Unprecedented Cu-catalyzed coupling of internal 1,3-diynes with azides: One-pot tandem cyclizations involving 1,3-dipolar cycloaddition and carbocyclization furnishing naphthotriazoles

Article abstract of DOI:10.1021/ol201092k

A one-pot protocol for the synthesis of triazole-annulated polyheterocycles via metal-catalyzed coupling of internal 1,4-disubstituted 1,3-diynes and organic azides has been described. The mechanistic rationale for the reaction suggests tandem cyclization

Full text of DOI:10.1021/ol201092k

ORGANIC
LETTERS
2011
Vol. 13, No. 12
3162–3165
Unprecedented Cu-Catalyzed Coupling of
Internal 1,3-Diynes with Azides: One-Pot
Tandem Cyclizations Involving 1,3-Dipolar
Cycloaddition and Carbocyclization
Furnishing Naphthotriazoles†
Anil K. Mandadapu,‡ Sudhir K. Sharma,‡ Sahaj Gupta,‡ Deevi G Venkata Krishna,§
and Bijoy Kundu*,‡
Medicinal Chemistry Division and Sophisticated Analytical Instrument Facility,
Central Drug Research Institute, CSIR, Lucknow 226 001, India
bijoy_kundu@yahoo.com; b_kundu@cdri.res.in
Received April 26, 2011
ABSTRACT
A one-pot protocol for the synthesis of triazole-annulated polyheterocycles via metal-catalyzed coupling of internal 1,4-disubstituted 1,3-diynes and
organic azides has been described. The mechanistic rationale for the reaction suggests tandem cyclizations involving copper-catalyzed cycloaddition and
6-endo carbocyclization reactions. The cascade cyclization leads to an increase in molecular complexity to furnish naphtho[1,2-d]triazoles in satisfactory
yields. The generality of the method has been demonstrated by using a series of aromatic/aliphatic azides and symmetrical internal 1,3-diynes.
In the past decade, azide alkyne Huisgen 1,3-dipolar
cycloaddition reaction and its variant click chemistry have
evolved as powerful strategies with many applications in
modern chemistry, drug discovery, macromolecules,
radiopharmaceuticals, material sciences, and biology.1
While the former startegy involves coupling under thermal
conditions, the click chemistry conventionally involves
copper(I)-catalyzedcouplingofazidewithterminal alkynes
leading to the regioselective formation of 1,4-disubstituted
1,2,3-triazoles;2 however, in subsequent studies, the
ruthenium-catalyzed reaction was found to furnish the
opposite regioselectivity furnishing 1,5-disubstituted 1,2,3-
triazoles.3 Interestingly, the Ru catalyst also facilitated
fusion of azides with internal alkynes furnishing 1,4,5-
trisubstituted 1,2,3-triazoles, a limitation generally ob-
served with conventionally used Cu catalysts. Indeed,
Nolan et al.4 used a NHCÀCu complex as a catalyst for
the cycloaddition reacton involving internal alkynes. La-
ter, several groups5 extended application of click chemistry
to diynes and reported coupling of terminal 1,3-diynes6
with azides under Cu-catalyzed conditions to furnish regio-
selective 4-ethynyl-1,2,3-triazoles. Recently, in a similar
study using terminal diynes, syntheses of bis-triazoles
were carried out by employing two consecutive Cu-cata-
lyzed cycloaddition reactions in one pot involving
† CDRI communication number: 8064.
‡ Medicinal Chemistry Division.
§ Sophisticated Analytical Instrument Facility.
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r
10.1021/ol201092k
Published on Web 05/17/2011
2011 American Chemical Society

monotriisopropylsilyl-protected diynes and azides.7 It is
worth mentioning that after the first cycloaddtion with
terminal 1,3-diyne the silyl group from the resulting
4-ethynyl-protected 1,2,3-triazole was removed in situ
followed by second engagement of the terminal alkyne at
C-4 with azides to afford bistriazole. Indeed, despite the
successful applications of Cu-catalyzed 1,3-dipolar cy-
cloaddition reactions to terminal diynes, their application
to internal 1,3-diynes has not yet been investigated.
Scheme 1. Copper-Catalyzed Coupling of 1-(4-Phenylbuta-1,3-
diynyl)benzene with 4-Azido-1,2-dimethoxybenzene
We envisaged that use of internal 1,4-disubstituted-1,3-
diynes may trigger sequential cyclizations by first forming
a triazole with the azide via cycloaddition followed by
carbocyclizaton involving alkynyl residue originating
either from C-4 or C-5 of the triazole and the nearest
phenyl ring present either at N-1 or at C-5/C-4. Indeed,
depending on the regioselective formation of the resulting
triazole, the second cyclization may furnish either
naphthotriazole8 or pyridotriazole9 as an annulated poly-
heterocycle. In recent years, an increasing number of
studies have been carried out to develop a cascade reaction
in one pot for the synthesis of triazole-annulated poly-
heterocycles,10 which in turn can be used to obtain bioac-
tive leads. Thus, the search for a concise and more efficient
method for the synthesis of 1,2,3-triazole-annulated poly-
heterocycles in one-pot reactions remains a challenging
task for chemists. In this paper, we describe Cu-catalyzed
coupling of internal 1,3-diynes with organic azides furnish-
ing naphthotriazoles via sequential cyclizations involving
cycloaddition and carbocyclization in one pot. The studies
are a continuation of our interest in the synthesis of
triazole/indole/pyrrole-based annulated polyheterocycles
in minimal steps involving either multistep or via sequen-
tial cyclizations/multicomponent reactions in one pot.11
In our initial studies, we treated 4-azido-1,2-dimethoxy-
benzene with 1-(4-phenylbuta-1,3-diynyl)benzene in the
presence of CuI in toluene at 110 °C. The progress of
reaction was monitored by TLC, and after 3 days of
stirring, we observed the appearance of a new spot along
with unreacted 1,3-diyne as the other component. After
workup and purification by column chromatography, we
observed a new product with a molecular weight of 381.15
Da in 45% isolated yield along with the recovery of
unreacted 1,3-diyne in 20% isolated yield (Scheme 1).
Since the 13C NMR spectrum showed the absence of any
alkyne carbon, we envisaged that triazole formation may
have been followed by carbocyclization. However, de-
pending on the regioselectivity of the triazole formation
during Cu-catalyzed 1,3-dipolar cycloaddition, there can
be a distinct possibility for three probable structures 1À3
(Scheme 1) with identical molecular weights following
carbocyclization. The structure of the product so obtained
was elucidated by the combined use of various homo- and
heteronuclear two-dimensional NMR experiments. Out of
the three probable structures, structure 3, 1-(3,4-dimeth-
oxyphenyl)-5-phenyl-1H-naphtho[1,2-d][1,2,3]triazole, was
thus designated to be the product arising from sequential
cycloaddition and carbocyclization in one pot.
Figure 1 highlights a few selected HMBC and NOE cor-
relations required for the confirmation of structure 3.12 This
was further supported by performing restrained molecular
dynamics calculations using Discover 3.0 software. Distance
restraints were derived on the basis of NOE intensities.12
The mechanistic details for this unprecedented copper-
catalyzed synthesis of triazole involving internal 1,3-diyne
need much more study since involvement of copper acet-
ylides is not possible. Based on our observation, we
propose a plausible mechanism for the formation of 3 as
depicted in Figure 2. The first step of the reaction involves
regioselective formation of triazole via cycloaddition reac-
tion resulting in an intermediate 1-(3,4-dimethoxy-
phenyl)-5-phenyl-4-(2-phenylethynyl)-1H-1,2,3-triazole 4.
Copper complex then presumably forms via alkyne moiety
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Synlett 2007, 1591–1594. (d) Saha, B.; Sharma, S.; Sawant, D.; Kundu, B.
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Org. Lett., Vol. 13, No. 12, 2011
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Figure 2. Plausible mechanism for the copper-catalyzed tandem
cyclizations.
Figure 1. Few important HMBC and NOE correlations for 3.
Table 1. One-Pot Tandem Cyclizations Involving 4-Azido-1,
2-dimethoxybenzene (2.5 Equiv) and 1-(4-Phenylbuta-1,
3-diynyl)benzene (1.0 Equiv) To Form Naphtho[1,2]triazole 3:
Optimization of Reaction Conditions
in the presence of CuI, thereby enhancing its electrophili-
city. The resulting electron-deficient triple bond then un-
dergoes nucleophilic attack by the carbon from the phenyl
ring originating from the C-5 of the triazole, thereby
facilitating intramolecular 6-endo-cyclization to furnish 3.
Interestingly, 3 appeared to be a useful template for the
generation of novel triazole-annulated polyheterocycles in
one pot via tandem cyclization reactions. This led us to
optimize the reaction conditions for improving the yield of
napthotriazole 3 (Table 1). We carried out this reaction by
employing a variety of copper salts, additives, and solvents.
While examining the effect of solvent, we observed an
increase in the yield of 3 to 58% in acetonitrile (entry 5).
Similarly, among various copper catalysts investigated, CuI
produced the best results. This gets further support from
the fact Cu(I) species when generated in situ by a redox
reaction involving FeCl3 and copper metal in water11c
furnished 3 in 40% isolated yield (entry 3). Attempts to
further improve the yield by either increasing the concen-
tration of azides or by extending reaction timings were not
fruitful. Thus, the optimal conditions involved treatment of
azide with 1,3-diyne in the presence of CuI in acetonitrile
under reflux for 2 days. Indeed, the long reaction time,
moderate yields, and absence of intermediate 4 in the
reaction mixture prompted us to explore the role of copper
in both steps. Accordingly, we initially examined the forma-
tion of 3 under thermal conditions in acetonitrile in the
absence of catalyst. The uncatalyzed reaction furnished
traces (<10%) of product 3 as evident by HPLC even after
3 days of reflux (entry 6). Next, in order to examine the effect
of elevated temperatures on the formation of 3in the absence
of catalyst, we carried out the reaction in toluene under
reflux for 2 days. The uncatalyzed reaction was very sluggish
and furnished a mixture of products with the formation 3 in
25% isolated yield (entry 2). This is in contrast to 45%
isolated yield obtained in the presence of copper catalyst in
toluene under reflux (entry 1). Our findings strongly suggest
that in the absence of copper catalyst and under thermal
conditions formation of 3 is extremely sluggish; however,
addition of Cu catalyst increased the yield of 3 in toluene
from 25% to 45% and in acetonitrile from <10% to 58%.
Once the reaction conditions for the synthesis of 3 were
optimized, we then proceeded with the utility of the
method to generate naphthotriazole-based heterosystems.
For this we synthesized 16 compounds (3aÀp) based on 3
temp
(°C)
time
(d)
product
(%)
entry
reaction conditions
CuI in toluene
toluene
Cu/FeCl3 in H2O
CuI in MeCN
CuI in MeCN
MeCN
CuI in THF
CuSO4/sodium ascorbate in
H2O/tBuOH
1
2
3
4
5
6
7
8
reflux
reflux
reflux
rt
reflux
reflux
reflux
rt
2
2
2
2
2
3
2
2
45
25
40
NRa
58
<10b
NRa
NRa
9
CuSO4/sodium ascorbate in
H2O/tBuOH
CuSO4/sodium ascorbate in
H2O/MeCN
CuI/Cu(OAc)2 in MeCN
PdCl2 in MeCN
reflux
reflux
2
2
NRa
NRa
10
11
12
reflux
reflux
2
2
NRa
NRa
a NR = no reaction. b Based on HPLC.
by treating a series of aliphatic and aromatic azides with
symmetrical 1,3-diynes. The compounds were purified by
silica gel chromatography and characterized by NMR
spectroscopy. As shown in Table 2, most of the reactants
examined provided naphthotriazoles in moderate yield. For
all of the reactions, we were able to recover unreacted diynes
which were found to be suitable for reuse. In general, no signi-
ficant difference of reactivity was observed for the examined
aromatic azides, aliphatic azides, and 1,3-diynes with varied
electronic properties. Aromatic azides furnished 3 in yields
ranging from 40 to 60%, whereas aliphatic azides furn-
ished products in 47À55% yield. Similarly, whereas 1-(4-
phenylbuta-1,3-diynyl)benzene furnished products in 42À
58% yield, introducing an electron-donating substituent
on the phenyl rings furnished products in 40À60% yield.
Replacing organic azides with sodium azide failed to facili-
tate tandem cyclizations under Cu-catalyzed conditions.
In summary, an experimentally convenient copper-
catalyzed process for the regioselective synthesis of naphtho-
triazole from organic azides and internal 1,3-diynes has been
developed. The salient features of the strategy comprise
Cu-catalyzed one-pot sequential cyclizations via 1,3-
dipolar cycloaddition and 6-endo carbocyclization. The
generality of the method has been demonstrated by
using a series of aromatic/aliphatic azides and symme-
trical internal 1,3-diynes.
3164
Org. Lett., Vol. 13, No. 12, 2011

Table 2. One-Pot Tandem Cyclizations Involving Copper-Catalyzed Cycloaddition and Carbocyclization To Furnish Diverse
Naphthotriazoles
a Isolated yield based on bis-alkyne, NMR yield using mesitylene as an internal standard.
Acknowledgment. A.K.M., S.K.S., S.G., and D.G.V.K.
are thankful to Council of Scientific and Industrial
Research, New Delhi, for financial support. We thank
Dr. Ravi S. Ampapathi, SAIF, CDRI, for carrying out
molecular dynamics calculations.
Supporting Information Available. Experimental pro-
cedure, characterization data (NMR, IR, HRMS), copies
of 1H and 13C NMR spectra, and restrained MD calcula-
tion details. This material is available free of charge via
the Internet at http://pubs.acs.org
Org. Lett., Vol. 13, No. 12, 2011
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