Synthesis of quinoxalines or quinolin-8-amines from N-propargyl aniline derivatives employing tin and indium chlorides

Article abstract of DOI:10.1039/c5ob01532d

Pyrazino compounds such as quinoxalines are 1,4-diazines with widespread occurrence in nature. Quinolin-8-amines are isomerically related and valuable scaffolds in organic synthesis. Herein, we present intramolecular main group metal Lewis acid catalyzed formal hydroamination as well as hydroarylation methodology using mono-propargylated aromatic ortho-diamines. The annulations can be conducted utilizing equal aerobic conditions with either stannic chloride or indium(iii) chloride and represent primary examples for main group metal catalyzed 6-exo-dig and 6-endo-dig, respectively, cyclizations in such settings. Both types of reactions can also be utilized in a one-pot manner starting from ortho-nitro N-propargyl anilines using stoichiometric amounts SnCl₂·2H₂O or In powder. Mechanistic considerations are presented regarding the substituent-depending regioselectivity.

Full text of DOI:10.1039/c5ob01532d

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Synthesis of quinoxalines or quinolin-8-amines
from N-propargyl aniline derivatives employing
tin and indium chlorides†
Cite this: DOI: 10.1039/c5ob01532d
Stefan Aichhorn,a Markus Himmelsbachb and Wolfgang Schöfberger*a
Pyrazino compounds such as quinoxalines are 1,4-diazines with widespread occurrence in nature. Quinolin-
8-amines are isomerically related and valuable scaffolds in organic synthesis. Herein, we present intra-
molecular main group metal Lewis acid catalyzed formal hydroamination as well as hydroarylation
methodology using mono-propargylated aromatic ortho-diamines. The annulations can be conducted
utilizing equal aerobic conditions with either stannic chloride or indium(III) chloride and represent primary
examples for main group metal catalyzed 6-exo-dig and 6-endo-dig, respectively, cyclizations in such
settings. Both types of reactions can also be utilized in a one-pot manner starting from ortho-nitro
N-propargyl anilines using stoichiometric amounts SnCl2·2H2O or In powder. Mechanistic considerations
are presented regarding the substituent-depending regioselectivity.
Received 24th July 2015,
Accepted 12th August 2015
DOI: 10.1039/c5ob01532d
www.rsc.org/obc
consist of an unknown compound. The seemingly mismatch-
ing simplicity of its NMR spectra encouraged us to elucidate
Introduction
Pyrazine motifs1 are widespread in biological organisms2 and the structure. It could be verified by HMBC experiments as
integrated into versatile chemical structures3 also with well as HR-MS that the resulting assembly appears to be
pharmaceutical value.4 1,4-Diazines are commonly prepared 3-methylpyrazino[2,3-c]quinoline 3. To the best of our knowl-
from α-keto carbonyl moieties and 1,2-diamines through edge, such 3-alkylated pyrazino[2,3-c]quinoline scaffolds and
twofold imine condensation.5 The second conventional route the preparation of pyrazine or quinoxaline derivatives in this
is to initiate self-condensation of α-amino ketones, often fashion have not been reported so far.
derived from phenacyl halides.6 These syntheses appear to be
quite straightforward cyclizations, but only a few supply a
broader substituent scope.7 Also, routes via N-oxides have
been utilized to synthesize polycyclic quinoxalines.8 On the
other hand, propargylic amines and related structures found
some use for the transition metal mediated construction of
aromatic nitrogen heterocycles.9 Furthermore, quinoline-8-
amines, which act as valuable directing groups,10 ligands for
coordination chemistry11 as well as agents for various dis-
eases,12 can be considered as structural isomers of methyl-
quinoxalines. Functionalized quinoline platforms found broad
interest with organic chemists over decades.13 In the course of
attempting to synthesize N4-propargylquinolin-3,4-diamine 2
from its 3-nitro precursor 1, the reduction using stannous
chloride dihydrate in ethanol gave a minor amount of 2, but a
considerable fraction of the product mixture was found to
Results and discussion
In order to exploit this observation towards more general
application for aromatic heterocycles, we investigated a one-
pot procedure for six-membered nitrogen motifs,14 starting
from ortho-nitro N-propargyl aniline derivatives. Furthermore,
we decided to examine whether next to tin also homologous
indium species could be facilitated in this context, as indium
powder is a reducing agent for nitro groups and In(III) has
been demonstrated to activate alkynes.15 Performing initial
screening reactions revealed that the use of methanol as
solvent did lead to high quantity of an unidentified side
product. It is noteworthy that it was possible to conduct the
six-membered nitrogen ring formations in aqueous solution at
85 °C, although such reactions resulted in decreased yields.
Farther, the same is true for employing toluene as solvent at
100 °C. Finally, we have developed two pragmatic protocols for
the construction of pyrazines (Fig. 1). Both standard pro-
cedures are based on the use of isopropanol as solvent
while stirring the reaction mixtures at reflux under aerobic
aInstitute of Organic Chemistry, Johannes Kepler University Linz, Altenberger Straße
69, 4040 Linz, Austria. E-mail: wolfgang.schoefberger@jku.at
bInstitute of Analytical Chemistry, Johannes Kepler University Linz, Altenberger
Straße 69, 4040 Linz, Austria
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
c5ob01532d
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Fig. 2 Alkynylanilides as substrates for either propargylic benz-imida-
zoles or quinoxalines.
panol and the respective reducing agent) gave the quinoxaline
11 in good yields.
Soon, it became inevitable to examine whether only term-
inal β-γ-alkynylamines would serve as platform for such formal
6-exo-dig cyclizations.16 To access 3′-alkylated derivatives, the
primary ortho-nitro arylamines were treated with sodium
hydride and 1-bromo-2-pentyne, which gave the internal
alkynes 13, 16, and 19. Those were subjected to reflux in iso-
propanol under the established aerobic one-pot conditions. At
this point, it was surprising to observe complete consumption
of educts without creation of pyrazine products.
Fig. 1 Substituent-dependent one-pot synthesis of either pyrazines or
quinolin-8-amines.
While the reduced primary amines in ortho-position
remained not further functionalized, we realized that indeed
six-membered rings were synthesized from 13 and 16 (Fig. 1),
conditions. To obtain the different 2-methylquinoxalines, the but in contrast to previous intramolecular annulations, quino-
best yields were obtained employing 5.5 equivalents of line-8-amines 15 (75%) and 18 (68%) were afforded, formally
SnCl2·2H2O. Moving to elementary indium, 3 equivalents in in a 6-endo-dig fashion, exclusively. In case of 3-nitro-N-(pent-
combination with hydrochloric acid gave similar results. With 2-yn-1-yl)quinolin-4-amine, only reduction giving the corres-
these optimized protocols in hand, we conducted one-pot ponding 3,4-diamine occurred. These tendencies allow for a
syntheses of quinoxalines using starting materials 1, 4, and 13. distinction between two different types of cascade reactions,
With reaction times ranging from two to 20 hours, derivatives which can be conducted employing identical conditions whilst
3, 6, and 15 could be afforded in good yields from 71–82% generating unlike heterocycles. When a para-diazine com-
(Fig. 1).
pound is generated, the initial cyclization of the reduced inter-
To explore a variant of this approach with related sub- mediate can be considered as intramolecular hydroamination
strates, readily available anilides as masked anilines were reaction. In contrast, the formation of quinolinamine struc-
chosen. The monofunctionalization of an anilide appears to tures follows a hydroarylation pathway prior to aromatization.
be less susceptible compared to primary ortho-nitro anilines.
With protocols for specific six-membered rings in hand, we
An acetyl group as in anisyl-compound 10 can be cleaved became interested in exploring the mechanistic aspects of this
under acidic conditions like present in the one-pot procedures. kind of annulation reactions. Preliminary experiments were
By subjecting the N-propargyl anilide to hot hydrochloric acid conducted with β-γ-alkynyl-diamines like 2 or 14 exposed to
solution, quantitative deacetylation can be established. When oxygen in isopropanol at 82 °C. In the absence of any addi-
a standard reductive one-pot cyclization-aromatization reaction tives, no conversion was observed. The same was true for the
is conducted with 10, almost exclusively N1-propargyl-C2- addition of water or stannic chloride. By using less than one
methyl-benzimidazole 12 is created. Under these circum- equivalent of SnCl2·2H2O or InCl3, product formation was
stances, reduction of the nitro-group and subsequent conden- achieved analogous to one-pot results. With these promising
sation of the five-membered ring seems to be faster than the results, we were interested to demonstrate our synthetic pro-
incorporation of the alkyne. In this fashion, functionalized cedures to obtain the six-membered rings in catalytic fashion
benzimidazoles can be generated in good yield (Fig. 2). For the with well-chosen substrates.
synthesis of quinoxalines, the protocol had to be adjusted by
A study of literature reveals that there are a number of
stirring the alkynyl–anilide in 3 M HCl at 90 °C first. Employ- related syntheses starting from propargylamine derivatives
ing our developed standard protocol in the same pot (isopro- towards either diaza-compounds (Fig. S1† – left column) or
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other six-membered rings (Fig. S1† – right column). Gold-cata-
lysis sets the standards in the field due to the advantageous
properties of Au-complexes concerning the interactions with
C–C triple bonds.17 Regarding the hydroamination type reac-
tions, a few older reports cover intramolecular conversions
attaining quinoxalines similarly to our approach. However,
copper and mercury based mediating reagents have to be uti-
lized in stoichiometric fashion.18 In this sense, the tin(II) as
well as indium(III) promoted cyclizations described here are
the first main group metal catalyzed 6-exo-dig hydroamination.
The situation with electrophilic aromatic substitution reac-
tions is different as there are no reports on vicinal monoalky-
nylated diamino-substrates, but several transition metal
catalyzed annulations giving quinoline derivatives.19 The best
matching related ring formations are In(III) catalyzed syntheses
of phenanthrenes and chromenes.20 Considering this, the
Sn(II) and In(III) mediated cyclizations described here are the
Table 1 Pyrazine/quinoline syntheses in catalytic fashion
Entry
Catalyst
Mol%
t/h
s.m.a
Product
Yield
1
2
3
4
5
6
SnCl2
InCl3
SnCl2
InCl3
SnCl2
InCl3
50
50
50
25
25
25
12
12
12
36
36
36
2
2
5
8
17
14
3
3
6
9
18
15
91%
93%
85%
66%
76%
80%
a Conditions: 1 eq. starting material (0.1 M isopropanol soln), 82 °C,
cat., 2 eq. H2O, air.
first examples of main group metal catalyzed 6-endo-dig hydro- measure. Moreover, it turned out to be an important finding
arylation to afford quinoline derivatives.
that a minimum amount of water is necessary for conversion
To provide starting materials for several screening reac- of educts to proceed. With respect to one-pot procedures,
tions, the nitro precursors had to be reduced to the corres- which are not quenched in presence of an excess of water, it is
ponding diamines in
a controlled manner. Therefore, noteworthy that water of crystallization from catalyst salts is
chemoselective transformations of 1, 4, 7, 13, and 16, respect- sufficient for successful conversions.
ively, were conducted employing sodium dithionite as redu-
Since a distinctly acidic regime is prevalent in a nitro-one-
cing agent to prepare 2, 5, 8, 14, and 17 (Fig. 3). This proved to pot reaction mixture, intensely protic or Brønsted acidic con-
be a useful reaction procedure, since the reaction stopped at ditions do not inhibit the intramolecular cyclization. In turn,
the ortho-diamine stages in reasonable yields.
our simple methodology demonstrated that product formation
Concerning the mediating metal species, tin(II) as well as is promoted by Lewis acids, which result in a moderately
indium(III) could be employed as catalysts (Table 1). In contrast acidic pH regime.
to that, Sn(IV) salts and In(0) did not convert the substrates to
The overall tendency revealed that a well-working standard
the desired products. Soon we realized that no product is protocol consisted of refluxing the isopropanol solution of
formed under strictly anaerobic conditions. On the other N1-β-γ-alkynyl ortho-diamine under air with stoichiometric water
hand, atmospheric oxygen supply usually proves adequate and along with 25–50 mol% main group metal chloride. We
O2-bubbling is crucial only when it comes to syntheses in reasoned that indium(III) is slightly more effective as catalyst
NMR tubes. It was observed that fast conversions are initiated than tin(II). In terms of catalyst loading, complete conversion
above 70 °C, hence refluxing at 82 °C was chosen as general could not be attained with less than 25 mol%. The best results
were obtained with 0.5 equivalents loading, when syntheses
could be completed within two to twelve hours. Decreasing the
amount of SnCl2 or InCl3 would elongate reaction times up to
two days. The highest yields with both catalyst systems were
achieved by refluxing 2 overnight using 50 mol% metal chlor-
ide affording 3 in 91% (SnCl2·2H2O) and 93% (InCl3). Results
of catalytic hydroamination and hydroarylation reactions are
listed in Table 1 (also compare Fig. 1, 3 and 4).
A set of control experiments was conducted: we examined
whether Brønsted acid could facilitate ring closure. Therefore,
solutions of 5 and 8 were refluxed after the addition of tosylic
acid, which only lead to the recovery of starting material both
with 0.5 and 5 equivalents of TsOH·H2O, respectively. To study
the behavior of the nitro-compounds, precursor 4 was reacted
in combination with a non-reducing metal chloride. During
both cases (catalytic and stoichiometric amounts of InCl3), no
conversion of starting material 4 was observed utilizing our
standard reaction protocol. The same was true for the N1-Boc-
protected derivative of 5. Additionally, 2-(prop-2-yn-1-yloxy)
Fig. 3 Dithionite as reducing agent to receive ortho-diamine com-
pounds for catalytic annulation.
aniline and 4-(pent-2-yn-1-yloxy)quinolin-3-amine were syn-
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possible to afford derivative 19 in very good yield (Fig. 4). Sub-
jecting it to standard conditions with 25 mol% of indium(III)
chloride for 36 h, 4-p-tolylquinolin-8-amine 20 was synthesized
in 89% yield. This result evidently demonstrates the tendency
that in settings with ortho-diamino-scaffolds substituted triple
bonds follow a hydroarylation pathway, whereas terminal
alkynes undergo hydroamination. This distinction at ring
closing reactions with propargylic amine-type substrates cata-
lyzed by InCl3 was also described in a recent publication.22
As it could be confirmed that the unexpected ring closing
reactions, depending on the given substrates, indeed produce
either methylpyrazino- or quinoline-8-amino-compounds, the
explored set of reactions can therefore be differentiated
between 6-exo-dig and 6-endo-dig annulations, respectively.23
Under the given conditions, this would involve a Lewis acid
(LA) complex to increase the electrophilic character of an
alkyne. Metallic Lewis acids can bind weakly in a side-on
manner to the triple bond or attach directly to an sp-carbon.24
Besides the more frequent reports on transition25 or main
group26 metals and iodine27 to promote exo- and endo-dig-
cyclizations,28 indium(III) species29 are able to promote such
Fig. 4 Sonogashira coupling for aryl–alkynes, subsequent cyclization,
and literature comparison concerning In(III).
thesized in order to study the probability of generating oxygen- bond formations. The given reaction mixtures seem to be
heterocycles with our main group metal system. None of the favouring intramolecular hydroaminations30 or hydroaryla-
alkynyloxy-compounds was converted to a cyclized scaffold tions.31 In order to examine mechanistic aspects of the annula-
after treatment with catalytic amounts of SnCl2·2H2O.
Further insight regarding the reactivity of the substrate- mixtures analyzed by means of NMR and HR-MS.
catalyst combinations could be achieved by subjecting simple
The 1H NMR spectra of reactions in isopropanol-d8 reveal
tion, syntheses were conducted in deuterated solvent and the
N-(prop-2-yn-1-yl)-p-toluidine as well as N-(pent-2-yn-1-yl)-p- which hydrogen positions are affected during the procedure. The
toluidine to standard catalytic conditions with both Sn(II) and most striking spectroscopic difference to standard protic con-
In(III), respectively. After two days of stirring, the attempts with dition spectra is the low intensity of two signals: the aryl-singlet
terminal alkynes just gave starting materials. On the other of the pyrazine ring as well as the methyl-peak show integrals of
hand, reactions employing internal alkynes afforded small less than a third compared to their supposed values. This is true
amounts of the hydroarylation product 4-ethyl-6-methyl- for every successfully tested experiment in deuterated reaction
quinoline (“Sn”: 7%; “In”: 9%) besides educt.
mixture, only the relative amounts of decreased peak area vary
Considering those tendencies, we have performed quantum specifically with the employed metal salt type. The corres-
mechanics calculations to determine the atomic charges and ponding 13C NMR spectra exhibit split signals for those carbons,
total charge densities (electrostatic potentials, ESPs) of com- which hold primarily deuterium instead of protons. Hence, het-
pounds 5 and 17, respectively. By juxtaposing their relative eronuclear coupling of carbons with 2H nuclei is observable
charges concerning the propargylic moiety, there is a trend (1JC–D = 27 Hz). Furthermore, the aromatic peaks in the quinoxaline
that the triple bond is much less polarized at the internal case appear to display differently overlapping multiplicities and
alkyne (Fig. S7 and S8†). In turn, the β-carbon of the terminal to a minor extent reduced integrals, which can be explained by
alkyne is clearly more electrophilic.
isotope exchange effects. ESI-mass spectra illustrated a range
It is particularly remarkable that catalytic annulations of of product isomers with various deuteration grades. The influ-
internal N1-β-γ-alkynyldiamines produce quinoline-8-amines ence of the alkyne-manipulation and cyclization on the initial
equally exclusive as with the corresponding one-pot attempts. aromatic body of the molecule can also be studied by a qui-
This indicates that the nature of the alkyne moiety decides noxaline synthesis in deutero-solvent32 (Fig. 5): 1H and 13C
about the type of ring closure. There does not seem to be a NMR spectra indicate changes in peak patterns and intensities
competition between rates of conversion for reduction vs. aro- for the phenylene scaffold, mass spectra signify considerable
matic substitution reaction, which would have had influenced amounts of isomers with more than four Ds (Fig. S2–5†). Most
the given selectivity.
importantly, this experiment proves that the ortho-H position,
An important remaining aspect was, if aryl-substituents21 at which gives rise to the electrophilic aromatic substitution
the alkyne would favour an equal mode of ring closing as pathway, is also activated at substrates with terminal alkynes,
ethyl-alkynes. We did not succeed to functionalize ortho-nitro but does not afford quinoline product in such cases.
precursors like 4 employing Sonogashira cross-coupling meth-
Comprehension of the ring closure might be facilitated by
odology. However, we could generate that kind of internal investigating certain screening reactions using 2 at reflux
alkynyl–amine by using the reduced compound 5. It was times of only 20 minutes along with catalytic amounts of Sn(II)
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the isotope distribution effects in deuterated media. A range of
tautomeric equilibria might foster H/D exchange. Indium(III)
and tin(II) chlorides lower the signal intensity of the methylene
group (HCvN in products) down to values between 15–30%.
The need of molecular oxygen for the progress of the reac-
tion can clearly be related to the oxidation of the 1,2-dihydro
compounds (Scheme 1) to the final product. The gain of stabi-
lity by reaching aromaticity explains the fast conversion of the
cyclized skeleton. No evidence was found for the formation of
an allene prior to ring closure.33 The prerequisite of water for
the reactions to proceed might favour a hydration step prior to
ring closure. Both tin and indium are known to be able to
facilitate hydration reactions of alkynes to generate ketones.34
Those carbonyl intermediates could additionally be activated
by Lewis acids. In a quinoxaline case, a structure like II may
give rise to the condensation resulting in dihydro-compound
III (Scheme 1 and Fig. S2†).
Fig. 5 (A) Reaction of 5 to 6 to with 50 mol% SnCl2·2H2O in isopro-
panol-d8 to study the degree of activation on certain positions. (B)
Time-course 1H NMR spectra of A).
Applying this concept to a hydroarylation reaction, the
hydration step (IV to V) would create the ketone at γ-position.
This would then be attacked in an SEAr manner (V to VI), fol-
lowed by rearomatization and water elimination (VI to VII to
and In(III) chlorides. After work-up, NMR spectra indicated VIII). However, there is no evidence for such reactivity,
approx. 50/50 mixtures of pyrazino-product and a species that although it would serve as credible explanation for the exten-
was determined to be an intermediate. A similar observation sive deuteration also (Fig. S4 and S5†). For all those reasons
was made during NMR-tube reactions of 14 with InCl3 (resem- mentioned, the course of the reactions might be covered by
bling the experiment depicted in Fig. 5). Considerable the sequence of steps depicted in Scheme 1.
amounts of compound holding
a
CH2-group positioned
What appears to be of special importance for the conception
between a double bond and an NH-group could be detected. of a mechanism and the composition of the Lewis acid catalyst
HRMS and NMR measurements suggested dihydropyrazine/ is the lack of reactivity in cases of nitro-precursors like 4 in com-
dihydroquinoline species (Scheme 1, structures III/VIII), which bination with metal chlorides. The aromatic ortho-diamines are
is likely to be a somehow stable structure prior to oxidation of well suitable to act as bidentate ligand. As a consequence, we
the C–N-bond. We were not able to isolate these intermediates wish to emphasize that there could be deciding influence of a
by column chromatography through silica, as the whole metal cation centred complex, involving an ortho-phenylene
reduced species were converted into final product. The obser- diamine type ligand,35 on mediating the cyclization steps.
vation of those intermediates allows better understanding of
Conclusions
We have demonstrated the utility of stannous chloride as well
as indium powder under acidic conditions for intramolecular
one-pot synthesis of either methylquinoxaline or quinolin-8-
amine derivatives. Starting from ortho-nitro-N-propargylaniline
compounds, selectivity is dependent on the substitution of the
alkyne. It was shown that such aerobic annulation reactions
are suitable to be conducted in catalytic fashion employing tin
(II) and indium(III) chlorides as Lewis acids starting from ortho-
diamino compounds. Those are the first examples of 6-exo-dig
hydroaminations and 6-endo-dig hydroarylations with alkynyl-
anilines, respectively, catalyzed by main group metals.
Experimental part
General procedure for one-pot syntheses of quinoxalines or
quinolin-8-amines
SnCl2·2H2O (5.5 equiv.) or indium powder (3 equiv. – in combi-
Scheme 1 Proposed mechanisms of the annulation reactions.
nation with hydrochloric acid solution (3 M; 15 equiv.)) were
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added to a stirred 0.15 M solution of ortho-nitro N-propargyl-
3-Methylpyrazino[2,3-c]quinoline (3). Pale orange solid,
1
aniline compound (1 equiv.) in 2-propanol at room temperature. m.p. 120–122 °C; H NMR (700 MHz, CDCl3, 298 K): δ = 2.88
The mixture was heated at reflux under air until judged com- (s, 3H), 7.81 (t, J = 7.5 Hz, 1H), 7.90 (t, J = 7.6 Hz, 1H), 8.27
pleted as indicated by thin layer chromatography. The mixture (d, J = 8.1 Hz, 1H), 9.01 (s, 1H), 9.07 (d, J = 8.1 Hz, 1H), 9.52
was brought to room temperature, filtrated and the filtrate con- (s, 1H) ppm; 13C NMR (176 MHz, CDCl3, 298 K): δ = 22.4,
centrated under reduced pressure. The residue was quenched 123.5, 124.7, 128.2, 129.6, 130.6, 135.4, 141.4, 146.0, 148.6,
with saturated NaHCO3 solution until pH 10. The aqueous 153.9, 155.2 ppm; IR (film): ν = 2921, 2853, 1458, 1376,
¯
solution was extracted with EtOAc three times, the combined 951, 773 cm−1; HRMS (ESI): m/z calcd for C12H9N3: 196.0869
organic layers were dried over anhydrous Na2SO4 and evapo- [M + H]+; found: 196.0870.
rated under reduced pressure. The residue was purified by
column chromatography (silica gel, heptanes/EtOAc = 3/1).
7-Methoxy-2-methylquinoxaline (11). To N-alkynyl-ortho-
nitro-anilide (1 equiv.) was added 3 M hydrochloric acid solu-
tion (30 equiv.). The mixture was stirred at 90 °C under N2
atmosphere for 7 h. Then, the mixture was directly subjected
to one-pot reaction conditions as described in the General pro-
General procedure for main group metal chloride catalyzed
formation of quinoxalines or quinolin-8-amines
25–50 mol% of stannous chloride dihydrate or indium(III) cedure. Physical and spectroscopic properties are in accord-
chloride were added to a stirred 0.1 M solution of ortho-amino ance with published data.36 1H NMR (300 MHz, CDCl3, 298 K):
N-propargylaniline compound (1 equiv.) in 2-propanol at room δ = 2.74 (s, 3H), 3.96 (s, 3H), 7.31 (d, J = 2.7 Hz, 1H), 7.35 (dd,
temperature. Unless water of crystallization was present, J = 2.7 Hz, 9.1 Hz, 1H), 7.94 (d, J = 9.1 Hz, 1H), 8.59 (s, 1H)
1 equiv. H2O was added. The mixture was heated at reflux ppm; HRMS (ESI): m/z calcd for C10H10N2O: 175.0866 [M + H]+;
under air until judged completed as indicated by thin layer found: 175.0862.
chromatography. The mixture was concentrated under reduced
5-Methoxy-2-methyl-1-(prop-2-yn-1-yl)-1H-benzo[d]imidazole
pressure and the residue quenched with saturated NaHCO3 (12). Brown solid, m.p. 110–116 °C; eluent DCM/MeOH = 7/1;
solution until pH 10. The aqueous solution was extracted with 1H NMR (300 MHz, CDCl3, 298 K): δ = 2.34 (t, J = 2.5 Hz, 1H),
EtOAc three times, the combined organic layers were dried 2.62 (s, 3H), 3.84 (s, 3H), 4.80 (d, J = 2.5 Hz, 2H), 6.90 (dd, J =
over anhydrous Na2SO4 and evaporated under reduced 2.4 Hz, 8.8 Hz, 1H), 7.18 (d, J = 2.4 Hz, 1H), 7.25 (d, J = 8.8 Hz,
pressure. The residue was purified by column chromatography 1H) ppm; 13C NMR (75 MHz, CDCl3, 298 K): δ = 13.9, 33.3,
(silica gel, heptanes/EtOAc = 3/1).
56.0, 73.6, 76.7 (overlaid by solvent signal), 102.1, 109.5, 112.0,
129.3, 143.4, 151.5, 156.3 ppm; IR (film): ν = 3194, 2112, 1519,
¯
General procedure for alkynylation of ortho-nitro anilines
using NaH
1489, 1439, 1276, 1198, 1151, 1034, 787 cm−1; HRMS (ESI): m/z
calcd for C12H12N2O: 201.1022 [M + H]+; found: 201.1027.
Sodium hydride (95%, 1.1 equiv.) was added to a 0.2 M aceto-
4-Ethyl-5,6-dimethylquinolin-8-amine (15). Brownish orange
1
nitrile solution of 2-nitroaniline compound (1 equiv.). The oil; H NMR (700 MHz, CDCl3, 298 K): δ = 1.33 (t, J = 7.5 Hz,
mixture was stirred at 0 °C for 15 min. Then, 1-bromoalk-2-yne 3H), 2.40 (s, 3H), 2.62 (s, 3H), 3.25 (q, J = 7.5 Hz, 2H), 6.82
(1.1 equiv.) was added and the mixture was brought to room (s, 1H), 7.18 (d, J = 4.4 Hz, 1H), 8.55 (d, J = 4.4 Hz, 1H) ppm;
temperature. It was thoroughly stirred under N2 atmosphere 13C NMR (176 MHz, CDCl3, 298 K): δ = 16.2, 18.6, 22.1, 29.8,
for 40 h. The suspension was quenched with H2O and satu- 113.3, 120.0, 122.7, 128.7, 135.7, 138.4, 142.1, 145.7,
rated NaHCO3 solution was added until pH 10. The resulting 150.9 ppm; IR (film): ν = 2922, 2853, 1519, 1459, 1325, 1260,
¯
aqueous layer was extracted with DCM three times, the com- 1013, 797 cm−1; HRMS (ESI): m/z calcd for C13H16N2: 201.1386
bined organic layers were dried over anhydrous Na2SO4 and [M + H]+; found: 201.1386.
evaporated under reduced pressure. The residue was purified
by column chromatography (silica gel, heptanes/EtOAc or 1H NMR (300 MHz, CDCl3, 298 K): δ = 1.14 (t, J = 7.5 Hz, 3H),
N1-(Pent-2-yn-1-yl)benzene-1,2-diamine (17). Brown oil;
MeOH/DCM).
2.21 (qt, J = 2.2 Hz, 7.5 Hz, 2H), 3.44 (br s, 3H), 3.89 (t, J =
2.2 Hz, 2H), 6.70–6.79 (m, 3H), 6.80–6.88 (m, 1H) ppm;
13C NMR (75 MHz, CDCl3, 298 K): δ = 12.5, 14.0, 34.5, 76.5,
General procedure for the reduction of ortho-nitro
N-alkynylanilines to diamines using Na2S2O4
To a stirred 0.1 M EtOH solution of 2-nitro-N-alk-2′-ynylaniline 3334, 3042, 1573, 1506, 1455, 1315, 1269, 738 cm−1; HRMS
compound (1 equiv.) at 0 °C were added portions of sodium (ESI): m/z calcd for C11H14N2: 175.1230 [M + H]+; found:
dithionite (85%, 6 equiv.) and H2O (half volume of EtOH) alter- 175.1232.
85.4, 113.0, 116.5, 119.8, 120.6, 135.1, 136.7 ppm; IR (film): ν =
¯
natingly. Then the mixture was allowed to warm to room temp-
N1-(3-(p-Tolyl)prop-2-yn-1-yl)benzene-1,2-diamine (20). Pre-
erature and stirred for 1 h. Then it was filtrated and the bulk pared in analogy to literature.37 To a solution of 5 (0.68 mmol,
of aqueous EtOH of the filtrate was evaporated in vacuo. Under 99 mg, 1 equiv.) in 4 ml acetonitrile were added 1-iodo-4-
reduced pressure, quick column chromatographic purification methylbenzene (0.75 mmol, 165 mg, 1.1 equiv.), triethylamine
of the residue over a short pad of silica in a sintered glass (4.1 mmol, 566 µl, 6 equiv.), copper(I) iodide (0.026 mmol,
filter was performed using a solvent gradient from DCM/ 5 mg, 0.04 equiv.), and bis(triphenylphosphine)palladium(II)
MeOH (10/1) to pure MeOH. The polar fractions were collected dichloride (0.026 mmol, 19 mg, 0.04 equiv.). The mixture was
and concentrated in vacuo.
stirred under N2 atmosphere at room temperature for 20 h.
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Then it was filtrated and washed with EtOAc. The filtrate was
quenched with water and saturated NaHCO3 solution was
added until pH 10. It was extracted with EtOAc three times, the
combined organic layers were dried over anhydrous Na2SO4
and evaporated under reduced pressure. The residue was puri-
fied by column chromatography (silica gel, heptanes/EtOAc =
3/1) and gave 20 as a light brown oil (0.578 mmol, 137 mg,
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1
85%). H NMR (300 MHz, CDCl3, 298 K): δ = 2.34 (s, 3H), 3.49
(br s, 3H), 4.14 (s, 2H), 6.73–6.89 (m, 4H), 7.10 (d, J = 8.0 Hz,
2H), 7.31 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (75 MHz, CDCl3,
298 K): δ = 21.6, 35.1, 83.8, 85.9, 113.4, 116.6, 120.0, 120.1,
120.6, 129.1 (2C), 131.7 (2C), 135.3, 136.6, 138.4 ppm;
IR (film): ν = 3334, 2920, 1597, 1508, 1450, 1271, 816,
¯
740 cm−1; HRMS (ESI): m/z calcd for C16H16N2: 237.1386
[M + H]+; found: 237.1384.
4-(p-Tolyl)quinolin-8-amine (21). Pale yellow oil; 1H NMR
(700 MHz, CDCl3, 298 K): δ = 2.46 (s, 3H), 5.05 (br s, 2H), 6.94
(dd, J = 1.9 Hz, 6.7 Hz, 1H), 7.24–7.30 (m, 3H), 7.32 (d, J =
7.9 Hz, 2H), 7.41 (d, J = 7.9 Hz, 2H), 8.77 (d, J = 4.4 Hz, 1H)
ppm; 13C NMR (176 MHz, CDCl3, 298 K): δ = 21.3, 109.9, 114.3,
121.7, 127.2, 127.4, 129.1 (2C), 129.4 (2C), 135.7, 138.1, 138.8,
144.2, 146.9, 148.4 ppm; IR (film): ν = 3447, 3319, 2360, 1618,
¯
1502, 1358, 1282, 818, 761 cm−1; HRMS (ESI): m/z calcd for
C16H14N2: 235.1230 [M + H]+; found: 235.1230.
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Acknowledgements
WS kindly acknowledges the financial support of the project
836532 (“Prä-klinische Entwicklung einer Off-the-Shelf indvi-
dualisierten Krebsimmuntherapie”) by the Austrian Research
Promotion Agency (FFG). The NMR spectrometers were
acquired in collaboration with the University of South 10 (a) B. M. Monks, E. R. Fruchey and S. P. Cook, Angew.
Bohemia (CZ) with financial support from the European
Union through the EFRE INTERREG IV ETC-AT-CZ program
(project M00146, “RERI-uasb”).
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