Reaction of quinones and guanidine derivatives: Simple access to bis-2-aminobenzimidazole moiety of benzosceptrin and other benzazole motifs

Article abstract of DOI:10.1021/ol403672p

A new strategy for the synthesis of 2-aminobenzimidazol-6-ols via a reaction of quinones with guanidine derivatives is reported. Sequential application of this methodology provided a simple access to the first benzosceptrin analogue bearing a bis-2-aminoimidazole moiety. A concomitant addition of two guanidines to the naphtho[1′,2′:4,5]imidazo[1,2-a] pyrimidine-5,6-dione, which includes the redox neutral debenzylation and guanidine-assisted cleavage of the 2-aminopyrimidine part resulted in the synthesis of the free challenging contiguous bis-2-aminoimidazole moiety of benzosceprins in one step.

Full text of DOI:10.1021/ol403672p

Letter
pubs.acs.org/OrgLett
Reaction of Quinones and Guanidine Derivatives: Simple Access to
Bis-2-aminobenzimidazole Moiety of Benzosceptrin and Other
Benzazole Motifs
Minh Quan Tran, Ludmila Ermolenko, Pascal Retailleau, Thanh Binh Nguyen,* and Ali Al-Mourabit*
Centre de Recherche de Gif-sur-Yvette, Institut de Chimie des Substances Naturelles, CNRS, 91198 Gif-sur-Yvette Cedex, France.
S
* Supporting Information
ABSTRACT: A new strategy for the synthesis of 2-amino-
benzimidazol-6-ols via a reaction of quinones with guanidine
derivatives is reported. Sequential application of this method-
ology provided a simple access to the first benzosceptrin
analogue bearing a bis-2-aminoimidazole moiety. A concom-
itant addition of two guanidines to the naphtho[1′,2′:4,5]-
imidazo[1,2-a]pyrimidine-5,6-dione, which includes the redox
neutral debenzylation and guanidine-assisted cleavage of the 2-
aminopyrimidine part resulted in the synthesis of the free challenging contiguous bis-2-aminoimidazole moiety of benzosceprins
in one step.
enzimidazoles are one of the most important classes of
heterocycles for drug and material development purposes.1
Particularly intriguing is the challenging structure of the marine
alkaloids benzosceptrins A and B (Scheme 1), a subgroup of
diseases or conditions such as asthma, osteoarthritis,
rheumatoid arthritis, acute or chronic pain, and neuro-
degenerative diseases.6
B
In this context, we were eager to initiate a synthetic project of
analogues of benzosceptrins and their biological activities. For
this purpose and in view of the pharmacological relevance of
the structures exemplified above, a simple and efficient
approach to 2-aminobenzimidazoles is obviously of consid-
erable importance in medicinal chemistry. The common
methods for the synthesis of 2-aminobenzimidazoles are
based on the condensation of o-phenylenediamines with
cyanogen bromide7 and related compounds,8 with isonitriles
under oxidizing conditions,9 or using copper-catalyzed
guanidination of 1,2-dihalobenzenes,10 amination of 2-unsub-
stituted- or 2-halo-benzimidazoles,11 cyclization of arylguani-
dines,12 (2-aminophenyl)thioureas,13 N-cyano-N′-arylhydra-
zines,14 and propargylguanidine cyclization.15
Scheme 1. Benzosceptrins and Other Bioactive 2-
Aminobenzimidazoles with Possible Approach from
Quinone and Guanidine
Nevertheless, such methods suffer from difficulties in the
preparation of readily oxidized o-phenylenediamines, the
toxicity of cyanogen bromide, and the disagreeable smell of
isocyanide.16
On several occasions, we have used oxidative addition of
substituted guanidines including 2-aminopyrimidine as versatile
bis-nucleophilic building blocks with olefins as in the synthesis
of different target 2-aminoimidazole systems.17 Generally, the
addition−cyclization of 1,3-bis-nucleophiles such as enamines
(Nenitzescu indole synthesis),18 thioureas,19 2-aminothiazoles,
2-aminooxazoles and related 2-amino aza heterocycles,20 and 2-
aminopyridine21 to benzoquinones is known to provide a
benzazole bearing a hydroxy group in the benzo ring (possibly
useful for further functionalization). On the basis of
the pyrrole-2-aminoimidazole family that we have isolated from
the sponges Agelas cf. mauritiana and Phakellia sp.2
Interestingly, the benzimidazole substructure exists in numer-
ous bioactive molecules such as a as inhibitors of VEGFR-2 and
TIE-2 kinase receptors, both of which are implicated in
angiogenesis,3 simple benzimidazole b as inhibitors of
urokinase,4 6-aryl/heteroalkyloxy benzimidazoles c as c-Met
inhibitors,5 and tricyclic d as inhibitors of microsomal
prostaglandin E synthase-1 (mPGES-1) and therefore useful
in the treatment of pain and/or inflammation from a variety of
Received: December 18, 2013
© XXXX American Chemical Society
A
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Organic Letters
Letter
a
retrosynthetic disconnections for compounds presented in
Scheme 1, we reasoned that the same reaction between a
quinone and a guanidine derivative would constitute a
straightforward approach to the desired 2-aminobenzimidazol-
6-ols. Surprisingly, such reactions are only known for
benzoquinone itself with 2′-deoxyguanosine as a guanidine
analogue in low yields.22
We report herein our studies on the reaction between
quinones with guanidine derivatives and their applications in
the synthesis of several interesting 2-aminobenzimidazole
systems.
To test our idea, we first examined the reaction of p-
benzoquinone 1 with guanidine itself as free base or as
carbonate salt at room temperature or lower in different
solvents ranging from aprotic (DMF, DMSO, Et2O) to protic
(MeOH, H2O) (Scheme 2).
Table 1. Reaction of Quinone 1a with Arylguanidines 2
b
entry
arylguanidine 2
Ar
3, yield (%)
1
2
3
4
5
6
7
8
2a
2b
2c
2d
2e
2f
C6H5
3a, 66
3b, 61
3c, 73
3d, 71
3e, 60
3f, 62
3g, 58
3h, 62
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-MeC6H4
3-MeC6H4
3-MeOC6H4
3,5-Me2C6H3
2g
2h
a
Reaction conditions: 1 (2.5 mmol), 2 (2 mmol) in CH2Cl2 (4 mL), 0
b
Scheme 2. Reaction of Quinone 1a with Guanidines
°C to rt then 16 h at rt. Isolated yield.
Table 2. Reaction of Quinone 1 with N,N′-Diarylguanidines
a
4
b
Unfortunately, contrary to our expectations, under these
conditions, while guanidine remained unchanged, p-benzoqui-
none is transformed into an intractable mixture possibly due to
strong base-promoted polymerization. Although unsubstituted
guanidine itself is more nucleophilic than most ordinary
amines,23 this highly basic compound is capable of deprotonat-
ing water and other hydroxylic compounds (for example, the
presumably formed product b) to yield a strongly resonance-
stabilized and non-nucleophilic guanidinium cation and the
corresponding oxygenated anion. The latter species, due to its
sufficient basicity, can trigger a chain reaction of polymerization
of p-benzoquinone 1a. To overcome this problem, other
guanidine derivatives with lower basicity should be used. While
acetylguanidine and Boc-guanidine were shown to be
unreactive in dichloromethane or toluene, they catalyzed the
polymerization of the benzoquinone in methanol.
entry
diarylguanidine 4
Ar
5, yield (%)
1
2
3
4
5
6
7
8
4a
4b
4c
4d
4e
4f
C6H5
5a, 93
5b, 66
5c, 95
5d, 82
5e, 78
5f, 81
5g, 79
5h, 85
4-MeC6H4
4-MeOC6H4
4-ClC6H4
2-MeC6H4
3-MeC6H4
3-MeOC6H4
3,5-Me2C6H3
4g
4h
a
Reaction conditions: 1 (2.5 mmol), 2 (2 mmol) in CH2Cl2 (4 mL), 0
b
°C to rt then 16 h at rt. Isolated yield.
out from the reaction mixture and could be isolated by simple
filtration.
Initial mechanistic consideration suggested that various
regioisomers of 3 and 5 in which the aryl groups located
differently in three nitrogen atoms might be envisioned. This
point was clarified unambiguously by X-ray crystallography
(Figure 1) that confirmed that the formed 2-aminobenzimida-
zoles have structures 3 and 5.
In time, we found that the reaction of phenylguanidine 2a
with benzoquinone smoothly afforded 2-aminobenzimidazole
3a as a single regioisomer in good yield (Table 1, entry 1). The
reaction of p-benzoquinone 1a with various arylguanidines 2
was next investigated under the optimized conditions to yield 1-
aryl-2-amino-6-hydroxybenzimidazoles 3. The effects of sub-
stituent (methyl, methoxy, chloro) of arylguanidines 2 were
then investigated. All tested arylguanidines 2 could react with p-
benzoquinone 1a and gave similar results, indicating that the
substituent on the aromatic ring had little effects in this
1
reaction. Careful analysis by H NMR of the reaction mixture
indicated that the primary adduct 3′ had been produced and
was next dehydrated into 3 (see the Supporting Information).
To further broaden the scope of this reaction, we next
extended the method to N,N′-diarylguanidines 4. Gratifyingly,
under similar conditions, this reaction worked efficiently and
provided the dehydrated adduct 5 as a single regioisomer.
Compared to the previous case (Table 1), the polymerization
of p-benzoquinone 1a in the present case (Table 2) is limited,
possibly because 4 is less basic than 2, thus resulting in better
yields of 5. In some trials, benzimidazole products 5 crystallized
Figure 1. X-ray structure of 3d and 5a.
B
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Organic Letters
Letter
Finally, the feasibility of the reaction was also tested using 2-
aminopyrimidine 6 as a weakly basic guanidine derivative
(Scheme 3). In this case, the reaction with benzoquinone 1a
Scheme 5. Approach to Benzosceptrin Analogue 11 from 9
Scheme 3. Fused Benzimidazole 7 from Quinone 1 and 2-
Aminopyrimidine 6. Deprotection of 7 with N2H4
and naphthoquinone 1b required the presence of a strong acid
(HCl) and gave good yields of fused 2-aminobenzimidazoles 7.
The regiochemistry of 7 was secured from a NOESY analysis.
Deprotection17b,24 of 2-aminobenzimidazole 7a,c was effected
efficiently by heating with hydrazine hydrate and afforded
quantitatively the desired products 8a,c.
We next turned our attention to the application of our
quinone−guanidine methodology to a 2-fold reaction to
provide the bis-2-aminoimidazole core of benzosceptrins. It is
important to note that even if the total synthesis of
benzosceptrins skeleton was not achieved, the Molinski and
Romo groups described de novo synthesis of benzosceptrin C
through the dimerization of oroidin using cell-free enzyme
preparation.25
nated naphthalene 11 as a result of a series of reactions where
the reaction order is arbitrarily proposed (Scheme 5).
In fact, the addition occurred probably stepwise starting with
the introduction (step 1) of the benzylguanidine moiety by an
addition cyclization (9 → A) giving the first adduct A where the
bis-imidazolimine is highly electron demanding. This process is
potentially reversible, but an intramolecular base-induced
proton transfer (step 2) irreversibly gave the exocyclic iminium
B. Interestingly, the outcome of this tautomerism is the
reduction of the bis-imidazolimine moiety (A → B) rendered
possible by the concomitant debenzylation via the oxidation of
the benzyl group (step 3) generating the iminium salt.
Hydrolysis of the iminium B gave benzaldehyde and 2-
aminoimidazole derivative C. The reaction mixture had the
distinctive odor of benzaldehyde that was identified by TLC
analysis. The final result is redox-neutral, but the hydrolysis of
the iminium resulted in the reduced species C. Finally, the
interesting deprotection (step 4) of the aminopyrimidine
moiety resulted in the transfer of the trimethine moiety on the
free benzylguanidine (C → 11). The outcome of this transfer is
interesting in the sense that aminopyrimidine is regenerated. It
is noteworthy that using an excess amount of NaOH was
crucial, as the intramolecular redox process A → B required a
base to deprotonate the α position of the benzyl group to
trigger the tautomerism. The unoptimized low yield of the
reaction could be explained by the formation of (1) byproducts
(benzaldehyde, 2-benzylaminopyrimidine) and (2) side prod-
ucts issued from the degradation of quinone 9 and byproducts
in a strongly basic reaction medium along with all the
difficulties encountered during the column chromatography
purification of highly polar and basic product 11. One of the
degradation products of quinone 9 was identified as sodium
phthalate. When the reaction was performed without NaOH,
the basic effect of the guanidine was not sufficient for
transforming 9 into 11. The starting material was mainly
recovered with some degradation.
Having successfully obtained the fused condensed product
7c, in which the benzo moiety could be considered as a
disubstituted motif of the central benzene ring of benzoscep-
trins, we have chosen 7c as a model substrate to investigate this
́
idea. Oxidation of 7c with Fremy’s salt led to o-quinone
(Scheme 4).26 At this stage, the choice of guanidine derivative
Scheme 4. Possible Pathway for the Subsequent Reductive
Guanidination of o-Quinone 9
plays a crucial role for the success of the guanidination because
the final product of type 10 has a lower oxidation state than the
theoretical quinone−guanidine adduct of type A (Scheme 5).
Consequently, the condensation of 9 with a guanidine should
be carried out under reducing conditions. We initially
envisioned the use of an external reducing agent.
Attempted reductive guanidination using unsubstituted
guanidine, methylguanidine, (di)phenylguanidines 2a or 4a,
or 2-aminopyrimidine 6 in the presence of a reducing agent
capable of promoting the well-known reaction of reductive
amination such as NaBH3CN or NaBH(AcO)3 did not lead to
any satisfactory result.
In summary, we have described a new simple and efficient
one-step approach to a diverse range of 2-aminobenzimidazol-
6-ols by the addition−cyclization reaction between quinones
and guanidine derivatives. This finding is a new access to
various interesting 2- aminobenzimidazole motifs. In addition
to the total synthesis of benzosceptrin A that became
conceivable using this approach, the prepared molecules such
To our delight, use of benzylguanidine as a guanidinating
agent in a basic aqueous solution of NaOH27 led to a
surprisingly interesting formation of unprotected bis-guanidi-
C
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Organic Letters
Letter
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benzosceptrin skeleton is currently considered to envision the
total synthesis of benzosceptrin A.
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ASSOCIATED CONTENT
* Supporting Information
■
S
Experimental procedures, product characterization, and copies
1
of the H and 13C NMR spectra. This material is available free
of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: nguyen@icsn.cnrs-gif.fr.
*E-mail: ali.almourabit@icsn.cnrs-gif.fr.
Notes
(15) Gibbons, J. B.; Gligorich, K. M.; Welm, B. E.; Looper, R. E. Org.
Lett. 2012, 14, 4734.
(16) Popov, I. I.; Boroshko, S. L.; Tertov, B. A. Chem. Heterocycl.
Compd. 1984, 20, 224.
(17) (a) Salvatory, M.; del, R. S.; Jneid, R. A.; Ghoulami, S.; Martin,
M. T.; Zaparucha, A.; Al-Mourabit, A. J. Org. Chem. 2005, 70, 8208.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
́
(b) Schroif-Gregoire, C.; Travert, N.; Zaparucha, A.; Al-Mourabit, A.
Financial support from CNRS, ICSN, and ANR (POMARE
project) is gratefully acknowledged.
Org. Lett. 2006, 8, 2961. (c) Picon, S.; Tran Huu Dau, M. E; Martin,
M.-T.; Retailleau, P.; Zaparucha, A.; Al-Mourabit, A. Org. Lett. 2009,
11, 2523.
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(b) Granik, V. G.; Lyubchanskaya, V. M.; Mukhanova, T. I. Pharm.
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