Sequential decarboxylative azide-alkyne cycloaddition and dehydrogenative coupling reactions: One-pot synthesis of polycyclic fused triazoles

Article abstract of DOI:10.3762/bjoc.10.321

Herein, we describe a one-pot protocol for the synthesis of a novel series of polycyclic triazole derivatives. Transition metalcatalyzed decarboxylative CuAAC and dehydrogenative cross coupling reactions are combined in a single flask and achieved good yi

Full text of DOI:10.3762/bjoc.10.321

Sequential decarboxylative azide–alkyne cycloaddition and
dehydrogenative coupling reactions: one-pot synthesis of
polycyclic fused triazoles
Kuppusamy Bharathimohan1,2, Thanasekaran Ponpandian3, A. Jafar Ahamed*1
and Nattamai Bhuvanesh4
Letter
Open Access
Address:
Beilstein J. Org. Chem. 2014, 10, 3031–3037.
1PG and Research Department of Chemistry, Jamal Mohamed
College, affiliated to the Bharathidasan university, Thiruchirapalli -
620020, Tamilnadu, India, 2Orchid Chemicals & Pharmaceuticals Ltd,
Drug Discovery Research, R&D Center, Sholinganallur, Chennai -
600119, India, 3Inogent Laboratories Pvt Ltd, API R&D, 28A, IDA,
Nacharam, Hyderabad-500076, India and 4X-ray Diffraction
Laboratory, Department of Chemistry, Texas A&M University, College
Station, Texas 77842, United States
doi:10.3762/bjoc.10.321
Received: 09 September 2014
Accepted: 02 December 2014
Published: 17 December 2014
Associate Editor: T. J. J. Müller
© 2014 Bharathimohan et al; licensee Beilstein-Institut.
License and terms: see end of document.
Email:
A. Jafar Ahamed* - agjafar@yahoo.co.in
* Corresponding author
Keywords:
copper(II) acetate; decarboxylative CuAAC; dehydrogenative
coupling; fused triazoles; one-pot synthesis
Abstract
Herein, we describe a one-pot protocol for the synthesis of a novel series of polycyclic triazole derivatives. Transition metal-
catalyzed decarboxylative CuAAC and dehydrogenative cross coupling reactions are combined in a single flask and achieved good
yields of the respective triazoles (up to 97% yield). This methodology is more convenient to produce the complex polycyclic mole-
cules in a simple way.
Introduction
The copper-catalyzed Huisgen [3 + 2] cycloaddition (or copper- bond formation method including the stability and preparation
catalyzed azide–alkyne cycloaddition, CuAAC) between an of the starting material and the non-hazardous byproducts. In
organic azide and a terminal alkyne is a well-established 2011, Kolarovič et al. [6] first reported the copper-catalyzed de-
strategy for the construction of 1,4-disubstituted 1,2,3-triazoles carboxylative [3 + 2] cycloaddition reaction of 2-alkynoic acid
[1-4]. In a recent development, this decarboxylative coupling with organic azides. This kind of decarboxylative CuAAC reac-
reaction was well documented for the generation of C–C bonds tion has not been further investigated. Transition metal-medi-
[5]. This method has several advantages over the classical C–C ated C–H bond activation has become a hot topic in recent years
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Beilstein J. Org. Chem. 2014, 10, 3031–3037.
[7-11]. Formally, it requires insertion of a transition metal describing the combination of decarboxylative CuAAC reac-
(usually Pd, Ru, Rh or Ir) across a strong C–H bond tion and C–H activation in an one-pot fashion. This strategy
(90–105 kcal/mol) to form a new, weaker C–M bond describes the preparation of fused triazoles by one-pot reaction
(50–80 kcal/mol), followed by generation of a new C–C bond. of 2-alkynoic acid and azide derivatives.
Generally, transition metal-catalyzed sp2 C–H activation is
facilitated by directing groups [10-13] or heteroatoms in the Results and Discussion
heterocyclic compounds [14-18]. This methodology has been According to the report of Kolarovič et al., the decarboxylative
applied in the synthesis of polycyclic frameworks as well as in CuAAC reaction occurs efficiently with a CuSO4/NaAsc/
the preparation of biologically important compounds [19-23]. DMSO catalytic system [6]. The palladium-catalyzed oxidative
Further development of this reaction has led to double C–H ac- dehydrogenative coupling reaction may be effected by various
tivation which has been used for the construction of biaryl com- oxidants [42,43] such as Ag2O, AgOAc, Ag2CO3, Na2S2O8,
pounds [24-33]. The double C–H activation (dehydrogenative Cu(OPiv)2, Cu(OAc)2, benzoquinone and O2 among others. In
cross coupling) reaction can be classified into two categories: the present study, we have chosen a Cu2+ salt because it can be
intermolecular and intramolecular. There are several reports in used as an oxidant and as a pre-catalyst for the C–H functional-
literature describing intermolecular sp2 C–H/C–H coupling ization and the decarboxylative CuAAC reaction, respectively.
reactions [24-33], whereas only limited reports are available for 1-(2-Azidophenyl)-1H-benzo[d]imidazole (1a) and phenylpro-
intramolecular sp2 C–H/C–H coupling reactions [34-38]. Com- piolic acid (2a) were selected as model substrates to optimize
pounds containing a fused triazole skeleton show remarkable the reaction conditions. Initially, the decarboxylative CuAAC
biologically activities [39] and new strategies to prepare this reactions were carried out with 10 mol % of CuSO4∙5H2O and
class of molecules are highly warranted. Several methodologies 20 mol % of NaAsc in DMSO at 80 °C. After 2 h, TLC showed
were developed for the synthesis of fused triazoles [40]. Acker- the completion of the cycloaddition reaction and mass spectro-
mann referred to an intramolecular dehydrogenative coupling of metric analysis, [M + 1] peak at 338.1, of the reaction mixture
1,4-disubstituted triazoles to achieve tri- and tetracyclic tria- confirmed the formation of 3a. The reaction mixture was
zoles [34]. Recently, Lautens et al. [41] described a one-pot divided into three equal portions and transferred to separate
synthesis of fused triazoles through CuAAC reaction followed round bottom flasks and the cross coupling was carried out with
by C–H functionalization (Scheme 1).
5 mol % of three different Pd2+ catalysts and 2 equivalents of
CuSO4∙5H2O (Cu2+ used for decarboxylative CuAAC) at
Specifically, they demonstrated a C–H functionalization of an 120 °C for 12 h. It failed to undergo the oxidative dehydrogena-
indole nucleus with 5-iodo-1,2,3-triazoles. In the present study, tive coupling reaction and the triazole derivative 3a was
we replaced the 5-iodo-1,2,3-triazoles with 5H-1,2,3-triazoles isolated in 79–82% yield (Table 1, entries 1–1b). A similar
with intramolecular sp2 C–H/C–H cross coupling reaction. To reaction sequence was performed with different copper salts
the best of our knowledge, until now there have been no reports such as CuCl2∙H2O, Cu(OAc)2∙H2O and Cu(NO3)2∙3H2O
Scheme 1: Synthesis of polycyclic fused triazoles.
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Beilstein J. Org. Chem. 2014, 10, 3031–3037.
Table 1: Optimization of reaction conditions for the preparation of 4a.
Entry
Cu2+
Solvent
DMSO
Pd2+
Additive
Time [h]
12
Yield(%)a
3a
4a
1
CuSO4∙5H2O
Pd(OAc)2
PdCl2
–
80
82
79
81
85
80
76
77
78
50
58
52
58
78
76
38
–
–
1a
1b
2
–
–
Pd(PPh3)2Cl2
Pd(OAc)2
PdCl2
–
–
CuCl2∙H2O
DMSO
DMSO
DMSO
DMSO
–
12
12
12
12
–
2a
2b
3
–
–
Pd(PPh3)2Cl2
Pd(OAc)2
PdCl2
–
–
Cu(OAc)2∙H2O
Cu(NO3)2∙3H2O
Cu(OAc)2∙H2O
–
10
trace
–
3a
3b
4
–
Pd(PPh3)2Cl2
Pd(OAc)2
PdCl2
–
–
–
4a
4b
5
–
–
Pd(PPh3)2Cl2
Pd(OAc)2
–
–
pivalic acid
AcOH
35
15
19
39
87
trace
21
24
–
5a
5b
6
TFA
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
Cu(OAc)2∙H2O
dioxane
toluene
1,2-DCE
DMF
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
–
pivalic acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
pivalic acid
–
12
3
7
8b
9
12
12
12
12
12
46
70
66
97
75
10
11
12
NMP
toluene
toluene
Pd(OAc)2
22
aIsolated yield. bReaction was performed at 100 °C.
instead of CuSO4∙5H2O (Table 1, entries 2–4b). Among the toluene, 1,2-dichloroethane, DMF, and NMP were tested in this
Cu2+ salts tested, Cu(OAc)2∙H2O was found to be better than sequential reaction (Table 1, entries 6–10). Toluene was found
others and yielded 10% of 4a (Table 1, entries 3–4b). In the to be superior to other solvents tested, affording a good yield
literature, we found that additives, such as Brønsted acids, (87%) of fused triazole 4a (Table 1, entry 7). No product forma-
enhance the acidity of the C–H bond in several C–H activation tion was observed if the reaction was carried out in the absence
reactions [44-48]. Thus, the reaction was carried out with addi- of Pd(OAc)2 (Table 1, entry 11) and without pivalic acid the
tives such as pivalic acid, acetic acid or trifluoroacetic acid in yield of 4a was only 22% (Table 1, entry 12). All these results
the above catalytic system (Table 1, entries 5–5b). When pivalic demonstrated that the additive and solvent played a crucial role
acid was used, the product formation was improved to 35% in the dehydrogenative coupling reaction.
(Table 1, entry 5a) whereas acetic acid and trifluoroacetic acid
conditions yielded 15% and 19% of 4a, respectively. None of The sequential reaction was performed with phenylacetylene
these modifications provided the desired product in good yield. instead of phenylpropiolic acid and the product 4a was isolated
Therefore, finally we studied the effect of solvents on these in 79% yield (Scheme 2). This result clearly shows that the use
reactions. Several polar and non-polar solvents such as dioxane, of 2-alkynoic acid is more advantageous for this reaction.
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Beilstein J. Org. Chem. 2014, 10, 3031–3037.
Scheme 2: Synthesis of fused triazole 4a using phenylacetylene.
The 1-(2-azidophenyl)-1H-imidazole derivatives 1b and 1c also
participates effectively in the optimized reaction conditions.
The azide derivatives 1a, 1b and 1c were prepared from
1-fluoro-2-nitrobenzene (Scheme 3) according to literature
procedure [49]. Using the optimized reaction conditions, the re-
activity of different 2-alkynoic acids was investigated with 1a
and 1b and the results are shown in Scheme 4.
The electron-donating substituents (OMe)-bearing phenyl ring
in 2b resulted in a good yield of triazole analogs 4b and 4i in
contrast 2c with electron withdrawing methoxycarbonyl substi-
tution provided moderate yields of 4c and 4h (62% and 60%).
Notably, the carboxylate group in 4c and 4h offers a versatile
synthetic functionality for further derivatization reactions. The
thiophene-derived alkynoic acid, 2d, provided the corres-
ponding triazole analogs 4d and 4j in 79% and 73%, respective-
ly. Likewise, the alkynoic acid derived from short and long
linear alkyl chains also provided good yields (75–88%) of poly-
cyclic fused triazoles 4e, 4f, 4k, 4l and 4m (Scheme 4).
Figure 1: ORTEP diagram of 4f (CCDC 979471).
ence of the Cu+ catalyst which is generated by the reduction of
The structures were fully characterized by NMR, IR and mass Cu2+ with sodium ascorbate. The obtained copper acetylide
spectroscopic techniques. Furthermore, the structure of 4f has undergoes regioselective [3 + 2] cycloaddition with azide
been confirmed by single crystal X-ray crystallographic study derivative 1 to yield the copper salt of 3 and a transmetalation
(Figure 1).
reaction gave the intermediate B. We assumed that the pivalate
group replaces the acetate group in B and may produce C. The
The proposed reaction mechanism for the formation of 4 is pivalate group in C facilitates the palladium insertion to the
described in Scheme 5. Initially alkynoic acid 2 undergoes C–H bond to give D and subsequent reductive elimination reac-
decarboxylation to form the copper acetylide (A) in the pres- tion yields the polycyclic triazoles 4.
Scheme 3: Synthesis of 1a, 1b and 1c.
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Beilstein J. Org. Chem. 2014, 10, 3031–3037.
Scheme 4: Synthesis of fused polycyclic triazole analogs 4.
Conclusion
(1b) (0.85 mmol), 2-alkynoic acid (2) (1.02 mmol) and
In summary, we have successfully developed an efficient and Cu(OAc)2∙H2O (0.085 mmol, 10 mol %) in toluene (8 mL) was
convenient one-pot protocol for the synthesis of novel benzimi- added to sodium ascorbate (0.17 mmol, 20 mol %) at room
dazole and imidazole-fused 1,2,3-triazoloquinoxaline deriva- temperature. The mixture was stirred at 80 °C for 2 h.
tives. The key finding of this work is the bifunctional behavior Cu(OAc)2∙H2O (1.7 mmol), Pd(OAc)2 (0.043 mmol, 5 mol %)
of Cu(OAc)2∙H2O in the reaction sequence.
and pivalic acid (2.55 mmol) were added into the above reac-
tion mixture and then refluxed at 120 °C for 3 h. The reaction
mixture was cooled to room temperature and diluted with ethyl
acetate (200 mL). The mixture was filtered through a pad of
celite and the filtrate was washed with water, dried over anhy-
drous Na2SO4 and concentrated under vacuum. The residue was
purified by column chromatography using hexane/ethyl acetate
as eluent to obtain the desired product 4 (60–97%).
Experimental
General procedure for the synthesis of fused
triazoloquinoxaline derivatives 4
Substituted phenylpropiolic acids (2) were prepared by the
literature procedure [50]. To a mixture of 1-(2-azidophenyl)-
1H-benzo[d]imidazole (1a) or 1-(2-azidophenyl)-1H-imidazole
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Beilstein J. Org. Chem. 2014, 10, 3031–3037.
Scheme 5: Proposed mechanism for the formation of 4.
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X-ray crystallographic data of 4f, characterization, 1H and
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