Phosphine Supported Ruthenium Nanoparticle Catalyzed Synthesis of Substituted Pyrazines and Imidazoles from α-Diketones

Article abstract of DOI:10.1021/acs.joc.6b03032

A new methodology has been developed for the synthesis of highly substituted nitrogen heterocycles such as pyrazines and imidazoles starting from α-diketones using phosphine supported ruthenium nanoparticles (RuNPs) as catalysts. Ruthenium nanoparticles Ru1-Ru4 supported with different phosphines such as dbdocphos, dppp, DPEphos, and Xantphos are screened, of which Ru1 and Ru4 are found to be the most active. Interestingly, aryl-substituted and alkyl-substituted α-diketones produced different products: namely, pyrazine and imidazoles, respectively. This reaction methodology has been applied to the synthesis of a key intermediate (2m) of the marine cytotoxic natural product Dragmacidin B and an estrogen receptor (2l). This work represents the first examples of pyrazines prepared by RuNPs.

Full text of DOI:10.1021/acs.joc.6b03032

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Article
Phosphine Supported Ruthenium Nanoparticles Catalyzed
Synthesis of Substituted Pyrazines and Imidazoles from #-Diketones
Prasad Ganji, and Piet W. N. M. van Leeuwen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b03032 • Publication Date (Web): 11 Jan 2017
Downloaded from http://pubs.acs.org on January 11, 2017
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Phosphine Supported Ruthenium Nanoparticles Catalyzed
Synthesis of Substituted Pyrazines and Imidazoles from αꢀ
Diketones
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a
a,b
Prasad Ganji and Piet W. N. M. van Leeuwen*
a
Institute of Chemical Research of Catalonia (ICIQ), The Barcelona Institute of Science and
Technology, Av. Països Catalans 16, 43007 Tarragona, Spain
Laboratoire de Physique et Chimie des Nano Objets, LPCNO, UMR5215 INSAꢀUPSCNRS,
Université de Toulouse; Institut National des Sciences Appliquées, 135 Avenue de Rangueil, 31077
Toulouse, France
b
Email: vanleeuw@insaꢀtoulouse.fr
_________________________________________________________________________
_
Ru@Xantphos
O
R
R
R
R
N
N
R
R
O
N
HCOONH4
HCOONH4
R
R
R
o
o
DMF, 85 C, 1 h
DMF, 85 C, 1 h
O
2
a
1
a
3
a
>
98%
Abstract: A new methodology has been developed for the synthesis of highly substituted nitrogen
heterocycles such as pyrazines and imidazoles starting from αꢀdiketones using phosphine supported
ruthenium nanoparticles (RuNPs) as catalysts. Ruthenium nanoparticles (Ru1 Ru2, Ru3 and Ru4)
supported with different phosphines such as dbdocphos, dppp, DPEphos and Xantphos are screened of
which Ru1 and Ru4 are found to be the most active. Interestingly, aryl substituted and alkyl
substituted αꢀdiketones produced different products namely pyrazine and imidazoles respectively.
This reaction methodology has been applied to the synthesis of key intermediate (2m) of the marine
cytotoxic natural product Dragmacidin B and an estrogen receptor (2l). This work represents the first
examples of pyrazines prepared by RuNPs.
_
_____________________________________________________________________________
Introduction
Pyrazines represent an important class of nitrogen heterocycles that have important applications in the
field of medicine as antibacterial, antiviral, antituberculotic, antiꢀinflammatory agents and kinase
1
inhibitors. Pyrazine compounds are of great interest in cosmetic and food industries as flavoring
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agents and have also attracted attention in material science. Typical methods for the preparation of
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pyrazines involve condensation of vicinal diamines with αꢀdiketones followed by dehydrogenation,
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or autoꢀcondensation of αꢀamino ketones. In addition to these methods, pyrazines have been
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synthesized using different class of starting materials such as αꢀhydroxy ketones αꢀhalo ketones, αꢀ
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halo enolacetates, nitro epoxides, 2H-azirines and βꢀketoꢀγꢀamino esters. Other strategies include
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Suzuki–Miyaura reactions of tetrachloropyrazine, biocatalytic reduction of βꢀketoꢀαꢀoximinoester
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with Baker’s yeast, two step synthesis via epoxide opening with βꢀamino alcohol followed by Swern
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oxidation, and ruthenium pincer complex catalyzed dehydrogenative condensation of βꢀamino
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alcohols. However, most of these approaches require more than one class of substrates for the
preparation of pyrazines and in some cases additional steps are needed for synthesizing the starting
materials. Therefore, the development of new methodologies for the synthesis of pyrazines from
simple, readily available inexpensive starting materials is highly desirable.
In recent years, transition metal nanoparticles have attracted great interest in the field of catalysis due
16
to their physical and chemical properties over their traditional organometallic complexes. Amongst
these, RuNPs have been considered as one of the most studied nanoparticles in catalytic
transformations. Ru particles have been successfully employed in number of catalytic transformations
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7
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which includes arene hydrogenations, hydrogenation of carbonyl compounds oxidation of
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alcohols, hydrogen generation from ammoniaꢀborane complexes, CO
2
hydrogenations, and the
2
2
FischerꢀTropsch process. Unlike organoruthenium complexes the direct application of RuNPs for
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3
developing new organic synthetic methodologies is still a challenge and remains less established.
Recently, our group reported the synthesis of ruthenium nanoparticles having various stabilizing
ligands such as bidentate phosphines containing wide bite angles, secondary phosphine oxides and Nꢀ
heterocyclic carbenes along with catalytic applications of these nanoparticles in the hydrogenation of
2
4
aromatics. In this paper, we report a direct synthesis of tetra substituted pyrazines from αꢀdiketones
using phosphine supported RuNPs as catalysts without need of vicinal diamines.
Results and Discussion
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As part of our ongoing research with catalytic applications of ligand modified RuNPs, our
investigations focused on transfer hydrogenation of αꢀdiketones. Initially the reaction was studied on
2
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transfer hydrogenation of benzil (1a) to achieve hydrobenzoin with dbdocphos stabilized ruthenium
nanoparticles Ru1 (0.5 mol%). Surprisingly the reaction outcome was different and led to the
formation of tetraphenyl pyrazine 2a as a clean product in >98% conversion by GC analysis
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(
coproducts are water, cabon dioxide and dihydrogen). When the reaction was conducted under
similar conditions without using Ru1, it produced triphenyloxazole (3a) in 30% conversion (Scheme
).
1
Scheme 1. Attempted catalytic transfer hydrogenation of benzil with ruthenium nanoparticles Ru1
This unusual reactivity of the αꢀdiketones with RuNPs allowed us to study and expand the scope of
this reaction for the preparation of tetra substituted pyrazines.
Several phosphine supported RuNPs were synthesized by reaction of [Ru(COD)(COT)] in the
presence of 0.1 equiv. of the appropriate phosphine under 3 bars of hydrogen pressure for 16 h
16a,b
according to the procedures reported earlier.
Bidentate phosphines such as dbdocphos, dppp,
DPEphos and Xantphos were used for synthesis of RuNPs and labelled as Ru1 to Ru4 as shown in
Scheme 2.
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Scheme 2. Synthesis of ruthenium nanoparticles with different phosphine ligands
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All the RuNPs stabilized with these phosphine ligands were characterized by transmission electron
microscopy (TEM) and the size of the nanoparticles were found to be < 2ꢀ3 nm with a broad
distribution of size (see supporting information).
The results obtained after screening of this reaction at different conditions are tabulated in Table 1. At
the beginning of the study, to ruleꢀout any background reactions for the formation of tetraphenyl
pyrazine 2a, experiments were planned without using RuNPs and reactions were run for longer
reaction times (16 h) and at higher temperatures. Interestingly, both reactions led to the formation
triphenyl oxazole 3a rather than pyrazine 2a (Table 1 entries 2 and 3). These reactions clearly
evidence that the Ru particles catalyze the reaction and form pyrazine as the clean product. The
reactions were also conducted with the precursor for RuNPs such as [Ru(COD)(COT)] complex,
under the same reaction conditions. However, this reaction proceeded to 2a slowly compared to Ru1
catalyzed synthesis (Table 1 entry 4 vs 1) and when the reaction was carried out at room temperature
o
(~ 22 C) it failed to give the product (Table 1 entry 5). The reaction was also conducted in different
solvents such as isopropanol, ethyl acetate, 1,4ꢀdioxane and toluene. The reaction in isopropanol
produced a mixture of 2a/3a (Table 1 entry 6), but the remaining solvents failed to produce any
product (Table entries 7ꢀ10) hence DMF was adopted as solvent of choice.
a
Table 1. Screening of different reaction conditions.
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b
entry
RuNPs
solvent
DMF
temp
85
85
156
85
rt
conv. (%)
ratio 2a:3a
100:0
0:100
15:85
100:0
N/A
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Ru1
>98
>98
>98
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DMF
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ꢀꢀ
DMF
Ru(COD)(COT)
DMF
c
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Ru1
DMF
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Ru1
Ru1
IPA
80
76
85
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85
85
45
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71:29
N/A
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EtOAc
dioxane
Toluene
DMF
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Ru1
0
N/A
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Ru1
0
N/A
e
10
Ru2
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>98
81:19
100:0
100:0
e
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Ru3
DMF
e
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2
Ru4
DMF
Ru(COD)(COT)+
Xantphos (1:1)
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DMF
85
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100:0
14
Ru(Xantphos)
Ru/C
2
H
2
DMF
DMF
85
85
7
100:0
100:0
15
69
a
b
all the reactions were performed using 1.0 mmol of substrate; conversion is determined using GC
analysis relative to the substrate; 0.5 mol% of the catalyst used based on Ru content by elemental
analysis elemental analysis; reaction time 16 h.; 1.0 mol% of the catalyst used based on Ru content
by EDX analysis; N/A = not applicable.
c
d
e
The reactions were also run with different RuNPs such as Ru2, Ru3 and Ru4 under similar conditions
as those used for Ru1. Amongst these Xantphos supported RuNPs (Ru4) showed activity and
selectivity similar to (Ru1) (Table 1, entries 11ꢀ13). In order to find if any traces of molecular
complex Ru(Xantphos) present in the RuNPs were acting as the catalyst, we conducted the reaction
using 1:1 mixture of Ru(COD)(COT) and Xantphos (both 1.0 mol% of loading) under similar reaction
conditions used for Ru4 catalysis. However, this reaction produced only 16% conversion to pyrazine
2
a (Table 1, entry 13). The second experiment was performed with freshly prepared molecular
o
complex such as Ru(Xantphos) H , from 1:1 mixture of Ru(COD)(COT) and Xantphos at 150 C
2
2
2
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under 3 bars of hydrogen. This reaction also failed to produce the desired product in good
conversion (Table 1, entry 14). The reaction was also carried out with commercially available 5%
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ruthenium on carbon (Ru/C) under the same reaction conditions which produced 69% conversion to
pyrazine 2a. Thus, Ru metal surfaces show activity for this reaction, but phosphine modified RuNPs
2
4a
show a much higher reactivity as was found before for arene hydrogenation.
The reactions conducted with different nitrogen sources such as NH OAc, NH
solution failed to deliver the 2a, but formation of oxazole 3a was observed when NH OAc was used
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4 3
Cl, aqueous NH
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30% conversion). Based on these studies RuNPs stabilized with dbdocphos Ru1 and Xantphos Ru4
were found to be the efficient catalysts for this transformation. However, Xantphos is commercially
available and cheaper ligands for the stabilization of RuNPs hence we further expanded the substrate
scope with Xantphos stabilized ruthenium nanoparticles Ru4 and the results are tabulated in Table 2.
Having established the screening conditions with Ru4 (Table 1 entry 13), we next sought to screen the
major substrate scope with Ru4 as the catalyst (Table 2). Firstly, 4ꢀfluoro substituted benzil 1b was
screened with nanoparticles Ru1, Ru4 and 5% Ru/C. Ru/C proved to be less reactive (Table 2,
entry1). Ru1 and Ru4 gave greater conversion to the product and in the latter case, the desired
pyrazine 2b was isolated in 86% after flash chromatography (Table 2 entries 2 and 3). The reaction of
bromo substituted benzil 1c with Ru4 nanoparticles gave complete conversion to pyrazine 2c with an
yield of 45% (Table 2, entry 4). The substrates containing electron rich groups on the arenes ring such
as pꢀmethyl 1d and pꢀmethoxide substituted benzils 1e were found to be less reactive in the reaction.
The reaction of 1d with Ru4 gave complete conversion to product 2d after 5h and the desired product
was isolated in 91% yield (Table 2, entry 5). Similarly, p-anisil 1e required longer reaction times (12
h) and the desired pyrazine was isolated in 78% yield (Table 2, entry 6). The reaction conducted with
mꢀanisil 1f was found to be faster than that of pꢀanisil and the reaction was complete in 1 h and the
corresponding pyrazine 2f was isolated in 72% yield (Table 2 entry 7). The substrate containing
heteroarene substituent such as furil, under the same catalytic conditions, after 1h, produced pyrazine
2g in 61% yield (Table 2, entry 8). The cyclic substrates such as 1,2ꢀcyclohexanedione 1h gave
complete conversion to the desired products 2i and the product was purified over neutral alumina in
decent yield (Table 2, entry 9). The reaction with 1,2ꢀcyclopentadione gave the desired pyrazine in
moderate yield of 51% as crude product (Table 2, entry 10).
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a
Table 2. RuNPs catalyzed synthesis of pyrazines from αꢀdiketones.
b,c
entry
RuNPs
5% Ru/C
Ru1
product
time (h)
yield (%)
F
F
F
F
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3
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1
12
79
N
N
2b
2c
2d
2e
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Ru4
>98 (86)
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Ru4
Ru4
Ru4
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>98 (45)
>98 (84)
>98 (76)
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7
12
Ru4
Ru4
2f
1
1
>98 (72)
>98 (61)
8
9
2g
N
N
>
98 (78)
Ru4
Ru4
2h
2i
1
2
d
1
0
>98 (51)
a
b
all the reactions were carried out using 1.0 mmol of substrate and 1.0 mol% Ru catalyst; conversión
determined either crude 1HNMR/GC analysis; yields reported in parenthesis; isolated as a crude product
c
d
In order to adapt this methodology for the synthesis of alkylꢀsubstituted pyrazines, we screened
acyclic αꢀdiketones such as biacetyl and 3,4ꢀhexanedione under the same reaction conditions as those
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for Ru4. Surprisingly, these reactions failed to produce the expected alkyl pyrazines, but instead the
reactions gave trisubstituted imidazoles (Scheme 3). Synthesis of trisubstituted imidazoles from αꢀ
2
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diketones is a wellꢀknown preparation method. However, this reaction requires additional substrate
aldehyde along with αꢀdiketones, also needed super heating conditions and microwave irradiation or
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micro reactor system under pressure. Our reaction conditions with Ru4 for the first time yields
imidazoles from αꢀdiketones without requiring aldehydes in the reaction with mild conditions. We
believe that the reaction proceeds in situ giving rise to the generation of acyl equivalent from the
diketone via retro aldol condensation followed by condensation with diketone and ammonium formate
under similar conditions as reported in the literature.
Scheme 3. Synthesis of trisubstituted imidazoles from acyclic αꢀdiketones
The proposed mechanism for the formation of pyrazines assumes that αꢀdiketone undergo
reductive amination under transfer hydrogenation conditions to produce αꢀamino ketone in
presence of RuNPs followed by selfꢀcondensation to give the intermediate 2,3,5,6ꢀ
tetraphenylꢀ2,5ꢀdihydropyrazine which then aromatizes to give the pyrazines (Scheme 4).
Scheme 4. Proposed mechanism for the formation of pyrazines
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In order to demonstrate the general synthetic utility of this methodology, we chose to synthesize
biologically important pyrazines such as 2l and 2m. The pyrazine 2l is an estrogen receptor which has
been synthesized in the literature in 2 steps, first, condensation between pꢀanisil and 1,2ꢀbis(4ꢀ
3
methoxyphenyl)ethylenediamine to give the pyrazine which was demethylated with BF .DMS to give
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the pyrazine 2l. We were able to synthesize this pyrazine 2l from diketone 1l under our optimized
reaction conditions with Ru4 (1.0 mol%) in 52% isolated yield. Pyrazine 2m is a key intermediate for
a marine cytotoxic natural product Dragmacidin B. There are several synthetic routes reported in
literature for the preparation of 2m which include condensation of bromo substituted oxotryptamine in
o
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ethanol/xylene at 135 C for 72 h or Pdꢀcatalyzed Suzuki coupling of 2,5ꢀdibromopyrazine. Our
approach for the synthesis of 2m involves starting with diketone 1m which is obtained by treating
32
with 5ꢀbromoꢀindole with oxalyl chloride followed by reduction with nBu
3
SnH, which then was
subjected under Ru4 catalyzed conditions to give pyrazine 2m in 40% yield (Scheme 5).
Scheme 5. Synthetic application of the methodology for the preparation of 2l and 2m.
Conclusion
In conclusion, during our attempts of transfer hydrogenation with Ru NPs and formate as a hydrogen
donor we have discovered a new general synthetic protocol for the synthesis of substituted pyrazines
and imidazoles from readily available αꢀdiketones. The Ru NPs play a role in hydrogen borrowing
during this reaction and as dehydrogenation catalyst. Phosphine ligands influence the catalyst
properties, and as Xantphos performed well, the scope was studied with this commercially available
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ligand. This ruthenium based catalytic system requires only low catalyst loadings, mild reaction
conditions and shows a good substrate scope. The catalyst can be removed by adsorption on silica or
alumina. Aryl and alkyl diketones reacts differently with RuNPs and produced pyrazines and
imidazoles respectively. This newly developed protocol offers rapid access to biological important
pyrazine scaffolds such as 2l and 2m.
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Experimental section
1.
General remarks
All air and moisture sensitive reactions were performed under argon atmosphere using ovenꢀdried
glassware by standard Schlenkꢀline techniques. Unless specified, all reagents and starting materials
were purchased from commercial sources and used as received. All the dry solvents were obtained
from solvent purification system (SPS). Thinꢀlayer chromatography was performed on aluminum
sheets (silica gel 60); detection was by UV and by coloration with vanillin. Flash column
chromatography was performed using silica gel 60 (230−400 mesh).
NMR spectra were recorded on 500, 400 and 300 MHz spectrometers at room temperature. All NMR
1
13
spectra are referenced relative to the solvent residual peak. All the Chemical shifts of H, C and are
reported in ppm. Signals are quoted as s (singlet), d (doublet), dd (double doublet), m (multiplet), b
(
broad).
All the αꢀdiketones were purchased from commercial sources and the substrates 1l and 1m were
29,31
prepared according to literature protocols.
Ru(COD)(COT) was purchased from NanoMePS (and
used as received. Xantphos, DPEphos, dppp were purchased and dbdocphos was prepared according
to literature procedure.
TEM analyses were performed on a Zeiss 10 CA electron microscope at 100 kV with a resolution of 3
Å. Samples were prepared drop casting (from various THF) onto a holey Formvar/carbonꢀcoated
copper grid.
2
4
General procedure for synthesis of Ruthenium nanoparticles
In an oven dried 100 mL Schlenk tube was added appropriate phosphine ligand (0.1 equiv.) and
o
anhydrous degassed THF (60 mL) under argon. The reaction mixture was cooled to ꢀ110 C with
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liquid nitrogen and transferred the solution into a Fischerꢀporter reactor containing [Ru(COD)(COT)]
o
complex (60.0 mg 0.19 mmol, 1.0 equiv.) at ꢀ110 C. Then the reactor was pressurized with 3 bars of
hydrogen and stirred at room temperature for 16 h. Reaction mixture turned to black solution and a
drop of solution was deposited on copper grid for TEM analysis. Degassed pentane was added to the
solution to precipitate the nanoparticles and the solvent was removed in vacuo, the resulting solid
nanoparticles were washed with degassed pentane (2x 10 mL). The resulting particles were dried in
vacuo overnight. The obtained RuNPs were stored in Schlenk tube under argon for the catalytic
reactions.
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Ru1 Elemental analysis: Ru 32.02, P 5.71, C 27.13, H 4.45
Ru2 EDX analysis: Ru 43.95, P 2.18, C 17.59, O 33.03, Si 3.24
Ru3 EDX analysis: Ru 48.29, P 1.28, C 15.77, O 30.11, Si 4.55
Ru4 EDX analysis: Ru 47.45, P 2.42, C 20.61, O 28.53, Si = 0.99
33
2,4,5ꢀTriphenyloxazole (3a)
In an ovenꢀdried Schlenk tube benzil (1a) (210 mg, 1.0 mmol), anhydrous DMF (3.0 mL) and
ammonium formate (315 mg, 5.0 mmol) were charged under argon atmosphere. The resulting reaction
mixture was stirred at 85 °C for 16 h. The reaction mixture was poured into water and extracted with
EtOAc (2×10.0 mL). The combined organic layers were washed with water (2x10.0 mL), brine (2x10
2 4
mL) dried over Na SO . The volatiles were removed under reduced pressure to afford the crude
product, which was purified by flash column chromatography (SiO ; 0ꢀ10% EtOAc in hexane) to
2
1
afford the title compound 3a as a white solid (174 mg, 87%). H NMR (500 MHz, CDCl
3
): δ 7.34ꢀ7.45
(
m, 6 H), 7.46ꢀ7.52 (m, 3 H), 7.60ꢀ7.72 (m, 2 H), 7.75ꢀ7.77 (m, 2 H), 8.17ꢀ8.20 (m, 2 H);
13
1
C{ H}NMR (125 MHz, CDCl ): δ 126.8, 126.9, 127.8, 128.5, 128.6, 128.9, 129.0, 129.1, 129.4,
3
130.7, 133.0, 137.2, 145.9, 160.5.
General Procedure for the Preparation of Pyrazines and imidazoles using Ru4.
In an ovenꢀdried Schlenk tube, a αꢀdiketone (1aꢀ1m) (1.0 mmol), anhydrous DMF (3.0 mL) and
ammonium formate (5.0 mmol) were charged under argon atmosphere. The reaction mixture was
degassed by three vacuum/argon cycles, followed by ruthenium nanoparticles (Ru4, 1.0 mol%) were
added. The resulting mixture was stirred at 85 °C for the appropriate time (1 h to 12 h). Reaction
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mixture was poured into water (5 mL) and extracted with EtOAc (2x10.0 mL). The combined organic
layers were washed with water (2x10.0 mL), brine (2x10 mL), dried over Na SO . The solvent was
2
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removed in vacuo to afford the crude product, which was purified by flash column chromatography
(SiO or neutral alumina; hexane/EtOAc) to afford the pyrazines (2aꢀ2h) and imidazoles.
2,3,5,6ꢀTetraphenylpyrazine (2a)
Synthesized according to General procedure, substrate 1a (210.0 mg, 1.0 mmol), ammonium formate
2
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9
0
3
4
(
315.0 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%) in anhydrous DMF (3.0 mL) were
o
stirred at 85 C for 1h. The title compound was obtained after flash column chromatography (SiO ,
2
1
hexane/EtOAc 95:5) as a white solid (177 mg, 92%). H NMR (500 MHz, CDCl
3
): δ 7.32 ꢀ 7.39 (m,
13
1
1
2 H), 7.66 ꢀ 7.69 (m, 8 H); C{ H}NMR (125 MHz, CDCl
3
): δ 128.4, 128.7, 130.0, 138.6, 148.6.
12
2,3,5,6ꢀTetrakis(4ꢀfluorophenyl)pyrazine (2b)
Synthesized according to General procedure, substrate 1b (246.0 mg, 1.0 mmol), ammonium formate
(
315.0 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%)) in anhydrous DMF (3.0 mL) were
o
stirred at 85 C for 1h. The title compound obtained after flash column chromatography (SiO
2
,
o
1
hexane/EtOAc 95:5) as a pale yellow solid (197 mg, 86%). MP: 232ꢀ235 C; IR (DCM): H NMR
13
1
(
500 MHz, CDCl ): δ 6.99ꢀ7.10 (m, 8 H), 7.53ꢀ7.64 (m, 8 H); C{ H}NMR (125 MHz, CDCl ): δ
3
3
1
15.6, 115.7, 131.7, 131.8, 134.2, 134.3, 147.5, 162.4, 164.3; HRMS (ESI): C28H1
6
F
4
N
2
[M]+
calculated: 456.1250, found: 456.1230.
,3,5,6ꢀTetrakis(4ꢀbromophenyl)pyrazine (2c)
Synthesized according to General procedure, substrate 1c (365.0 mg, 1.0 mmol), ammonium formate
3
5
2
(
315.0 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%)) in anhydrous DMF (3.0 mL) were
o
stirred at 85 C for 1h. The title compound was isolated after flash column chromatography (SiO ;
2
1
hexane/EtOAc 95:5) as a white solid (158 mg, 45.2% yield); H NMR (500 MHz, C
6
D
6
): δ 7.18ꢀ7.20
): δ 123.8, 131.5, 131.9, 136.8, 147.5;
HRMS (MALDI): calculated for (C H Br3 BrN )+, [M+H]+: 698.8099, found: 698.8120.
1
3
1
(
m, 8 H), 7.28ꢀ7.30 (m, 8 H); C{ H}NMR (126 MHz, CDCl
3
79
81
2
8
17
2
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2,3,5,6ꢀTetraꢀ(pꢀtolyl)pyrazine (2d)
Synthesized according to General procedure, substrate 1d (238.0 mg, 1.0 mmol), ammonium formate
(315 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%)) in anhydrous DMF (3.0 mL) were
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o
stirred at 85 C for 5h. The title compound was isolated after flash column chromatography (SiO
2
;
hexane/EtOAc 95:5) as a white solid (186.0 mg, 84% yield). H NMR (500 MHz, CDCl ): δ 2.36 (s,
3
13
1
3
12 H), 7.17 – 7.04 (m, 8 H), 7.54 (d, J = 8.1 Hz, 1H); C{ H}NMR (101 MHz, CDCl ): δ 21.3, 128.9,
+
129.7, 135.9, 138.4 147.8; HRMS (MALDI) calculated for C32H2
8
N
2
., [M]+: 440.2247, found:
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440.2252.
1
29
2,3,5,6ꢀTetrakis(4ꢀmethoxyphenyl)pyrazine (2e)
Synthesized according to General procedure, substrate 1e (270.0 mg, 1.0 mmol), ammonium formate
(
315 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%)) in anhydrous DMF (3.0 mL) were
o
stirred at 85 C for 12 h. The title compound was isolated after flash column chromatography (SiO
2
;
1
hexane/EtOAc 90:10) as a white solid (192.0 mg, 76% yield). H NMR (CDCl
3
δ 3.71 (s, 6 H), 6.89
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1
(
dd, J = 2.7, 1.4 Hz, 1 H), 6.90 (dd, J = 2.6, 1.4 Hz, 1 H), 7.16ꢀ7.25 (m, 6 H); C{ H}NMR (125
MHz, CDCl ): δ 55.4, 115.0, 115.1, 122.6, 129.4, 139.9, 148.4, 159.6.
3
3
3
2,3,5,6ꢀTetrakis(3ꢀmethoxyphenyl)pyrazine (2f)
Synthesized according to General procedure, substrate 1f (270.0 mg, 1.0 mmol), ammonium formate
(
315 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%)) in anhydrous DMF (3.0 mL) were
o
stirred at 85 C for 5 h. The target compound was isolated after flash column chromatography (SiO ;
2
1
hexane/EtOAc 95:5) as a white solid (182.0 mg, 72% yield); H NMR (500 MHz, CDCl
3
):δ 3.71 (s,
12 H), 6.89 (dd, J = 2.7, 1.4 Hz, 4 H), 6.90 (dd, J = 2.6, 1.4 Hz, 4 H), 7.16ꢀ7.25 (m, 8 H);
13
1
C{ H}NMR (125 MHz, CDCl ): δ 55.4, 115.0, 115.1, 122.6, 129.4, 139.9, 148.4, 159.6.
3
6a
2,3,5,6ꢀTetrakis(2ꢀfuryl)pyrazine (2g)
Synthesized according to General procedure I, substrate 1g (190.0 mg, 1.0 mmol), ammonium
formate (315 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%) in anhydrous DMF (3.0 mL)
o
were stirred at 85 C for 1 h. The title compound was isolated after flash column chromatography
1
(
SiO
2
; 0ꢀ20% EtOAc in hexane) as a white solid (105.0 mg, 61% yield). H NMR (500 MHz, CDCl
3
):
δ 6.54 (dd, J = 3.6, 1.8 Hz, 4 H), 6.80 (dd, J = 3.4, 0.8 Hz, 4 H), 7.56 (dd, J = 1.8, 0.8 Hz, 4 H);
13
1
C{ H}NMR (125 MHz, CDCl
3
): δ 112.0, 112.9, 138.0, 144.1, 150.7; HRMS (ESI) calculated for
+
C
20
H
12
N
2
O
4, [M+Na] : 367.0687, found: 367.0685.
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4
1,2,3,4,6,7,8,9ꢀOctahydrophenazine (2h)
Synthesized according to General procedure I, substrate 1h (112.0 mg, 1.0 mmol), ammonium
formate (315 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%)) in anhydrous DMF (3.0 mL)
o
were stirred at 85 C for 2 h. The title compound was isolated by flash column chromatography
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(neutral Al O ; 1ꢀ5% EtOAc in hexane) as a white solid (73.0 mg, 78% yield). H NMR (500 MHz,
2
3
1
3
1
3 3
CDCl ): δ 1.88ꢀ1.91 (m, 8 H), 2.85ꢀ2.90 (m, 8 H); C{ H}NMR (125 MHz, CDCl ): δ 23.0, 31.8,
149.5.
3
6
1
,2,3,5,6,7ꢀHexahydroꢀdicyclopentapyrazine (2i)
Synthesized according to General procedure, substrate 1i (98.0 mg, 1.0 mmol), ammonium formate
(
315 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%)) in anhydrous DMF (3.0 mL) were
o
stirred at 85 C for 2 h. The title compound was isolated as the crude product. (41.0 mg, 51%
1
yield). H NMR (500 MHz, CDCl
3
): δ 2.04 (dt, J = 14.1, 6.7 Hz, 4 H), 2.48 (t, J = 7.1 Hz, 3 H), 2.62
(
t, J = 6.7 Hz, 5 H).
26a
2,4,5ꢀTrimethylꢀ1Hꢀimidazole (2j)
Synthesized according to General procedure, substrate 1j (86.0 mg, 1.0 mmol), ammonium formate
(
315 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%) in anhydrous DMF (3.0 mL) were
o
stirred at 85 C for 1 h. The title compound was isolated by flash chromatography as a grey solid (62
1
13
1
mg, 85%). H NMR (500 MHz, CDCl
3
): δ 2.10 (s, 6 H), 2.30 (s, 3 H); C{ H}NMR (126 MHz,
CDCl ): δ 10.6, 13.8, 125.8, 141.9.
3
3
7
2,4,5ꢀTriethylꢀ1Hꢀimidazole (2k)
Synthesized according to General procedure, substrate 1l (114.0 mg, 1.0 mmol), ammonium formate
(
315 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%)) in anhydrous DMF (3.0 mL) were
o
stirred at 85 C for 16 h. The title compound was isolated after flash chromatography as a viscous oil
1
(
90 mg, 89% yield). H NMR (300 MHz, CDCl
3
): δ 1.16 (t, J = 7.6 Hz, 6 H), 1.24 (t, J = 7.6 Hz, 3
H), 2.50 (q, J = 7.7 Hz, 4 H), 2.67 (q, J = 7.7 Hz, 2 H), 5.5ꢀ6.0 (bs, 1H).
1
2
4,4',4'',4'''ꢀ(pyrazineꢀ2,3,5,6ꢀtetrayl) Tetraphenol (2l)
Synthesized according to General procedure, substrate 1l (121 mg, 0.5 mmol), ammonium formate
(175 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 1.1 mg, 1.0 mol%) 1.0 mg) in anhydrous DMF (3.0 mL)
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were stirred at 85 C for 16 h. The title compound isolated by flash chromatography (SiO , 0ꢀ30%
1
EtOAC in hexane) as a grey solid (57 mg, 51% yield). H NMR (300 MHz, Acetone): δ 6.82 (dd, 8H),
7.52 (dd, 8H), 8.60 (s, 4H).
3
0a
6ꢀBromoꢀ3ꢀ(5ꢀ(6ꢀbromoꢀ3a,7aꢀdihydroꢀ1Hꢀindolꢀ3ꢀyl)pyrazinꢀ2ꢀyl)ꢀ1Hꢀindole (2m)
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Synthesized according to General procedure, substrate 1m (252.0 mg, 1.0 mmol), ammonium formate
(
315 mg, 5.0 mmol) and Ru4 (47.5 wt% Ru, 2.2 mg, 1.0 mol%) in anhydrous DMF (3.0 mL) were
o
stirred at 85 C for 16 h. The product was isolated after flash chromatography on silicagel using 10%
1
EtOAc in hexane as yellow solid (93 mg, 40% yield). H NMR (300 MHz, DMSOꢀd ): δ 7.33 (dt, J =
6
8.6, 2.0 Hz, 1H), 7.71 (q, J = 1.7 Hz, 1H), 8.32 (t, J = 2.5 Hz, 1H), 8.41 (dd, J = 8.6, 2.7 Hz, 1H), 8.88
(
d, J = 2.3 Hz, 1H), 11.85 (s, 1H).
Acknowledgement
This work was supported by The European Union is acknowledged for ERC Advanced Grant
(
NANOSONWINGS 2009ꢀ246763). The authors also acknowledge Dr. Marta Giménez Pedrós and
Dr. Yvette Mata Campaña for assistance with high pressure experiments, Maria José Hueso Estornell
for GCꢀMS measurements and Marta Serrano Torné for technical support. The authors gratefully
thank Dr. Rita Marimon and Dr. Mariana Stefanova for TEM and EDX measurements.
Supporting Information
NMR spectra of all compounds in the Experimental Section and TEM images, UV, TGA and HRMS
spectra are available in the supporting information document. This material is available free of charge
via the Internet at http:// pubs.acs.org.
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