Chemistry of polyhalogenated nitrobutadienes, 10: Synthesis of highly functionalized heterocycles with a rigid 6-amino-3-azabicyclo[3.1.0]hexane moiety

Article abstract of DOI:10.3762/bjoc.8.69

The nitropolychlorobutadienes 3, 4 are valuable building blocks for various amination and successive heterocyclization products. Nucleophilic substitution reactions of the partially protected, bioactive amines 1, 2 with either vinyl, imidoyl or carbonyl c

Full text of DOI:10.3762/bjoc.8.69

Chemistry of polyhalogenated nitrobutadienes, 10:
Synthesis of highly functionalized heterocycles with
a rigid 6-amino-3-azabicyclo[3.1.0]hexane moiety
Viktor A. Zapol’skii1, Jan C. Namyslo1, Armin de Meijere2
and Dieter E. Kaufmann*1
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2012, 8, 621–628.
1Institute of Organic Chemistry, Clausthal University of Technology,
Leibnizstr. 6, 38678 Clausthal-Zellerfeld, Germany and 2Institute of
Organic and Bioorganic Chemistry, Georg-August-University
Göttingen, Tammannstrasse 2, 37077 Göttingen, Germany
doi:10.3762/bjoc.8.69
Received: 06 January 2012
Accepted: 23 March 2012
Published: 23 April 2012
Email:
Dieter E. Kaufmann* - dieter.kaufmann@tu-clausthal.de
Associate Editor: D. O'Hagan
* Corresponding author
© 2012 Zapol’skii et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
isothiazole; nitrochlorobutadiene; nitropyrazole; nucleophilic
substitution; pyrimidine; small rings
Abstract
The nitropolychlorobutadienes 3, 4 are valuable building blocks for various amination and successive heterocyclization products.
Nucleophilic substitution reactions of the partially protected, bioactive amines 1, 2 with either vinyl, imidoyl or carbonyl chlorides
result in the formation of the enamines 11, 12, 13, 16, 25, the amidine 6, and the amides 20, 21, respectively. In the following,
cyclization to the highly functionalized pyrazoles 27, 28, pyrimidine 26 and pyridopyrimidine 24 succeeded. Deprotection of 21, 12
and 28 proved to be only partially feasible.
Introduction
Nitropolychlorobutadienes are potent precursors for a variety of hexanes 1 and 2, which are obtained upon reaction with
highly functionalized acyclic and (hetero)cyclic compounds. polychloronitrobutadienes 3 and 4 (Figure 1).
The readily accessible 2-nitroperchloro-1,3-butadiene (3) [1] is
one of the most prominent members of this rather new class of The rigid bisamine 6-amino-3-azabicyclo[3.1.0]hexane is an
dienes. During the past nine years we have published the essential building block of several pharmaceuticals, such as the
syntheses of a wide range of diverse substance classes, applying potent gyrase inhibitor Trovafloxacin (Figure 2) [8,9]. As a 4th
this useful starting material [2-7].
generation topoisomerase inhibitor, this fluoroquinolone
anticipates replication of the bacterial DNA [10]. Other
The present work focuses on pharmacologically promising azabicyclo[3.1.0]hexane derivatives, for example with oxo-,
derivatives of the protected 6-amino-3-azabicyclo[3.1.0]- oxazolidino-, quinolino-, oxobenzothiazolo[3,2-a]quinolino, or
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Beilstein J. Org. Chem. 2012, 8, 621–628.
Figure 1: Promising starting materials for biologically active com-
pounds.
Figure 2: Pharmaceuticals bearing an azabicyclo[3.1.0]hexane unit.
pyrrolidino substituents, exhibit remarkable antibacterial as
well as antiprotozoal activity [11-15]. Furthermore, the 2-azabi-
cyclo[3.1.0]hexane derivative of 3-hydroxyadamantylglycine, yield (Scheme 1). The interest in such compounds derives
named Saxagliptin, is a pharmaceutical of the dipeptidyl pepti- from the fact that a number of similar hydrazones, e.g.,
dase IV (DPP-4) inhibitor class against type 2 diabetes mellitus phenyl(phenylchloromethylidene)hydrazine, exhibit fungicidal,
and entered the market in 2009 (Figure 2) [16].
antibacterial, and fungistatic activity [17,18].
Results and Discussion
In view of the insecticidal properties of some recently published
Driven by the promising stepwise reactivity of the highly [19] analogues of imidacloprid (N-[1-[(6-chloro-3-
substituted butadienes 3, 4 and with the above mentioned hints pyridyl)methyl]-4,5-dihydroimidazol-2-yl]nitramide), the
to biological activities in mind, we set out to develop structural substitutions of the imidazolidines 9 and 10 with 1 were also
conjunctions of the nitropolychlorobutadienes 3 and 4 with the tested. Compounds 9 and 10 were prepared from the nitrodiene
3-azabicyclo[3.1.0]hexane building blocks 1 and 2. Upon treat- 3 and the ethylenediamines 7 and 8. The formal nucleophilic
ment with N,N-dibenzyl-3-azabicyclo[3.1.0]hexan-6-amine (1) substitution of the α-chloro substituent within the trichlorovinyl
in methanol the (tetrachloroallylidene)hydrazine 5 [4,7] derived group of 9 and 10 by the amine 1 proceeded smoothly to give
from 3 reacted in a formal nucleophilic substitution at the both of the novel imidacloprid analogues 11 and 12, each in
imidoyl chloride unit to give the derivative 6 in 80% isolated 90% yield (Scheme 2).
Scheme 1: Synthesis of the azabicyclic hydrazone 6.
Scheme 2: Novel imidacloprid analogues 11, 12.
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Beilstein J. Org. Chem. 2012, 8, 621–628.
It is worth noting that all these nitroenamines 9–12 are formed treatment of 14 with p-phenetidine the 4-triazolyl-4-(4-
as E-isomers, which are stabilized by an intramolecular ethoxyphenylamino)butadiene 15 was obtained in 83% yield.
hydrogen bridge bond in a six-membered pseudocycle Subsequent reaction of 15 with tert-butyl 6-amino-3-azabi-
(Figure 3).
cyclo[3.1.0]hexane-3-carboxylate (2) provided the
tris(amino)butadiene 16 in 70% yield (Scheme 4).
Figure 3: Stabilizing hydrogen bond in nitrobutadiene-derived imida-
cloprid analogues 9–12.
Upon treatment of 1,3-dinitro-1,4,4-trichlorobutadiene (4),
which was obtained in a four-step sequence from 1,2-
dichloroethylene (mixture of diastereomers) [20,21], with a
fourfold excess of the azabicyclo[3.1.0]hexane 1 in methanol at
−40 °C, a twofold vinylic substitution led to the 4,4-
bis(aminoazabicyclo[3.1.0]hexyl)-1-chloro-1,3-dinitrobuta-
diene 13 in 80% yield (Scheme 3).
Scheme 4: Synthesis of the highly substituted trisaminodichloroni-
trobutadiene 16.
It is noteworthy that the diaminonitrovinyl moiety in com-
pound 15 remains unaffected in the last substitution step.
Apparently, the 2-nitroenamine substructure in 15 is less elec-
trophilic at C-3 than its conceivable tautomeric structure 16A
would suggest. After the third formal nucleophilic substitution
at C-2, the resulting product 16 has a second enamine substruc-
Scheme 3: Synthesis of the 4,4-bis(aminoazabicyclo[3.1.0]hexyl)-1-
chloro-1,3-dinitrobutadiene 13.
In an analogous treatment of the pentachloronitrobutadiene 3 ture as in 16A, rather than a dichloromethylimine subunit as in
with a fourfold excess of 1,2,4-triazole in diethyl ether the 4,4- 16B. This is obvious from the 1H NMR spectrum of 16, which
bistriazolyltrichloronitrobutadiene 14 (92% yield) was obtained does not show a signal corresponding to a dichloromethyl
[22] and turned out to be an appropriate substrate for a transam- proton, and in addition the 13C NMR spectrum shows four
ination, as the triazole is an excellent leaving group. Thus, by signals associated with olefinic carbon atoms (Figure 4).
Figure 4: Conceivable tautomeric structures of 16.
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Beilstein J. Org. Chem. 2012, 8, 621–628.
In addition to the direct attachment of heteroatoms or even (each with the expected 2J coupling of about 13 Hz). Appearing
heterocycles to nitropolychlorobutadienes by formal vinylic at 3.59 and 3.54 ppm, respectively, they are attached to isochro-
nucleophilic substitution reactions as described above, it was of nous carbon atoms at 59.0 ppm. Furthermore, the proton of the
interest to incorporate a persubstituted diene unit as in 3 and 4 NCH fragment (13C NMR: δ = 47.3 ppm) of the cyclopropane
into a heterocycle. For example, the isothiazole 17 was obtained ring appears as a triplet at 1.54 ppm (J = 2.3 Hz). Interestingly,
from the nitrodiene 3 upon treatment with elemental sulfur at the chemical shift of both of the bridgehead protons is 1.35 ppm
200 °C [23]. Subsequent reaction with fuming nitric acid (dd, J = 4.2, 2.3 Hz), whereas the corresponding carbon atoms
provided the dichloroisothiazolocarboxylic acid 18 [24], which have slightly different chemical shifts of 25.5 and 24.5 ppm,
could be easily converted with thionyl chloride to the corres- respectively. Most of the quarternary carbon shifts are unam-
ponding acid chloride 19 (93% yield). The latter smoothly biguous, whereas an HMBC spectrum was necessary for the
reacted with the azabicyclohexane derivatives 1 and 2 to assignment of two downfield signals: 160.5 ppm (C=O) and
provide the corresponding amides 20 and 21, respectively 160.4 ppm (SC). 14N NMR (one-dimensional, direct detection)
(Scheme 5). These amides 20 and 21 are hot candidates for bio- and an inverse-detected 1H/15N-HMBC gave the nitrogen shifts
logical testing, as some known amides of 4-chloroisothiazol-3- (internal MeNO2 at 0.0 ppm): −65.8 ppm (C=N), −244.2 ppm
carboxylic acid have been shown to exhibit high antibacterial (NCO), and −319.5 ppm (NBn).
activity [25-27].
In addition to the twofold triazole substitution, the nitrodiene 3
The high number of heteroatoms in 20 and 21, accompanied by was treated with four equiv of benzotriazole in THF. Thus, the
only a few hydrogen atoms, requires 1H/13C-2D as well as bisbenzotriazole derivative 22 was obtained in 76% yield [28].
nitrogen NMR spectra for structural assignments. For example, Having the target of further compounds with insecticidal activi-
aside from aromatic protons in 20, the methylene groups within ties in mind, 22 was treated with 2-aminopyridine, but the
the pyrrolidine ring each appear as a set of one single doublet simple substitution product, a benzotriazolyl-1-(pyrid-2-
(geminal coupling only) and a doublet of doublets (with addi- ylamino)diene, which must have been formed initially, appar-
tional coupling to the bridgehead proton due to an appropriate ently must have tautomerized to a pyridin-2(1H)-imine deriva-
dihedral angle). Narrow shifts of the corresponding carbon tive, which then underwent cyclization by a formal nucleo-
atoms were assigned by means of an HSQC spectrum. The philic substitution leading to the 4H-pyrido[1,2-a]pyrimidine
benzylic methylene protons give two slightly separated doublets 23. The remaining benzotriazole group in 23, which is acti-
Scheme 5: Syntheses of the perfunctionalized isothiazole derivatives 20, 21.
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Beilstein J. Org. Chem. 2012, 8, 621–628.
vated by the adjacent nitro substituent allows for a further A conceivable mechanism for the cascade reaction that leads to
nucleophilic substitution. Therefore, upon treatment with the the pyrazoles 27 and 28 is presented in Scheme 7. Initially, the
azabicyclohexane 1 under mild conditions (methanol, rt) the trichlorobutene I is formed upon addition of the arylhydrazine
enamine 24 was formed in 86% yield (Scheme 6). Similar to the nitro-substituted butadiene 25. Subsequent elimination of
pyrido[1,2-a]pyrimidines show antiviral [29], antithrombotic benzotriazole results in the diaminobutadiene II, which
[30] and antibacterial [31-34] activities.
tautomerizes to the stable amidine III. The pyrazoline IV is
then formed by an intramolecular SNVin reaction. Finally, HCl
Alternatively, conversion of bis(benzotriazolyl)butadiene 22 elimination affords the pyrazoles 27, 28. The stimulus to
with one equiv of amine 1 led to transamination at C-1 of the investigate such compounds originated from the known phar-
butadiene to furnish the azabicyclohexyl-nitrobutadiene 25 in macological activities of 4-nitropyrazoles [35-42].
95% yield. The latter, on one hand was converted by treatment
with acetamidine hydrochloride in THF to the pyrimidine 26 At the end of our synthetic work, three of the intricate 6-amino-
(yield 58%), which apparently proceeds by transamination and 3-azabicyclo[3.1.0]hexane derivatives were subjected to
subsequent intramolecular SNVin reaction. The structure of an common deprotection conditions on a micromole scale
analogous derivative of this heterocycle was previously (Scheme 8). Interestingly, in the case of the removal of the
confirmed by X-ray crystallography [5]. On the other hand, N-Boc group from 21 by means of surplus trifluoroacetic acid
nitrodiene 25 was treated with arylhydrazines to give the under mild conditions, the corresponding free amine 29 was
persubstituted aminonitropyrazoles 27–28 in 75–90% yield obtained in 83% yield, without any further optimization.
(Scheme 6).
However, accurately tailored conditions seemed to be neces-
Scheme 6: Preparation of the pyrazoles 27, 28, the pyrimidine 26 and the pyridopyrimidine 24.
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Beilstein J. Org. Chem. 2012, 8, 621–628.
Scheme 7: Proposed reaction mechanism for the formation of 27, 28.
sary for the N-debenzylation of the protected amino com- N-benzylated rigid amine 31 in 45% yield. With Pd/C at
pounds 12 and 28. The application of the usual reductive condi- ambient hydrogen pressure and ethanol as a solvent, no reduc-
tions (i.e., hydrogen under atmospheric pressure, palladium on tion of the nitro group or the aromatic chlorine atoms in 12 and
charcoal suspended in, e.g., ethanol) to the protected amine 12 28 was observed. To avoid the described side reactions, further
led to a multiple reaction involving the deprotection, a experiments should comprise the optimization of the hydrogen
bisdechlorination and final hydrolysis of an intermediate imine. volume and pressure as well as some fine tuning of the catalyst/
The resulting ketone 30 was isolated in 44% yield. On the other solvent system.
hand, the highly substituted dibenzylamino compound 28
showed another interesting reaction pathway: One of its benzyl To the best of our knowledge, the transformation observed for
groups was unmodified, even though the competing reduction compound 12, i.e., the reduction of a 1-amino-2,2-dichlorovinyl
of the dichloromethyl substituent took place to give the mono- group to an acetyl substituent, is hitherto unprecedented.
Scheme 8: Attempted deprotection of the azabicyclic compounds 21,12, and 28.
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This work was supported financially by Bayer AG (Leverkusen,
Germany). The authors are grateful to Dr. C. Stratmann
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of the bicyclic diamine derivatives 1 and 2 as well as to
Dr. H. Frauendorf for HR–ESI MS. We thank Dr. G. Dräger
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resolution mass spectra.
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