Synthesis of N -Boc-Protected Bis(2-benzimidazolylmethyl)amines

Article abstract of DOI:10.1055/s-0029-1218579

Preparation of bis(1-tert-butoxycarbonyl-2-benzimidazolylmethyl)amines from N-tert-butoxycarbonyl-protected 2-chloromethylbenzimidazole is described. The reaction with primary amines containing several functional groups afforded bis(1-tert-butoxycarbonyl-

Full text of DOI:10.1055/s-0029-1218579

LETTER
423
Synthesis of N-Boc-Protected Bis(2-benzimidazolylmethyl)amines
N
a
-Boc-Protect
a
edBis(2-be
u
nzimidazoly
l
lmethy
i
l)amine
n
s
a R. Martínez-Alanis,a Manuel López Ortiz,b Ignacio Regla,*b Ivan Castillo*a
Instituto de Química, Universidad Nacional Autónoma de México, Circuito Exterior, Ciudad Universitaria, México, D. F., 04510, México
Fax +52(55)56162217; E-mail: joseivan@unam.mx
Facultad de Estudios Superiores-Zaragoza, Universidad Nacional Autónoma de México,
Batalla del 5 de mayo esq. Fuerte de Loreto, Ejército de Oriente, México, D. F., 09230, México
Fax +52(55)56230795; E-mail: regla@unam.mx
b
Received 8 September 2009
the preparation of both tris- and bis(2-benzimidazolylme-
thyl)amines requires elevated reaction temperatures.5a
Whereas the tris(benzimidazole) compound 1 (Figure 1)
can only be further functionalized at the benzimidazole ni-
Abstract: Preparation of bis(1-tert-butoxycarbonyl-2-benzimida-
zolylmethyl)amines from N-tert-butoxycarbonyl-protected 2-chlo-
romethylbenzimidazole is described. The reaction with primary
amines containing several functional groups afforded bis(1-tert-
butoxycarbonyl-2-benzimidazolylmethyl)amines in good yields. trogen atoms, the bis(benzimidazole) compound 2 offers
Hydrogenolysis of bis(2-benzimidazolylmethyl)benzylamine, cata-
an additional reactive site at the secondary amine. This
lyzed by Pd(OH)2/C, cleaved the benzyl group, leaving the tert-
butoxycarbonyl and 2-benzimidazolylmethyl groups intact. The
tional groups to obtain novel bis(benzimidazoles) with
product of the latter reaction, bis(1-tert-butoxycarbonyl-2-benzimi-
can be exploited for the incorporation of different func-
modified biological activity, as well as for generating a se-
dazolylmethyl)amine, was thus obtained in 56% yield; the presence
ries of new chelating ligands for transition-metal chemis-
try. Discrimination of the nucleophilic sites of 2 to attain
a regioselective substitution at the central nitrogen atom
exclusively, poses a synthetic challenge that requires care-
ful analysis.
of the tert-butoxycarbonyl groups at the N-benzimidazole positions
makes it amenable to further functionalization at the central nitro-
gen atom.
Key words: chemoselectivity, benzimidazoles, protecting groups,
ligands
N
NH
Benzimidazoles constitute a class of compounds that have
attracted increasing interest in recent years due to their bi-
ological activity as antitumor,1 antiparasitic,1c,2 and anti-
helminthic agents.3 In addition, the biological activity of
benzimidazoles can be modified upon formation of metal
complexes;4 this finding has encouraged the design of
benzimidazole derivatives with the potential to act as
ligands in transition-metal chemistry. This development
of benzimidazole-based ligands has also led to the synthe-
sis of metal complexes with applications in the field of
catalysis5 and in bioinorganic chemistry where they can
act as mimics of metalloenzyme active sites.6 In this con-
text, the assembly of two or more benzimidazole units is
necessary for the preparation of chelating compounds
with at least two nitrogen donors. In catalysis, benzimida-
zole derivatives have applications in metal-catalyzed
transformations: the cycloaddition of alkynes and organic
azides (click chemistry),5a and the selective oxidation of
hydrocarbons are representative examples.5b The assem-
bly of two or more benzimidazoles is also crucial in the
field of bioinorganic chemistry because this class of com-
pounds can also be employed as ligands in biomimetic
systems in which they can emulate the active sites of his-
tidine-rich metalloenzymes.7
N
N
H
N
N
NH
HN
N
N
N
H
N
H
1
2
H
N
NH2
N
3
Figure 1 Chemical structures of benzimidazoles 1–3
The dihydrochloride of 2-aminomethylbenzimidazole (3)
was employed as a model system. It is reasonable to as-
sume that addition of one equivalent of triethylamine to
3·2HCl would result in the selective deprotonation of the
more acidic N-H proton of the benzimidazole ring; the
free base sp2-hybridized nitrogen atom would thus be
available to act as a nucleophile upon treatment with
di-tert-butyldicarbonate [(Boc)2O], resulting in a Boc-
protected benzimidazolic nitrogen atom (Scheme 1, path
a). Instead, the reaction resulted in the protection of both
the benzimidazolic and aliphatic nitrogen atoms
(Scheme 1, path b). The double substitution occurred even
in the presence of only 1.1 equivalents of triethylamine
and (Boc)2O, albeit in low yield.8 A similar behavior has
In the specific case of benzimidazoles assembled around
a central nitrogen atom, the reported synthetic method for
SYNLETT 2010, No. 3, pp 0423–0426
1
2.
0
2.
2
0
1
0
Advanced online publication: 17.12.2010
DOI: 10.1055/s-0029-1218579; Art ID: S09909ST
© Georg Thieme Verlag Stuttgart · New York

424
P. R. Martínez-Alanis et al.
LETTER
been observed in the reaction of diethyl pyrocarbonate This method allows the assembly of two benzimidazole
with histidine-containing peptides, which results in the units around a central nitrogen atom, avoiding the drastic
protection of both amino and imidazole nitrogen atoms.9 reaction conditions necessary in the condensation of o-
This regioselectivity issue has been addressed by reduc- phenylenediamine with iminodiacetonitrile or iminodi-
tive amination of the aliphatic N-atom of a benzimidazole acetic acid, to obtain compound 2. In addition, compound
derivative similar to 3.10
5 has already incorporated two Boc groups as substituents
on the benzimidazolic nitrogen positions, which would
otherwise be difficult to introduce onto compound 2 selec-
tively. As mentioned earlier, protection of 2 would likely
result in the introduction of Boc groups at both the benz-
imidazole nitrogen atoms and the secondary amine, based
on the observations described for the model compound 3
and on literature reports.9
As an alternative, we devised a method to circumvent this
regioselectivity problem of discrimination between the
benzimidazolic and aliphatic N-atoms by assembling 2-
benzimidazolylmethyl moieties previously protected with
Boc. This methodology offers the possibility of easily re-
moving the Boc group, through known procedures, after
the introduction of the desired substituents at the aliphatic
amine. The synthetic route required the initial preparation The procedure shown in Scheme 2 was adapted for use
of N-Boc-2-(chloromethyl)benzimidazole (4) by a slight with primary amines with different functional groups to
modification of the literature procedure.10 Reaction of two give a range of bis(2-benzimidazolylmethyl)amines;
equivalents of 4 with benzylamine resulted in formation the reactions were performed with 2-(amino-
of the crystalline compound bis(1-tert-butoxycarbonyl-2- methyl)thiophene, 2-(2,4-dimethylphenylthio)ethylamine
benzimidazolylmethyl)benzylamine (5) in good yield [6; prepared from (N-benzyloxycarbonyl)-2-aminoethyl
(Scheme 2).
p-toluenesulfonate11 and 2,4-dimethylbenzenethiol], and
2-(S)-aminobutanol. The corresponding compounds 7–9,
which incorporate additional heteroatoms for potential li-
gation, were obtained in good yields. In the case of 9,
which was obtained from 2-(S)-aminobutanol, the chiral
center lends itself to potential applications in asymmetric
catalysis.
t-Bu
O
O
N
N
+
NH3
O
O
t-Bu
t-Bu
Cl–
O
O
O
Deprotection of 5 to obtain the debenzylated bis(1-tert-
butoxycarbonyl-2-benzimidazolylmethyl)amine (10) was
achieved by palladium-catalyzed hydrogenolysis, which
did not affect the Boc groups. We carried out the hydro-
genolysis of 5 in the presence of a weak acid (tartaric acid)
in order to prevent coordination of the nitrogen donors to
the palladium catalyst and avoid cleaving the acid-sensi-
tive Boc groups. The reaction proceeded at a relatively
slow rate, possibly due to the steric hindrance at the N-
benzyl moiety, which arises from the proximity of the two
Boc substituents. Compound 10 was thus obtained in
crystalline form as the free base after neutralization with
a
H
N
DMF, Et3N
55%
+
N+
H
NH3
t-Bu
b
O
2 Cl–
O
N
t-Bu
+
O
N
HN
H
Cl–
O
Scheme 1 Reaction of 3·2HCl with 1.1 equivalents of Et3N and
(Boc)2O
O
t-Bu
t-Bu
O
NH2
O
O
N
N
N
N
N
MeCN, K2CO3, NaI
68%
N
2
O
O
Cl
N
t-Bu
4
5
Pd(OH)2/C, H2
EtOH, tartaric acid
56%
O
t-Bu
O
N
N
N
N
N
H
O
O
t-Bu
10
Scheme 2 Synthesis of bis(2-benzimidazolylmethyl)amine (10)
Synlett 2010, No. 3, 423–426 © Thieme Stuttgart · New York

LETTER
N-Boc-Protected Bis(2-benzimidazolylmethyl)amines
425
potassium carbonate. The 1H NMR spectrum of 10 reveals
the presence of inequivalent benzimidazole groups, as ev-
idenced by the presence of two tert-butyl Boc signals, as
well as two N-CH2-benzimidazole resonances. This be-
havior needs further investigation, however, we attribute
it to intramolecular hydrogen bonding between the amine
N-H group and the C=O moiety of a Boc group. Nonethe-
less, the identity of 10 was firmly established by combus-
tion analysis.
d = 1.48 (s, 9 H), 1.72 (s, 9 H), 4.79 (s, 2 H), 5.85 (br s, 1 H),
7.31 (m, 2 H), 7.68 (m, 1 H), 7.93 (m, 1 H). MS (EI): m/z
(%) = 347 (3) [M]+.
(9) Kalkum, M.; Przybylski, M.; Glocker, M. O. Bioconjugate
Chem. 1998, 9, 226.
(10) (a) Crawford, J. B.; Chen, G.; Gauthier, D.; Wilson, T.;
Carpenter, B.; Baird, I. R.; McEachern, E.; Kaller, A.;
Harwig, C.; Atsma, B.; Skerlj, R. T.; Bridger, G. J. Org.
Process Res. Dev. 2008, 12, 823. (b) Diispropylethylamine
was replaced by Et3N, without a significant drop in the yield.
(11) Miller, D. J.; Bashir-Uddin Surfraz, M.; Akhtar, M.; Gani,
D.; Allemann, R. K. Org. Biomol. Chem. 2004, 2, 671.
(12) Synthesis of bis(1-tert-butoxycarbonyl-2-benzimidazolyl-
methyl)amines 5–10; General procedure: To K2CO3 (7.74 g,
40 mmol), 4 (5.00 g, 18.7 mmol) and NaI (280 mg, 1.87
mmol) in MeCN (75 mL), were added the amines (9.35
mmol), and the mixture was heated to reflux for 10 h. After
filtering and washing the solid with CH2Cl2, the combined
organic layers were concentrated. Cooling to –25 °C
resulted in the formation of colorless crystals; alternatively,
purification could be achieved by column chromatography
on silica gel.
In summary, we have developed a method for the assem-
bly of Boc-protected benzimidazoles around a central ni-
trogen atom.12 Based on the examples presented, the
choice of the primary amine can result in the development
of bis(benzimidazole)amines with a variety of amine N-
functional groups. This can also be achieved via 5, which
allows the selective deprotection of the N-benzyl group to
obtain 10 with an amine N-H group available for further
functionalization.
Compound 5: 68% yield; mp 145–146 °C. 1H NMR (300
MHz, CDCl3): d = 1.61 (s, 18 H), 4.25 (s, 2 H), 4.63 (s, 4 H),
7.16 (m, 3 H), 7.28 (m, 6 H), 7.71 (m, 2 H), 7.84 (m, 2 H).
13C NMR (75 MHz, CDCl3): d = 27.81, 52.23, 56.80, 84.86,
114.42, 119.67, 123.60, 124.05, 126.46, 127.71, 128.64,
132.87, 139.10, 142.04, 148.51, 153.61. IR (KBr): 3025,
2975, 2923, 2859, 1743, 1542, 1453, 1365, 1344, 1258,
1209, 1155, 1118, 1090, 976, 939, 887, 840, 767, 741, 699,
571, 478 cm–1. Anal. Calcd for C33H40N5O5.5 (5·1.5H2O): C,
66.65; H, 6.78; N, 11.78. Found: C, 66.27; H, 6.31; N, 11.53.
Compound 7: 87% yield; mp 150–151 °C. 1H NMR (300
MHz, CDCl3): d = 1.64 (s, 18 H), 4.45 (s, 2 H), 4.63 (s, 4 H),
6.84 (m, 2 H), 7.14 (dd, J = 1.8, 4.6 Hz, 1 H), 7.30 (m, 4 H),
7.70 (m, 2 H), 7.87 (m, 2 H). 13C NMR (75 MHz, CDCl3):
d = 28.02, 51.36, 51.90, 85.12, 114.66, 119.90, 123.81,
124.25, 124.69, 125.99, 126.22, 133.05, 142.17, 142.84,
148.68, 153.63. IR (KBr): 3060, 2977, 2925, 2855, 1745,
1608, 1542, 1479, 1452, 1364, 1343, 1258, 1209, 1157,
1118, 1090, 971, 939, 887, 842, 767, 741, 692 cm–1. Anal.
Calcd for C31H35N5O4S (7·1.5H2O): C, 61.98; H, 6.38; N,
11.66. Found: C, 61.79; H, 5.89; N, 11.41.
Compound 8 was generated from (N-benzyloxycarbonyl)-2-
aminoethyl (2,4-dimethyl)benzenethioether hydrobromide
(6·HBr), which was prepared from 2,4-dimethylbenzene-
thiol and 2-tosyl-benzylformylaminoethane, and treatment
with HBr/AcOH. 6·HBr: mp 105–108 °C. 1H NMR (300
MHz, CDCl3): d = 2.24 (s, 3 H), 2.36 (s, 3 H), 3.22 (m, 4 H),
6.9 (d, J = 1.8 Hz, 1 H), 6.98 (s, 1 H), 7.30 (d, J = 1.8 Hz,
1 H), 8.04 (br s, 3 H). 13C NMR (75 MHz, CDCl3):
d = 20.74, 21.07, 30.47, 39.09, 127.64, 128.34, 131.60,
137.65, 139.75. IR (KBr): 3015, 2918, 2817, 2624, 2430,
1866, 1580, 1500, 1478, 1435, 1375, 1260, 1130, 1054,
1006, 930, 878, 812, 781, 745, 617 cm–1.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synlett.
Acknowledgment
We thank Dr. E. Juaristi and E. Jiménez, Cinvestav-IPN, for com-
bustion analysis of 10, R. Patiño, N. Zavala, and M. A. Peña for
technical assistance, and DGAPA for financial support (IN211509).
P.R.M. thanks Conacyt (Beca 27252), and I.R. the Instituto de Quí-
mica for the ‘Cátedra Especial Jesús Romo Armería’.
References and Notes
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2006, 14, 6106. (b) Boiani, M.; González, M. Mini-Rev.
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Mulia, L.; Cedillo-Rivera, R.; Tapia, A.; Vilpo, L.; Vilpo, J.;
Kazimierczuk, Z. Eur. J. Med. Chem. 2002, 37, 973.
(2) Soeiro, M. N. C.; de Souza, E. M.; Boykin, D. W. Expert
Opin. Ther. Pat. 2007, 17, 927.
(3) (a) Bhattacharya, S.; Chaudhuri, P. Curr. Med. Chem. 2008,
15, 1762. (b) Jasmer, D. P.; Yao, C.; Rehman, A.; Johnson,
S. Mol. Biochem. Parasitol. 2000, 105, 81.
(4) (a) Gumus, F.; Algul, O.; Eren, G.; Eroglu, H.; Diril, N.;
Gur, S.; Ozkul, A. Eur. J. Med. Chem. 2003, 38, 473.
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J. Med. Chem. 2005, 40, 135. (c) Saczewski, F.;
Dziemidowicz-Borys, E.; Bednarski, P. J.; Grünert, R.;
Gdaniec, M.; Tabin, P. J. Inorg. Biochem. 2006, 100, 1389.
(5) (a) Rodionov, V. O.; Presolski, S. I.; Gardinier, S.; Lim,
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G. P. Inorg. Chem. 2003, 42, 7799.
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2004, 248, 147. (b) Tehlan, S.; Hundal, M. S.; Mathur, P.
Inorg. Chem. 2004, 43, 6589.
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2004, 104, 1013.
(8) 3·2HCl (220 mg, 1.00 mmol), Et3N (111 mg, 1.10 mmol),
and (Boc)2O (240 mg, 1.10 mmol) in DMF (10 mL) were
stirred at 40 °C for 4 h to give crystals upon cooling to 4 °C
(212 mg, 55%). tert-Butyl 2-[(tert-butoxycarbonylamino)-
methyl]-1H-benzo[d]imidazole-1-carboxylate: 1H NMR:
Compound 8: 57% yield; 1H NMR (300 MHz, CDCl3):
d = 1.65 (s, 18 H), 2.18 (s, 3 H), 2.21 (s, 3 H), 3.09 (br t,
2 H), 3.30 (br t, 2 H), 4.65 (s, 4 H), 6.69 (d, J = 7.8 Hz, 1 H),
6.82 (s, 1 H), 7.08 (d, J = 7.8 Hz, 1 H), 7.30 (m, 4 H), 7.68
(m, 2 H), 7.87 (m, 2 H). 13C NMR (75 MHz, CDCl3):
d = 20.34, 20.92, 28.20, 31.34, 53.08, 53.31, 85.40, 114.87,
120.05, 124.00, 124.51, 127.09, 128.08, 130.93, 132.00,
133.19, 135.08, 137.24, 142.24, 148.83, 153.62. IR (KBr):
3058, 2978, 2930, 2868, 1746, 1607, 1541, 1478, 1452,
1348, 1296, 1259, 1209, 1154, 1118, 1088, 1059, 973, 939,
881, 842, 766, 744 cm–1. HRMS-FAB+: m/z calcd for
C36H44N5O4S [M + H]+: 642.3114; found: 642.3121.
Synlett 2010, No. 3, 423–426 © Thieme Stuttgart · New York

426
P. R. Martínez-Alanis et al.
LETTER
mg, 2.40 mmol), the product was dissolved in CH2Cl2,
Compound 9: 68% yield; mp 130–133 °C. 1H NMR (300
MHz, CDCl3): d = 0.93 (t, J = 1.8, 7.3 Hz, 3 H), 1.02 (m,
2 H), 1.68 (s, 18 H), 3.18 (m, 1 H), 3.41 (t, J = 9.8 Hz, 1 H),
3.62 (m, 1 H), 4.61 (s, 4 H), 7.18 (m, 4 H), 7.53 (m, 2 H),
7.71 (m, 2 H). 13C NMR (75 MHz, CDCl3): d = 11.77, 21.50,
28.19, 50.57, 63.40, 67.23, 85.49, 114.74, 119.60, 123.86,
124.35, 133.12, 141.63, 148.86, 155.86. IR (KBr): 3357,
2971, 2934, 2872, 1741, 1607, 1534, 1345, 1294, 1260,
1155, 1119, 1090, 845, 769, 746, 561 cm–1. Anal. Calcd for
C30H39N5O5: C, 65.55; H, 7.15; N, 12.74. Found: C, 65.56;
H, 7.12; N, 12.40. [a]D20 –33.6 (c 10 mg/mL, CH2Cl2).
Compound 10: Compound 5 (2.60 g, 4.60 mmol), 20%
Pd(OH)2/C (400 mg, 9.35 mmol), and tartaric acid (361 mg,
2.40 mmol) in EtOH (120 mL), were stirred under 60 lb/in2
H2 at 45 °C for 18 h. After neutralization with K2CO3 (330
filtered through Celite, dried with Na2SO4, and concentrated.
Purification by column chromatography afforded 10: 56%
yield (1.22 g); mp 161–162 °C. 1H NMR (300 MHz, CDCl3):
d = 1.20 (s, 9 H), 1.73 (s, 9 H), 4.82 (s, 2 H), 5.13 (s, 2 H),
7.23 (m, 2 H), 7.40 (m, 2 H), 7.57 (br m, 1 H), 7.72 (br m,
1 H), 7.82 (m, 1 H), 7.95 (m, 1 H). 13C NMR (75 MHz,
CDCl3): d = 27.94, 28.05, 49.92, 50.89, 81.32, 110.69,
114.96, 115.16, 118.93, 119.23, 121.40, 122.01, 124.62,
124.89, 125.07, 133.09, 133.87, 140.88, 143.73, 153.97,
154.33. IR (KBr): 3051, 2979, 2868, 2792, 2696, 1748,
1697, 1621, 1547, 1454, 1418, 1393, 1363, 1323, 1259,
1209, 1153, 1118, 1092, 1014, 947, 890, 835, 751, 642 cm–1.
Anal. Calcd for C33H40N5O5.5: C, 65.39; H, 6.54; N, 14.66.
Found: C, 65.53; H, 6.69; N, 14.73.
Synlett 2010, No. 3, 423–426 © Thieme Stuttgart · New York

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