Lithium Hexamethyldisilazane Transformation of Transiently Protected 4-Aza/Benzimidazole Nitriles to Amidines and their Dimethyl Sulfoxide Mediated Imidazole Ring Formation

Article abstract of DOI:10.1021/acs.orglett.6b02359

Trimethylsilyl-transient protection successfully allowed the use of lithium hexamethyldisilazane to prepare benzimidazole (BI) and 4-azabenzimidazole (azaBI) amidines from nitriles in 58-88% yields. This strategy offers a much better choice to prepare BI/azaBI amidines than the lengthy, low-yielding Pinner reaction. Synthesis of aza/benzimidazole rings from aromatic diamines and aldehydes was affected in dimethyl sulfoxide in 10-15 min, while known procedures require long time and purification. These methods are important for the BI/azaBI-based drug industry and for developing specific DNA binders for expanded therapeutic applications.

Full text of DOI:10.1021/acs.orglett.6b02359

Letter
pubs.acs.org/OrgLett
Lithium Hexamethyldisilazane Transformation of Transiently
Protected 4‑Aza/Benzimidazole Nitriles to Amidines and their
Dimethyl Sulfoxide Mediated Imidazole Ring Formation
Reham A. I. Abou-Elkhair,*,†,‡ Abdalla E. A. Hassan,‡ David W. Boykin,*,† and W. David Wilson†
†Department of Chemistry, Georgia State University, Atlanta, Georgia 30303, United States
‡Applied Nucleic Acids Research Center & Chemistry Department, Faculty of Sciences, Zagazig University, Zagazig 44519, Egypt
S
* Supporting Information
ABSTRACT: Trimethylsilyl-transient protection successfully
allowed the use of lithium hexamethyldisilazane to prepare
benzimidazole (BI) and 4-azabenzimidazole (azaBI) amidines
from nitriles in 58−88% yields. This strategy offers a much
better choice to prepare BI/azaBI amidines than the lengthy,
low-yielding Pinner reaction. Synthesis of aza/benzimidazole
rings from aromatic diamines and aldehydes was affected in
dimethyl sulfoxide in 10−15 min, while known procedures
require long time and purification. These methods are
important for the BI/azaBI-based drug industry and for developing specific DNA binders for expanded therapeutic applications.
enzimidazole (BI) constitutes an important scaffold found
specific sequences augments a therapeutic strategy of
controlling gene expression as a venue for treating many
intractable diseases.19,20 DNA minor groove binders, typically,
possess positively charged moieties for stronger interaction with
the DNA backbone. Among known positively charged groups,
amidines are appealing for their excellent cellular and nuclear
uptake.12,21 Available methods to prepare amidino BI/azaBI
and also to construct substituted BI/azaBI rings, in general,
suffer from long reaction time and low efficiency.
B
in over a dozen approved pharmaceuticals.1,2 Additional BI
derivatives show potent antiplasmodial,3 antiinflammatory,4
antiviral,5 and anticancer activities.6 Derivatives of the BI
analogue 4-azabenzimidazole (azaBI) have recently been
studied in animal models and identified as potent antitumor,
anti-inflammatory,7 and antidiabetic agents8 (Figure 1).
Amidines are commonly prepared from nitriles by three
methods: the Pinner reaction,22 amidoxime method,23 and
nucleophilic addition of lithium hexamethyldisilazane24
(LHMDS). The latter approach is the most convenient,
because it takes a single step to give the silylated amidines,
which provides amidine salts upon HCl workup. It was also
adapted to prepare N-substituted amidines25 related to earlier
derivatives.26 However, for BI and azaBI systems, LHMDS
deprotonates the ring NH, preventing the desired reaction due
to a delocalized negative charge on the nitrile. Thus, amidines
of such systems are usually prepared by one of the other two
methods.27,28 The amidoxime method involves three steps, in
which the nitrile is converted to the amidoxime, followed by
acetylation to O-acetoxyamidoxime, and then hydrogenolysis to
give the amidine. The drawbacks of this method are not only
the multistep procedure but also the frequently sparingly
soluble intermediates, leaving the Pinner method, by default,
more popular. The Pinner reaction involves two steps: the
formation of imidate ester by the action of anhyd HCl-saturated
ethanol and conversion to the amidine by ammonia. Low
Figure 1. Representative, biologically active BI/azaBI structures.
Structures containing the BI nucleus can also be used as
light-up adenine thymine base pair (AT) specific DNA binders9
and fluorescent probes in biological systems with potential for
developing new biomarkers.10,11 Furthermore, rational design
of azaBI-based DNA minor groove binders led to morphing
traditional BI recognition of DNA from AT specific12−15 to
guanine (G)-containing sequence specific (Figure 1) by
introduction of the aza group.16−18 This represents a key
milestone showing that small molecules can be structured to
recognize any given sequence on DNA. Targeting DNA at
Received: August 7, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02359
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Letter
solubility of BI/azaBI molecules leads to long reaction times
with the Pinner method, where reactions requiring 3−10 days
for each step are commonly encountered.29−32 More problem-
atic is that imidate esters readily hydrolyze to amides,22 which is
difficult to avoid during their isolation to remove excess HCl.
These facts result in poor yields and failure of the reaction in
some cases.
Herein, we report a novel strategy that allows using LHMDS
with BI/azaBI nitriles to make amidines via transient protection
of BI/azaBI ring NH in a one-pot procedure. Given the
significance of BI/azaBI structure in industry and as biologically
active agents, we also present optimized conditions and suggest
a mechanism for a facile formation of BI/azaBI rings from
aldehydes and diamines in DMSO.
one-pot LHMDS method is much more efficient in terms of the
yield and reaction time.
DMSO-Mediated Cyclization
As mentioned above, we desired to optimize reaction
conditions for efficient construction of substituted BI/azaBI
rings. There are numerous conditions starting from aromatic
aldehydes and o-phenylenediamine or 2,3-diaminopyridine to
make the BI and azaBI, respectively, through an oxidative
cyclization. Indeed, a 2012 review by Panda et al. listed 118
different conditions for this synthesis.39 The first step in this
cyclization is the formation of the imine, followed by the cyclic
aminal, which is then oxidized to the imidazole ring. We
examined the most common conditions to make 1a. Reaction
40
in DMF in the presence of Na2S2O5 or NaHSO3 at 120 or
Transient Protection Strategy
165 °C took 48 h and produced side products which mandated
lengthy purification. A recent method stirring the reactants in
hot DMF/H2O (9:1)41 gave incomplete reaction.
The trimethylsilyl group (TMS) has extensively been used in
nucleoside chemistry for the silyl Hilbert−Johnson synthesis33
and for transient protection of 3′-OH groups.34 We employed
N,O-bis(trimethylsilyl)acetamide (BSA) as a mild and efficient
reagent35 to transiently protect BI and azaBI ring NH groups
with TMS. Thus, suspensions of the azaBI nitrile derivatives
1a−c in THF were treated with BSA for 0.5 h at rt (Scheme 1).
We speculated that catalyzing the oxidation would facilitate
the cyclization. Using p-benzoquinone as an oxidant,39
scandium triflate42 or ferric chloride43 as a recyclable oxidant
did not improve reaction time or yield of 1a. Although DMSO
is a known oxidant,44 it does not appear to have been explored
in this type of synthesis. Thus, we aimed to investigate the
effect of DMSO in comparison to DMF for the synthesis of 1a
(entry1, Table 1). Performing the reaction in DMSO under the
Scheme 1. One-Pot Synthesis of Simple azaBI Amidines
Table 1. Influence of Solvent on Cyclization of 1a at 165 °C
entry
solvent
catalyst
atmosphere
time (h)
yield (%)
1
2
3
4
DMF
Na2S2O5
Na2S2O5
none
air
48
56
97
0
DMSO
DMSO
DMSO
air
0.25
0.25−1
0.25
The silylation was visually indicated by the homogeneity of the
mixture within 5−10 min. Subsequent addition of excess
LHMDS led to the consumption of the silylated BI/azaBI
nitrile intermediates in 4−6 h. On the other hand, our initial
attempts to perform the reaction on Boc-protected 1a resulted
in deprotonation of the 5-methyl group as indicated by the
maroon color, cleavage of the Boc group, and failure of the
reaction. Thus, it is clear that the methyl on TMS-protected 1a
is stable. It is also worth noting that TMS intermediates
enabled highly concentrated reaction solutions, leading to
shorter reaction time. In contrast, the reaction of nitriles of
Boc-protected indoles, as a suspension in THF, with LHMDS
required up to 3 days.27 This demonstrates that our strategy is
successful and efficient.
air
Na2S2O5
argon
97
same conditions, surprisingly, resulted in a complete reaction in
only 15 min (entry 2). Most importantly, the product was easily
recovered by adding water and filtering the resulting precipitate,
1
where no further purification was required as indicated by H
NMR. The cyclization of more derivatives (1b−f) under the
same conditions was finished in 10−15 min, giving excellent
yields of 92−99% (Scheme 2).
Scheme 2. Efficient Cyclization of BI and azaBI Rings
Quenching the reaction with enough HCl to cause
desilylation normally produces large amounts of NH4Cl due
to reaction with excess LHMDS. To avoid this, we first
quenched with a stoichiometric amount of an acid to convert
LHMDS to hexamethyldisilazane (HMDS), which was
removed by evaporation. EtOH−HCl was then added to give
the amidine salts and remove the TMS transient protection.
The salts were precipitated by ether and mixed with water at
pH > 9 to give the free bases and to remove inorganic salts.
Conversion to the HCl salts and precipitation again gave 2a−c.
The resulting amidines were obtained in high yields (85−88%,
Scheme 1) and were pure as judged by NMR and elemental
analyses. This is highly remarkable because amidines prepared
by other methods often require purification by crystallization36
and chromatography on preparative HPLC,37,38 normal,36 or
C18 reversed-phase38 silica gel.
In order to evaluate the role of DMSO, we ran the reaction in
the absence of Na2S2O5 and air (entries 3 and 4). The results
indicated that both DMSO and Na2S2O5 are crucial. The
reactants were freely soluble in both DMF and DMSO; hence,
the role of DMSO was beyond solvation.45 Thus, we propose
the mechanism shown in Scheme 3, suggesting that DMSO
reacts with bisulfite to form an activated intermediate that takes
part in the oxidation. This hypothesis is supported by related
formation of an activated DMSO in the Swern, Moffatt−
Pfitzner, and Parikh−Doering oxidations of alcohols.44,46
We made 2a by the amidoxime method in a total yield of
21% (Scheme S1, Supporting Information), showing that the
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DOI: 10.1021/acs.orglett.6b02359
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Scheme 3. Plausible Mechanism for DMSO Reaction
Scheme 6. Synthesis of Diamidino-azaBI-Carrying Ether and
Benzyl Ether Linkages
Application on More Complex Molecules
We tested our transient protection strategy for amidine
synthesis on more complex BI/azaBI structures of six different
amidines, which were designed as minor groove binders for
specific recognition of DNA sequences. The synthesis of amide-
containing mono- and diamidino derivatives 7−9 is shown in
Scheme 4. Compound 1d was hydrolyzed to give acid 3, which
nitro derivative 10, which was reduced to the diamine and
immediately used in the DMSO-mediated cyclization described
above to give mononitrile 11 (Scheme 5). The dinitrile
intermediates 15 and 16 (Scheme 6) were prepared in a similar
fashion. The one-pot amidine synthesis gave 12, 17, and 18
(Schemes 5 and 6). All of the nitrile intermediates of Schemes
4−6 were highly soluble upon TMS protection. The cyclization
reactions for 11, 15, and 16 were again finished in 15 min, but
crystallization was required to afford pure azaBI products in
yields of 61−65%.
Scheme 4. Synthesis of Amidino-BI/azaBI-Carrying Amides
In conclusion, transient protection with TMS using BSA is a
convenient and efficient strategy, which allowed the use of
LHMDS to make BI and azaBI amidines from nitriles in a one-
pot procedure. This strategy is advantageous in two ways: (1) it
renders the nitrile intermediates highly soluble in THF leading
to shorter reaction times, (2) it results in pure products,
avoiding the need for extensive purification. This method is
applicable on amide-containing nitriles and is a much needed
alternative for the Pinner reaction. The amidines prepared by
our new strategy were obtained in high yields of up to 88%.
The transient protection should work in general where active
OH/NH protons obstruct the LHMDS reaction,35 and the
strategy is applicable for a wide range of cases where strong
bases are used or increased solubility is needed to enhance the
kinetics of a reaction.
The synthesis of the BI and azaBI imidazole rings from the
aldehyde and diamine in the presence of metabisulfite has been
optimized by using DMSO as a solvent. This condition led to
significantly shorter reaction time than known conditions,
where reactions were finished in only 10−15 min. The products
were highly pure in most cases. Activated DMSO oxidation,
presumably, plays an essential role in facilitating the imidazole
ring formation.
was coupled with both 4-aminobenzamide and 4-amino-
benzonitrile to give the azaBI mononitrile derivative containing
two amide groups (4) and the dinitrile with one amide (6),
respectively. Similarly, 1e was reacted to give the BI
mononitrile derivative (5) with one amide group. While
transiently protecting 4−6 for the one-pot preparation of
amidines 7−9, BSA was also expected to silylate the amide
groups.35,47 Hence, a molar ratio of BSA was used to fully
silylate all of the NHs. The amidines 7−9 were obtained in
good yields (Scheme 4) and high purity.
Schemes 5 and 6 represent the preparation of the
monoamidine 11 and the symmetric diamidines 17 and 18.
4-(Hydroxymethyl)benzamide48 was coupled with 2-amino-6-
chloro-3-nitropyridine in the presence of t-BuOK49 to form the
These methods present significant advances, important for
the facile synthesis of BI/azaBI derivatives industrially, for new
drug synthesis and for the design of ligands with specific
binding and recognition of DNA bases.
Scheme 5. Synthesis of Amidino-azaBI-Carrying Benzyl
Ether and Amide
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02359.
1
Experimental procedures, characterization, and H and
13C NMR spectra (PDF)
C
DOI: 10.1021/acs.orglett.6b02359
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Letter
(22) Dox, A. W.; Whitmore, F. C. Acetamidine Hydrochloride. In
Organic Syntheses, 2nd ed.; Blatt, A. H., Ed.; John Wiley and Sons: New
York, 1941; Vol. 1, p 5.
AUTHOR INFORMATION
■
Corresponding Authors
(23) Judkins, B. D.; Allen, D. G.; Cook, T. A.; Evans, B.; Sardharwala,
T. E. Synth. Commun. 1996, 26, 4351.
(24) Thurkauf, A.; Hutchison, A.; Peterson, J.; Cornfield, L.; Meade,
R.; Huston, K.; Harris, K.; Ross, P. C.; Gerber, K.; Ramabhadran, T. V.
J. Med. Chem. 1995, 38, 2251.
*E-mail: rabouelkhair1@gsu.edu, riham31@yahoo.com.
*E-mail: dboykin@gsu.edu.
Notes
The authors declare no competing financial interest.
(25) Khalifa, M. M.; Bodner, M. J.; Berglund, J. A.; Haley, M. M.
Tetrahedron Lett. 2015, 56, 4109.
ACKNOWLEDGMENTS
(26) Zhang, Y.; DeKorver, K. A.; Lohse, A. G.; Zhang, Y.-S.; Huang,
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■
We thank Dr. Moses Lee of Georgia State University for advice
on the synthesis of methyl 6-amino-5-nitropicolinate. This work
was supported in the United States by the National Institutes of
Health [GM111749 to W.D.W and D.W.B].
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