021/jo048686r

SCHEME 1a
Synthesis of N-Methylpyrrole and
N-Methylimidazole Amino Acids Suitable
for Solid-Phase Synthesis
David Jaramillo,† Qi Liu,‡ Janice Aldrich-Wright,† and
Yitzhak Tor*,‡
College of Science, Technology & Environment, University of
Western Sydney, Penrith South DC NSW 2560, Australia,
and Department of Chemistry and Biochemistry, University
of California, San Diego, La Jolla, California 92093-0358
ytor@ucsd.edu
Received July 29, 2004
a Reagents and conditions: (a) CCl3COCl, CH2Cl2, 24 h; (b) NBS,
CHCl3, -10 °C, 16 h; (c) NaOMe, MeOH, 1 h; (d) 10% CuI, K3PO4,
20% N,N′-dimethylethylenediamine, tert-butyl carbamate, dioxane,
110 °C, 48 h; (e) LiOH, H2O, THF/MeOH, 60 °C, 9 h.
Abstract: New and higher yielding synthetic routes to
N-protected N-methylpyrrole and N-methylimidazole amino
acids are introduced to circumvent difficulties associated
with established schemes. Key steps in each synthesis
include copper-mediated cross-coupling reaction to directly
install a carbamate-protected 4-amine in the N-methylpyr-
role derivative and effective nitration followed by a one-pot
reduction/Boc protection of the amine in the synthesis of the
N-Me-imidazole amino acid.
SCHEME 2a
Polyamides based on N-methylpyrrole and N-meth-
ylimidazole have emerged as a unique family of sequence-
specific DNA binders.1,2 These synthetic low MW ligands
form dimeric complexes within the DNA minor groove
with unprecedented affinity and selectivity. The recogni-
tion rules, established over the past decade by Dervan
and co-workers, allow one to control the sequence speci-
ficity of these “designer” molecules according to the linear
sequence of the individual building blocks.3 The strength
of this DNA recognition motif and its demonstrated
utility4 have therefore led to the development of efficient
solid-phase synthesis of such oligomeric polyamides.5
Key to the successful synthesis and application of these
DNA binders is the availability of the protected building
blocks, 4-[(tert-butoxycarbonyl)amino]-1-methylpyrrole-
2-carboxylic acid 5 and 4-[(tert-butoxycarbonyl)amino]-
1-methylimidazole-2-carboxylic acid 10 (Schemes 1 and
2, respectively). Unlike common amino acids, the prepa-
ration of these N-protected precursors requires rather
elaborate synthetic schemes typically starting from the
parent heterocycles.5 While the introduction of the 2-car-
a Reagents and conditions: (a) CCl3COCl, CH2Cl2, 9 h; (b)
fuming HNO3, H2SO4, Ac2O, 0 °C to rt, 24 h; (c) NaOMe, MeOH,
3 h; (d) Boc2O, 10% Pd/C, H2, MeOH, 28 h; (e) t-BuOK, H2O, THF,
rt, 1 h.
boxyl moiety is rather straightforward, the implementa-
tion of a nitrogen-containing moiety at the 4 position is
more challenging. Traditionally, nitration of the parent
heterocycles or their corresponding carboxylic acid de-
rivatives has been followed by hydrogenation and protec-
tion of the amine to afford the desired building blocks.5
This arduous sequence has been recognized as the
Achilles’ heel of these syntheses resulting in relatively
low overall yields (16% for 55a and 18% for 105b). We have
sought to explore alternative schemes to functionalize the
4 position, in particular, routes that rely on metal-
mediated amination/amidation reactions. In this paper,
we disclose our optimized protocols that afford these
useful building blocks in improved yields.
Scheme 1 shows the optimized scheme for the synthesis
of the pyrrole building block 5. The copper-catalyzed
amidation of methyl 4-bromomethylpyrrole-2-carboxylate
3 began with the synthesis of the trichloroacetyl hetero-
cycle 1 as previously reported.6 Bromination of 1 with
equimolar amounts of N-bromosuccinimide (NBS) at low
temperature gave 2 in 79-81% yield. Substitution of the
trichloroacetyl for the more stable carbomethoxy group
† University of Western Sydney.
‡ University of California.
(1) Dervan, P. B.; Edelson, B. S. Curr. Opin. Struct. Biol. 2003, 13,
284-299.
(2) Schmitz, K.; Schepers, U. Angew. Chem., Int. Ed. 2004, 43,
2472-2475.
(3) Marques, M. A.; Doss, R. M.; Urbach, A. R.; Dervan, P. B. Helv.
Chim. Acta 2002, 85, 4485-4517.
(4) For selected examples, see: Mapp, A. M.; Ansari, A. Z.; Ptashne,
M.; Dervan, P. B. Proc. Natl. Acad. Sci. U.S.A. 2000, 97, 3930-3935.
Gottesfeld, J. M.; Belitsky, J. M.; Melander, C.; Dervan, P. B.; Luger,
K. J. Mol. Biol. 2002, 321, 249-263. Arndt, H.-D.; Hauschild, K. E.;
Sullivan, D. P.; Lake, K.; Dervan, P. B.; Ansari, A. Z. J. Am. Chem.
Soc. 2003, 125, 13322-13323. Nguyen-Hackley, D. H.; Ramm, E.;
Taylor, C. M.; Joung, J. K.; Dervan, P. B.; Pabo, C. O. Biochemistry
2004, 43, 3880-3890.
(5) (a) Baird, E. E.; Dervan, P. B. J. Am. Chem. Soc. 1996, 118,
6141-6146. (b) Wurtz, N. R.; Turner, J. M.; Baird, E. E.; Dervan, P.
B. Org. Lett. 2001, 3, 1201-1203.
(6) Nishiwaki, E.; Tanaka, S.; Lee, H.; Shibuya, M. Heterocycles
1988, 27, 1945-1952.
10.1021/jo048686r CCC: $27.50 © 2004 American Chemical Society
Published on Web 10/15/2004
J. Org. Chem. 2004, 69, 8151-8153
8151

MHz, CDCl3) δ 172.8, 133.6, 124.0, 121.7, 108.8, 96.3, 38.5;
APCI-MS m/z calcd for C7H8Cl2NO [M + H - Cl]+ 191.99, found
191.98; C7H9ClNO [M + H - Cl2]+ 158.03, found 158.01.
4-Bromo-2-trichloroacetyl-1-methylpyrrole (2). To com-
pound 1 (5.0 g, 22 mmol) in CHCl3 (65 mL) at -10 °C was added
NBS (4.13 g, 23 mmol) and the reaction stirred for 2 h. The
solution was warmed to room temperature and stirred for a
further 16 h. The solution was concentrated and the residue
purified by flash chromatography (silica gel, 1:9 CH2Cl2/hexane,
Rf 0.23) yielding 2 (5.32 g, 79%) as a white solid:11 mp 105-107
with sodium methoxide followed, giving the ester 3 in
excellent yield. Reaction of 3 with tert-butyl carbamate
employing Buchwald’s catalyst system, comprised of CuI,
N,N′-dimethylethylenediamine, and K3PO4,7 produced
the Boc-protected precursor 4 in 99% yield. Final ester
hydrolysis using LiOH8 afforded the N-methylpyrrole
acid building block 5 in five steps, from N-methylpyrrole,
with an improved overall yield of 62-64%.
It is important to note that the synthetic scheme
outlined above represents the culmination of numerous
attempts to explore and optimize alternative reaction
conditions. The major difficulties we have encountered
with alternate schemes include (a) loss of selectivity in
reactions of 2 with NBS at room temperature, with both
the 5-bromo and 4,5-dibromo as the major products, (b)
unsatisfactory bromination of related N-methylpyrrole
esters resulting in low yields (20-30%), and (c) unsuc-
cessful palladium and copper catalyzed cross-coupling
reactions7,9 of 2 with other substrates, including ben-
zophenone imine, 4-methoxybenzylamine, and acetamide.
Additionally, the trichloroacetyl group was found to be
unstable under the various conditions employed.
Similar efforts for the synthesis of the imidazole amino
acid 10 utilizing the same and related cross-coupling
reactions failed. A possible reason may be the coordina-
tion of imidazole to the catalysts employed. Attempts to
displace 4-halogen-substituted N-methylimidazoles with
nitrogen-containing nucleophiles (such as N3-) were not
successful. This has led us to explore other modifications
of the existing method.5 Here, the versatility of the
trichloroacetyl group was again employed with the
synthesis of the nitro derivative 7 through initial trichlo-
roacetylation6 of N-methylimidazole and subsequent
nitration using HNO3/H2SO4. The nitro ester 8 was then
obtained through base hydrolysis of 7, and a one-pot
catalytic reduction and Boc-protection gave the desired
compound 9 in 91% yield for the two steps. Final
hydrolysis with t-BuOK in THF/H2O10 produced the
imidazole acid building block 10 in five steps, with an
improved overall yield of 28%.
1
°C; IR (KBr) 3131, 1677, 1464, 1358, 1191 cm-1; H NMR (400
MHz, CDCl3) δ 7.40 (d, 1H, J ) 1.6 Hz), 6.92 (d, 1H, J ) 1.6
Hz), 3.89 (s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 172.3, 132.8,
124.5, 122.1, 108.8, 96.1, 38.7; APCI-MS m/z calcd for C7H9BrNO
[M + H - Cl3]+ 201.98, found 201.98.
Methyl 4-Bromomethylpyrrole-2-carboxylate (3). To com-
pound 2 (2.0 g, 6.6 mmol) in dry MeOH (75 mL) was added
sodium methoxide (0.43 g, 7.9 mmol) and the mixture stirred
for 1 h. The reaction was cooled and quenched with HCl (1 M,
1.3 mL). The solvent was evaporated, H2O added, and the
mixture extracted with CH2Cl2. The organics were dried (Na2-
SO4), solvent removed, and the residue purified by flash chro-
matography (silica gel, 1:1 hexane/CH2Cl2, Rf 0.35), yielding 3
(1.34 g, 93%) as a white solid: mp 65-66 °C; IR (KBr) 3123,
1693, 1442, 1388, 1244 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.89
(d, 1H, J ) 2.0 Hz), 6.74 (d, 1H, J ) 2.0 Hz), 3.87 (s, 3H), 3.78
(s, 3H); 13C NMR (100.6 MHz, CDCl3) δ 160.8, 128.7, 122.8,
119.2, 95.0, 51.2, 36.9; GC-MS m/z calcd for C7H9BrNO2 [M +
H]+ 217.97, found 218.2.
Methyl 4-[(tert-Butoxycarbonyl)amino]-1-methylpyrrole-
2-carboxylate (4). CuI (0.020 g, 0.1 mmol, 10 mol %), K3PO4
(0.43 g, 2 mmol), and N,N′-dimethylethylenediamine (0.022 mL,
0.2 mmol, 20 mol %) in dry dioxane (5 mL) were stirred under
argon for 5 min. Compound 3 (0.22 g, 1 mmol) and tert-butyl
carbamate (0.47 g, 4 mmol) were added, and the mixture was
heated at 110 °C for 48 h. The solvent was removed and the
residue purified by flash chromatography (silica gel, gradient
1:19 MeOH/CH2Cl2, Rf 0.56) to yield 4 (0.26 g 99%) as a light
brown solid: mp 115-116 °C (lit.12 109 °C); IR (KBr) 3344, 2963,
1716, 1685, 1594 cm-1; 1H NMR [400 MHz, (CD3)2SO] δ 9.11 (s,
1H), 7.09 (s, 1H), 6.61 (s, 1H), 3.77 (s, 3H), 3.69 (s, 3H) 1.43 (s,
9H); 13C NMR [100.6 MHz, (CD3)2SO] δ 160.7,152.7, 123.1, 119.2,
118.6, 107.3, 78.5, 50.8, 36.0, 28.1; ESI-MS m/z calcd for
C12H18N2O4 [M + Na]+ 277.13, found 276.96.
4-[(tert-Butoxycarbonyl)amino]-1-methylpyrrole-2-car-
boxylic Acid (5). To compound 4 (0.05 g, 0.20 mmol) in THF/
MeOH (3:1, 4 mL) was added LiOH (1 M, 0.79 mL, 0.79 mmol)
and the mixture stirred at 60 °C for 9 h. H2O and EtOAc were
added, and the aqueous layer was acidified with HCl (1 M, 0.79
mL). The aqueous layer was extracted with EtOAc, dried (Na2-
SO4), and concentrated, yielding 5 (0.044 g, 94%) as a white solid
(1:9 MeOH/CH2Cl2, Rf 0.22): mp 160-161 °C (lit.13 151-151.5
°C); IR (KBr) 3395, 3131, 2930, 1693, 1590, 1450, 1393, 1250,
In summary, we have reported on alternative synthetic
schemes to two useful heterocyclic amino acids exten-
sively employed in the synthesis of highly selective DNA
minor groove binders.
1
1163 cm-1; H NMR [400 MHz, (CD3)2SO] δ 12.10 (s, 1H), 9.05
Experimental Section
(s, 1H), 7.04 (s, 1H), 6.56 (s, 1H), 3.76 (s, 3H), 1.42 (s, 9H); 13C
NMR [100.6 MHz, (CD3)2SO] δ 161.9; 152.7; 122.8, 119.6, 118.8,
107.4, 78.4, 36.1, 28.2; ESI-MS m/z calcd for C11H16N2O4 [M +
Na]+ 263.11, found 262.94.
2-Trichloroacetyl-1-methylpyrrole (1).6 N-Methylpyrrole
(10 g, 0.12 mol) in CH2Cl2 (40 mL) was added dropwise to
trichloroacetyl chloride (22 g, 0.12 mol) in CH2Cl2 (40 mL) over
a period of 3 h and then stirred overnight. The solvent was
removed and the residue purified by flash chromatography (silica
gel, 3:7 CH2Cl2/hexane, Rf 0.73) yielding 1 (25.3 g, 91%) as a
light yellow solid: mp 66-67 °C (lit.6 65-66 °C); IR (KBr) 3131,
1647, 1525, 1404, 1335 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.49
(dd, 1H, J1 ) 3.2 Hz, J2 ) 4.4 Hz), 6.95 (d, 1H, J ) 1.6 Hz), 6.21
(dd, 1H, J1 ) 2.4 Hz, J2 ) 4.4 Hz), 3.95 (s, 3H); 13C NMR (100.6
2-Trichloroacety-1-methylimidazole (6). N-Methylimida-
zole (10 g, 0.12 mol) in CH2Cl2 (80 mL) was added dropwise to
trichloroacetyl chloride (22 g, 0.12 mol) in CH2Cl2 (80 mL) over
a period of 2.5 h. The mixture was then stirred for 6 h and cooled
to 0 °C, and Et3N (17 mL, 0.12 mol) was added dropwise over 1
h. The solvent was evaporated and the residue purified by flash
chromatography (silica gel, 1:4 hexane/CH2Cl2, Rf 0.17) to yield
6 (21.8 g, 79%) as a light yellow solid: mp 83-84 °C (lit.6 79-
(7) Klapars, A.; Huang, X.; Buchwald, S. L. J. Am. Chem. Soc. 2002,
124, 7421-7428.
80 °C); IR (KBr) 3123, 1647, 1518, 1404, 1305 cm-1 1H NMR
;
(400 MHz, CDCl3) δ 7.29 (s, 1H), 7.13 (s, 1H), 4.01 (s, 3H); 13C
(8) Boger, D. L.; Fink, B. E.; Hedrick, M. P. J. Am. Chem. Soc. 2000,
122, 6382-6394.
(9) Klapars, A.; Antilla, J. C.; Huang, X.; Buchwald, S. L. J. Am.
Chem. Soc. 2001, 123, 7727-7729. Kwong, F. Y.; Buchwald, S. L. Org.
Lett. 2003, 5, 793-796.
(11) Slightly higher yield (81%) is obtained when the reaction is
executed on a smaller (ca. 0.5 g) scale.
(12) Bailly, C.; Pommery, N.; Houssin, R.; Henichart, J. P. J. Pharm.
Sci. 1989, 78, 910-917.
(10) Gassman, P. G.; Schenk, W. N. J. Org. Chem. 1977, 42, 918-
920.
(13) Grehn, L.; Ragnarsson, U. J. Org. Chem. 1981, 46, 3492-3497.
8152 J. Org. Chem., Vol. 69, No. 23, 2004

NMR (100.6 MHz, CDCl3) δ 172.0, 135.9, 130.4, 128.5, 94.7, 37.1;
ESI-MS m/z calcd for C6H6Cl3N2O [M + H]+ 226.95, found
226.96.
dried (Na2SO4), and the residue was purified by flash chroma-
tography (silica gel, 1:19 MeOH/CH2Cl2, Rf 0.45), yielding 9 (1.56
g, 91%) as a white solid: mp 130-132 °C; IR (KBr) 3291, 2979,
1
4-Nitro-2-trichloroacety-1-methylimidazole (7). To acetic
anhydride (38 mL) at 0 °C was added dropwise fuming HNO3
(3 mL, 0.07 mol), followed by H2SO4 (0.14 mL). Compound 6 (5
g, 0.02 mol) was added slowly, and the solution was warmed to
room temperature and stirred overnight. CHCl3 was added and
the solution washed with NaHCO3(aq) and brine. The organics
were dried (Na2SO4) and concentrated, and the residue was
purified by flash chromatography (silica gel, 1:1 EtOAc/ hexane,
Rf 0.43) yielding 7 (3.89 g, 65%) as a light yellow solid: mp 139-
140 °C (lit.6 mp 140-141 °C); IR (KBr) 3146, 2355, 1708, 1541,
1716, 1579 cm-1; H NMR [400 MHz, (CD3)2SO] δ 9.68 (s, 1H),
7.31 (s, 1H), 3.87 (s, 3H), 3.77 (s, 3H), 1.43 (s, 9H); 13C NMR
[100.6 MHz, (CD3)2SO] δ 158.8, 152.7, 138.1, 130.7, 113.8, 79.0,
51.6, 35.3, 28.0; APCI-MS m/z calcd for C11H18N3O4 [M + H]+
256.12, found 255.80.
4-[(tert-Butoxycarbonyl)amino]-1-methylimidazole-2-
carboxylic Acid (10). To potassium tert-butoxide (0.35 g, 3.13
mmol) in dry THF (6 mL) at 0 °C was added H2O (14 mL, 0.78
mmol) and the solution stirred for 5 min. Compound 9 (0.1 g,
0.39 mmol) was added and the mixture stirred at room temper-
ature for 1 h. It was then diluted with cold H2O and EtOAc, the
layers were separated, and the aqueous layer was acidified by
addition of HCl (1 M, 3.1 mL). The aqueous layer was extracted
with EtOAc, dried (Na2SO4), and concentrated, yielding 10 (0.08
g, 87%) as a white solid (1:9 MeOH/CH2Cl2, Rf 0.25): mp 200-
201 °C (lit.14 mp 201-202 °C); IR (KBr) 3389, 3230, 2979, 1716,
1343 cm-1 1H NMR (400 MHz, CDCl3) δ 7.94 (s, 1H), 4.15 (s,
;
3H); 13C NMR (100.6 MHz, CDCl3) δ 172.8, 133.6, 125.9, 94.4,
93.5, 38.3; ESI-MS m/z calcd for C6H5Cl3N3O3 [M + H]+ 271.93,
found 271.92.
Methyl 1-Methyl-4-nitroimidazole-2-carboxylate (8). To
compound 7 (3.47 g, 0.01 mol) in dry MeOH (130 mL) was added
sodium methoxide (0.83 g, 0.02 mol) and the solution stirred for
3 h. The reaction was cooled and quenched by the addition of
HCl (1 M, 13 mL). The solvent was evaporated, H2O added, and
the mixture extracted with CH2Cl2. The organics were dried
(Na2SO4), and the residue was purified by flash chromatography
(silica gel, 3:7 hexane/EtOAc, Rf 0.48) to yield 8 (1.65 g, 70%) as
a white solid: mp 157-158 °C; IR (KBr) 3435, 3138, 2956, 1731,
1556, 1487, 1305, 1114 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.85
(s, 1H), 4.09 (s, 3H), 3.93 (s, 3H); 13C NMR (100.6 MHz, CDCl3)
δ 158.5, 146.0, 134.6, 124.4, 52.9, 37.0; APCI-MS m/z calcd for
C6H8N3O4 [M + H]+ 186.04, found 185.96.
1
1624, 1571, 1358, 1160 cm-1; H NMR [400 MHz, (CD3)2SO] δ
9.63 (s, 1H), 7.25 (s, 1H), 3.86 (s, 3H), 1.42 (s, 9H); 13C NMR
[100.6 MHz, (CD3)2SO] δ 160.0, 152.8, 137.7, 131.7, 113.5, 78.9,
35.4, 28.1; ESI-MS m/z calcd for C10H15N3O4 [M + Na]+ 264.11,
found 263.93.
Acknowledgment. We thank the Australian Re-
search Council (Grant No. DP0343480 to J.A.W.) and
the National Institutes of Health (Grant No. GM69773
to Y.T.) for their generous support.
Methyl 4-[(tert-Butoxycarbonyl)amino]-1-methylimida-
zole-2-carboxylate (9). To compound 8 (1.24 g, 0.01 mol) in
dry MeOH (120 mL) was added tert-butyl dicarbonate (5.86 g,
0.03 mol) followed by 10% Pd/C (0.12 g), and the mixture was
stirred under a hydrogen atmosphere for 3 h. H2(g) was removed
and the mixture stirred for 28 h. The catalyst was filtered
(Celite) and the solvent evaporated. The residue was washed
with NaHCO3(aq) and extracted with CH2Cl2. The organics were
Supporting Information Available: 1H and 13C NMR
spectra for all compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
JO048686R
(14) Grehn, L.; Ding, L.; Ragnarsson, U. Acta Chem. Scand. 1990,
44, 67-74.
J. Org. Chem, Vol. 69, No. 23, 2004 8153