A gold-catalysed imine-propargylamine cascade sequence: Synthesis of 3-substituted-2,5-dimethylpyrazines and the reaction mechanism

Article abstract of DOI:10.1039/c4cc01485e

The gold-catalysed coupling reaction between propargylamine-derived imines and propargylamine exclusively afforded pyrazines. Besides, in order to understand the mechanism of this sequence, deuterium labeling and computational studies have been performed. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01485e

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A gold-catalysed imine–propargylamine cascade
sequence: synthesis of 3-substituted-2,5-
Cite this:DOI: 10.1039/c4cc01485e
dimethylpyrazines and the reaction mechanism†
Received 26th February 2014,
Accepted 12th March 2014
Benito Alcaide,*a Pedro Almendros,*b Jose M. Alonso,a Israel Fernandez,c
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Gonzalo Gomez-Campillosa and M. Rosario Torresd
´
DOI: 10.1039/c4cc01485e
www.rsc.org/chemcomm
The gold-catalysed coupling reaction between propargylamine-derived
imines and propargylamine exclusively afforded pyrazines. Besides, in
order to understand the mechanism of this sequence, deuterium labeling
and computational studies have been performed.
Scheme 1 Cyclization reaction of [(indol-2-yl)methylene]prop-2-yn-1-
amine 1a and propargylamine via gold catalysis.
Aromatic azaheterocycles are key components in a large number of
bioactive molecules. In particular, the electron-deficient pyrazine
nucleus is present in small molecule drugs, which exhibit anti-
tumoral, antiviral, and enzyme inhibitory activities, among others.1 pre-catalyst has little effect on the reaction, because replacing
Besides, the fragrance and agricultural industries take advantage of [(Ph3P)AuNTf2] by [P(tBu)2(o-biphenyl)AuNTf2] did not show
the pyrazine core.2 On the other hand, gold complexes continue to any appreciable difference. Consequently, the much cheaper
attract considerable interest of the synthetic community due to Ph3P complex was used in the following reactions. The gold-
their powerful soft Lewis acidic nature. We decided to analyse catalysed reaction was facile at room temperature in toluene or
the possibility of synthesizing carbolines through metal-catalysed dimethyl sulfoxide (DMSO) and provided the pyrazine product in
cyclization reactions of alkynes with imines derived from indole-2- good yield. Among all the solvents examined, 1,2-dichloroethane
carbaldehyde and propargylamine. Interestingly, it was found that (DCE) proved to be the best choice, affording product 2a in an
the gold-catalysed reaction between imine 1a and propargylamine excellent yield of 96% (Scheme 1). The addition of 3 Å molecular
exclusively afforded the indole-linked pyrazine 2a,3 instead of sieves (MS) to the reaction mixture considerably decreased the
the expected fused carboline 3a (Scheme 1).4 Remarkably, the yield, but did not affect regio- or chemoselectivity. The gold-
rearranged product 2a bears the nitrogen atom in the b-position, catalysed reaction between imine 1a and propargylamine in the
while in the starting imine the nitrogen atom is in the a-position. presence of 3 Å MS did not go to completion, thus highlighting the
Our catalyst screening employing indole-imine 1a led to the identifi- importance of adventitious water for the success of pyrazine
cation of Gagosz’ catalyst [(Ph3P)AuNTf2] as the most suitable formation. The addition of 5 equiv. of H2O to the gold-catalysed
promoter.5 Change in the nature of the phosphine in the gold reaction under otherwise identical conditions accelerated the
conversion and retained the excellent yield. This reaction could
a
also be catalysed by AuCl3, but with diminished effectiveness
because pyrazine 2a was isolated in just 12% yield after 4 days.
Different Lewis acid catalysts such as PtCl2, InCl3, Bi(OTf)3,
ZnCl2, and AgNTf2 were found to be completely ineffective in
carrying out any transformation of the imine.
The scope of the optimized reaction was demonstrated by
utilizing varied propargylamine-derived imines 1b–p. By examining
the influence of the substituent, we found that aromatic and
a,b-unsaturated aldehydes were smoothly transformed into pyra-
zines 2b–p in good yields (Scheme S1, see ESI†). The electronic
nature of the aromatic rings did not have a strong influence on the
above reaction. In fact, different heterocycles were well tolerated.
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Grupo de Lactamas y Heterociclos Bioactivos, Departamento de Quımica Organica,
´
Unidad Asociada al CSIC, Facultad de Quımica, Universidad Complutense de
Madrid, 28040-Madrid, Spain. E-mail: alcaideb@quim.ucm.es;
Fax: +34 91-3944103
b
c
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Instituto de Quımica Organica General, IQOG-CSIC, Juan de la Cierva 3,
28006-Madrid, Spain. E-mail: Palmendros@iqog.csic.es; Fax: +34 91-5644853
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Departamento de Quımica Organica, Facultad de Quımica, Universidad
Complutense de Madrid, 28040-Madrid, Spain
d
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CAI Difraccion de Rayos X, Facultad de Quımica, Universidad Complutense de
Madrid, 28040-Madrid, Spain
† Electronic supplementary information (ESI) available: Experimental proce-
dures, characterization data of new compounds, computational details, and
copies of NMR spectra. CCDC 953438. For ESI and crystallographic data in CIF
or other electronic format see DOI: 10.1039/c4cc01485e
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Scheme 2 Gold-catalysed one-pot protocol for the synthesis of pyra-
zines 2 from aldehydes and propargylamine.
Starting from the corresponding aldehyde and using two equiva-
lents of propargylamine, the gold-catalysed one-pot protocol can
also be accomplished in similar yields (Scheme 2), which in terms
of efficiency and simplicity would be more attractive. To evaluate
the practicability of our method, it was desirable to scale-up the
procedure to obtain gram quantities of pyrazine derivatives. It is
worth noting that no obvious loss of yield was observed for adduct
2g (isolated yield: 90%) when the reaction was carried out on a
1 gram scale and the catalyst loading was reduced from 5 mol% to
1 mol%. Unfortunately, imines derived from propargylamine and
aliphatic aldehydes were not as rewarding as their aromatic
counterparts. The single crystal XRD structure of nitroderivative
2c unambiguously confirmed the 1,4-relationship of the two nitro-
gen atoms of the heterocycle.6
Surprisingly, the reaction is very selective to the assembly of the
amine precursor involved during construction of the diazacycle.
For example, neither secondary propargylamines nor C-substituted
propargylamines were suitable coupling partners in the above gold-
catalysed transformation. On the other hand, when the allenyl-
derived imine 4a was employed, an intractable complex reaction
mixture was formed using buta-2,3-dien-1-amine (Scheme 3). The
reaction of allenyl imine 4a with propargylamine was sluggish and
pyrazine 2a was isolated in very low yield (Scheme 3).
Scheme 4 Deuterium labeling experiments leading to deuterated pyra-
zines [D]-2 via gold catalysis.
any intermediate. 31P NMR spectra were also recorded. The
rapid disappearance of the peak at d = 29.47 ppm (31P NMR
signal of the Gagosz’ catalyst) with concomitant appearance of
a new peak at d = 45.77 ppm may point to the formation of the
propargylamine gold complex. The reaction progress shows
several detectable 31P NMR signals, with an important peak
at d = 39.53 ppm, which appeared quickly (Fig. S3, see ESI†).
After completion of the reaction, the 31P NMR signal of Gagosz’
catalyst reappeared.
To gain mechanistic insights into this transformation,
a deuterium-labeled imine [D1]-1a was prepared. Reaction of
[D1]-1a with propargylamine in the presence of [(Ph3P)AuNTf2]
produced [D1]-pyrazine 2a with total deuterium incorporation
at the methylenic carbon [Scheme 4, eqn (1)]. No doubly
deuterated pyrazine was detected by mass spectrometry, thus
indicating that the rearrangement process occurred exclusively
in an intramolecular fashion. By contrast, triply deuterated
pyrazine [D3]-2f was obtained by an experiment involving mix-
ing equimolar amounts of deuterium-labeled imine [D1]-1f and
[D1]-propargylamine [Scheme 4, eqn (2)]. This triple deuteration
caused both the modification of the peaks at 3.39 and
2.46 ppm, which are the signals of the CHHH protons corres-
ponding to the methyl groups attached to the pyrazine ring, and
the decrease of the signal at 8.25 ppm, which is the signal of the
aromatic CH pyrazine proton, in adduct 2f. NMR calculations
showed, for both cases, a deuteration of 65%. An intermolecular
competition experiment involving equimolar amounts of non-
deuterated imine 1f and [D1]-propargylamine afforded triply
deuterated pyrazine [D3]-2f with 25% of D-isotope abundance
[Scheme 4, eqn (3)]. With the aim of trapping a possible organo-
metallic intermediate in order to understand the mechanism of
this reaction, we performed deuterium labeling studies with
deuterium oxide as well. Under the same above conditions but
with the addition of 20 equiv. of D2O, the reaction between
We monitored the tandem reaction by 1H NMR spectroscopy
(an NMR tube with an equimolecular mixture of imine 1f and
propargylamine and 5 mol% [(Ph3P)AuNTf2]) in order to track
the reaction intermediates (Fig. S2, see ESI†). Even at the early
stage of the reaction the only species that could be clearly
detected were imines 1 and final adducts 2. Unfortunately, we
could not observe, in appreciable amounts, the formation of
Scheme 3 Treatment of allenyl imine 4a with propargylamine as well as
buta-2,3-dien-1-amine via gold catalysis.
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Fig. 1 Computed reaction profile for the gold(I)-catalysed reaction between 1M-Au and propargylamine. Free energies (DG, at 298 K) and bond
distances are given in kcal molÀ1 and angstroms, respectively. [Au]+ denotes [(PMe3)Au]+. All data have been computed at the PCM(dichloroethane)M06/
def2-SVP//B3LYP/def2-SVP level.
imine 1f and propargylamine catalysed by [(Ph3P)AuNTf2] in nucleophilic addition of the imine to the activated-alkyne moiety
1,2-dichloroethane afforded pyrazine [D3]-2f with a 50% deu- through TS2. The ease of this process becomes evident from the low
terium content [Scheme 4, eqn (4)].
barrier (DGa = 5.5 kcal molÀ1) and high exergonicity (DGR = À17.1 kcal
Taking into consideration that the reaction is limited to molÀ1) computed for this step. The new cationic intermediate INT4
terminal alkynes, a reaction mechanism involving dual gold readily releases benzaldehyde by hydrolysis therefore producing INT5.
activation of the alkyne substrates may be contemplated.7 The Similar NTf2À-mediated protonolysis of the Au–C bond leads to the
potential species of this double activation by gold are shown in formation of 2,5-dimethylenepiperazine INT6 with concurrent regen-
Fig. S4 (see ESI†). However, this double activation pathway is eration of the gold catalyst. The latter intermediate readily isomerizes
not in accordance with some of the labeling studies shown in to its more stable 2,5-dimethyl-1,4-dihydropyrazine isomer
Scheme 4 because pentadeuterated [D5]-2 pyrazines should be INT7 (DDG298 = À6.5 kcal molÀ1).12 Then, an intermolecular
obtained instead of triply deuterated pyrazines [D3]-2.8
enamine addition from INT7 towards the gold-activated ben-
Density functional theory (DFT) calculations have been carried out zaldehyde occurs to produce INT8 via TS3, a saddle point
at the PCM-M06/def2-SVP//B3LYP/def2-SVP level9 to gain more insight associated with the formation of the new C–C bond. This
into the reaction mechanism10 of the above-discussed gold-catalysed reaction step also proceeds with a low activation barrier
pyrazine formation. The corresponding computed reaction profile of (DGa = 7.6 kcal molÀ1) in an exergonic transformation (DGR
=
the reaction of imine 1M (bearing a phenyl group as the aromatic À5.5 kcal molÀ1), compatible with a reaction at room tempera-
ring) and propargylamine in the presence of the model catalyst ture. Subsequent proton-migration forming INT9 and release of
[(PMe3)AuNTf2] is depicted in Fig. 1, which shows the corresponding the catalyst produces INT10, which after dehydration leads to
computed free energies (DG298, at 298.15 K) using DCE as the solvent. the 2-alkylidene-3,6-dimethyl-1,2-dihydropyrazine INT11. The
The process begins with the coordination of the gold(I)- last step of the transformation involves the isomerization by
catalyst to the triple bond of imine 1M to form 1M-Au. This species aromatization of INT11 to the final pyrazine 2-Ph.
then undergoes a chemo- and regioselective hydroamination reaction
The above reaction mechanism is fully compatible with the
with propargylamine to produce intermediate INT1. This exergonic deuterium labeling experiments depicted in Scheme 4. Despite
process (DGR = À14.0 kcal molÀ1) occurs through transition state TS1, that, one should expect the formation of doubly deuterated
which is associated with the formation of the first N–C bond, with an pyrazines [D2]-2 (Scheme S2, see ESI†) instead of the observed
activation barrier of DGa = 18.1 kcal molÀ1. INT1 then evolves to INT2 triple incorporation of deuterium in pyrazine [D3]-2f. This
via a 1,3-proton shift. This reaction proceeds very likely with the inconsistency may be explained from the fact that intermediate
assistance of NTf2À following a similar protonolysis of the Au–C bond [D2]-INT11 is in equilibrium with the p-allyl complex [D2]-12.13
to that reported by us in related [(PPh3)AuNTf2]-catalysed processes.11 Deuterolysis of the carbon–gold bond in species [D2]-12 generates
Exergonic coordination (DGR = À8.7 kcal molÀ1) of the cationic gold triply deuterated intermediate [D3]-INT11, which finally isomerizes14
in complex INT2 produces INT3, which experiences an intramolecular to form pyrazines [D3]-2 (Scheme 5).
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3 Indole-linked pyrazines 2a–e can be considered as analogues of the
antitumoral meridianins (M. A. A. Radwan and M. El-Sherbiny,
Bioorg. Med. Chem., 2007, 15, 1206) which bear a diazine ring at
the C3 indole position.
Scheme 5 Explanation for the formation of deuterated pyrazines [D3]-2.
4 For the gold-catalysed synthesis of quinoxalines (fused pyrazines)
from in situ generated glyoxals, see: S. Shi, T. Wang, W. Yang,
M. Rudolph and A. S. K. Hashmi, Chem. – Eur. J., 2013, 19, 6576.
In conclusion, it has been observed that the gold-catalysed
coupling reaction between propargylamine-derived imines and pro-
pargylamine exclusively afforded pyrazines. Besides, in order to
understand the mechanism of this sequence, both deuterium labeling
experiments and a computational study have been performed.
Support for this work by the MINECO [Projects CTQ2012-
33664-C02-01, CTQ2012-33664-C02-02, and CTQ2010-20714-C02-
01] and CAM (Projects S2009/PPQ-1752 and S2009/PPQ-1634) is
´
5 N. Mezailles, L. Ricard and F. Gagosz, Org. Lett., 2005, 7, 4133.
6 CCDC 953438. The intermolecular contact N(pyrazine)Á Á ÁH(indole)
in compound 2c may indicate hydrogen bonding; these contacts
link the molecules into dimers (Fig. S1, see ESI†).
7 I. Braun, A. M. Asiri and A. S. K. Hashmi, ACS Catal., 2013, 3, 1902.
8 A. S. K. Hashmi, I. Braun, M. Rudolph and F. Rominger, Organo-
metallics, 2012, 31, 644.
9 See computational details in the ESI†.
10 A. S. K. Hashmi, Angew. Chem., Int. Ed., 2010, 49, 5232.
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gratefully acknowledged. J. M. A. thanks Comunidad Autonoma
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11 (a) B. Alcaide, P. Almendros, S. Cembellın, T. Martınez del Campo and
de Madrid and Fondo Social Europeo for a postdoctoral contract.
G. G. C. thanks the MEC for a predoctoral grant.
´
I. Fernandez, Chem. Commun., 2013, 49, 1282. See also, ; (b) E. Soriano
´
and I. Fernandez, Chem. Soc. Rev., 2014, DOI: 10.1039/c3cs60457h.
12 This reaction mechanism is supported by the isolation of 2,5-dimethyl-
pyrazine during the gold-catalysed dimerization reaction of propargyl-
amine in the absence of an aldehyde.
13 For the study of allylic gold complexes: (a) S. Komiya and S. Ozaki, Chem.
Lett., 1988, 17, 1431; (b) A. S. K. Hashmi, A. M. Schuster, S. Litters,
F. Rominger and M. Pernpointner, Chem. – Eur. J., 2011, 17, 5661.
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1 (a) N. Sato, Pyrazines and their Benzo Derivatives, in Comprehensive
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Scriven and R. Taylor, Elsevier, Oxford, 2008, vol. 8, pp. 273–331; 14 For a quantum mechanical study of the gold-catalysed alkene
(b) M.-P. Cabal, Six-Membered Heterocycles: 1,2-, 1,3-, and
1,4-Diazines: and Related Systems, in Modern Heterocyclic Chemistry,
isomerization, see: A. Basak, K. Chakrabarty, A. Ghosh and
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Chem. Commun.
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