Additive-Controlled Switchable Selectivity from Cyanobenzenes to 2-Alkynylpyridines: Ruthenium(II)-Catalyzed [2+2+2] Cycloadditions of Diynes and Alkynylnitriles

Article abstract of DOI:10.1002/adsc.201800228

A highly efficient additive-dependent chemoselective protocol for the synthesis of fused cyanoarenes and 2-alkynylpyridines has been developed by the reaction of 1,6-diynes with alkynylnitriles using chloro(pentamethylcyclopentadienyl) (cyclooctadiyne)ruthenium(II) as catalyst in dimethoxyethane (DME). The course of the reaction can be drastically altered simply by adding a catalytic amount of AgOTf as an additive resulting in a comprehensive shift in product formation from cyanoarenes to 2-alkynylpyridines. Theoretical studies clearly indicate that the neutral Ru-complex is responsible for the formation of cyanobenzenes, whereas the in situ generated cationic Ru-complex plays a crucial role in the 2-alkynylpyridines formation. (Figure presented.).

Full text of DOI:10.1002/adsc.201800228

Title: Additive Controlled Switchable Selectivity from Cyanobenzenes
to 2-Alkynylpyridines: Ruthenium(II) Catalyzed [2+2+2]
Cycloadditions of Diynes and Alkynylnitriles
Authors: Divya Bhatt, Neha Patel, Hrishikesh Chowdhury, Prasad V
Bharatam, and Avijit Goswami
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800228
Link to VoR: http://dx.doi.org/10.1002/adsc.201800228

Advanced Synthesis & Catalysis
10.1002/adsc.201800228
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Additive-Controlled Switchable Selectivity from Cyanobenzenes
to 2-Alkynylpyridines: Ruthenium(II) -Catalyzed [2+2+2]
Cycloadditions of Diynes and Alkynylnitriles
a
b
a
b
Divya Bhatt, Neha Patel, Hrishikesh Chowdhury, Prasad V. Bharatam, and Avijit
a,
Goswami *
a
Department of Chemistry, Indian Institute of Technology Ropar, Nangal Road, Rupnagar, Punjab-140001, India
E-mail: agoswami@iitrpr.ac.in
Department of Medicinal Chemistry, National Institute of Pharmaceutical Education and Research (NIPER), Sector 67,
b
S. A. S. Nagar 160062, Punjab, India
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
A
highly efficient additive-dependent simple modification in the reaction conditions such as
chemoselective protocol for the synthesis of fused
cyanoarenes and 2-alkynylpyridines has been developed by
the reaction of 1,6-diynes with alkynylnitriles using chloro-
temperature, additive, etc., keeping the reactants,
solvent, and the catalyst unchanged. Therefore, for
this purpose, acetylene, and the nitrile moieties should
be present in the same compound and, thus, we
hypothesized that alkynylnitriles, in this respect,
(
pentamethylcyclopentadienyl)(cyclooctadiyne)-
ruthenium(II) as catalyst in dimethoxyethane (DME). The
course of the reaction can be drastically altered simply by
adding a catalytic amount of AgOTf as an additive could be the suitable candidates to react with 1,6-
resulting in a comprehensive shift in product formation diynes in a chemoselective manner to provide either
from cyanoarenes to 2-alkynylpyridines. Theoretical
fused cyanobenzenes or 2-alkynylpyridines under
studies clearly indicate that the neutral Ru-complex is
appropriate reaction conditions. The challenge was to
responsible for the formation of cyanobenzenes, whereas
find out a suitable catalyst and the reaction conditions
the in situ generated cationic Ru-complex plays a crucial
to make one functional moiety to react
role in the 2-alkynylpyridines formation.
chemoselectively in the presence of the other. In this
Keywords: alkynylnitriles; cyanobenzenes; 2-alkynyl-
pyridines; [2+2+2] cycloaddition; ruthenium catalyst
connection, our group has recently demonstrated a
protocol for the synthesis of fused cyanoarenes via
chemoselective iron-catalyzed [2+2+2] cycloaddition
[11]
reactions of diynes with alkynylnitriles. In addition,
Yamamoto et al. reported chemoselective synthesis of
The [2+2+2] cycloaddition reactions between 1,6- pyridine rings from the reaction of diynes with
[12]
diynes and acetylenes/nitriles have already conjugated alkynylnitriles. However, none of these
established themselves as elegant, atom-efficient, and reports present chemoselective synthesis of both the
group-tolerant processes for the synthesis of fused cycloadducts (benzenes and pyridines) applying the
aromatic carbo- and heterocycles, involving the same
formation of several C-C and C-heteroatom bonds in
a single step. Various transition-metal complexes of
[
1]
[2]
[3]
[4]
[5]
cobalt, iron, ruthenium, rhodium, iridium,
nickel,[ palladium,[7] gold, and niobium are
presently widely utilized for [2+2+2] cycloaddition
reactions of 1,6-diynes and acetylenes/nitriles (used
separately) to synthesize different types of fused
6]
[8]
[9]
[
10]
benzenes and pyridines, respectively (Scheme 1).
In continuation of our research in the field of metal-
catalyzed [2+2+2] cycloaddition reactions, we
devoted our effort to develop a [2+2+2] cycloaddition
protocol in which both benzene and pyridine rings
could be constructed in a chemoselective manner by
Scheme 1. Transition metal catalyzed [2+2+2] cyclo-
addition reactions for the synthesis of fused benzenes and
pyridines.
1
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Advanced Synthesis & Catalysis
10.1002/adsc.201800228
[
b]
starting materials, solvent, and catalyst. Such a type
of selectivity control is highly challenging and rare. In
this context, Joyanta et al. recently showed a
complete switch in the reaction pathway of a rhodium
catalyzed C-H functionalization reaction by a simple
change in anion and solvent polarity.[13]
Isolated yield.
cyanoarenes and 2-alkynylpyridines presented herein
is an atom-economical, straight-forward process
providing good to high yields within 3-30 min and
moreover, to the best of our knowledge, it is the first
report to utilize [2+2+2] cycloaddition protocol to
prepare arenes and heteroarenes using same reactants,
solvent and catalyst (Scheme 1).
To obtain the optimum reaction conditions for the
chemoselective [2+2+2] cycloaddition reactions for
synthesis of cyanoarenes 3aa and 2-alkynylpyridines
Over the last decade, the general synthetic routes to
prepare cyanobenzene compounds have mainly
encompassed transition-metal-catalyzed cyanation of
[14]
aryl halides,
which involves certain drawbacks
such as use of toxic reagents, harsh reaction
conditions and formation of undesired byproducts. On
the other hand, the synthesis of 2-alkynylpyridines
mainly rely on palladium-catalyzed Sonogashira
cross-coupling reactions,[15] which are generally
accompanied by the formation of Glaser homo-
coupling product. In this context, the ruthenium
catalyzed [2+2+2] cycloaddition protocol for the
synthesis of fused
4
aa, diyne 1a and 3-phenylpropiolonitrile 2a were
chosen as model substrates for the said purpose.
In the course of our previous survey on several
metal
complexes
dipimp/Zn, FeCl .4H
dppe, (PPh RhCl, Ni(COD)
PPh
[CpCo(CO)
O/dipimp/Zn, [Ir(COD)Cl]
/xantphos, Pd (dba)
2
],
CoCl
2
.6H O
2
/
/
/
2
2
2
3
)
3
2
2
3
3
as suitable catalysts for chemoselective [2+2+2]
cycloaddition reactions of alkynylnitriles with diynes,
the FeCl .4H O/dipimp/Zn catalytic system in DME
2
2
was found to be the best choice for the synthesis of
fused cyanoarenes 3 in a chemoselective manner
Table 1. Optimization of reaction conditions[a]
(
Table 1, entry 1). However, changing several
commonly used solvents and adding additive to the
said iron catalytic system did not give access to the
desired 2-alkynylpyridine 4 (Table 1, entries 2-5).
Therefore, we focused our attention on commercially
available and relatively inexpensive Cp*Ru(COD)Cl
as a catalyst for the said chemoselective cycloaddition
Entry Catalyst additive solvent time
Yield[b]
%)
aa 4aa
(
3
1
2
[Fe]
[Fe]
-
DME
DME
20
min
0.5 h 70
86
-
AgOTf
-
3
4
5
6
7
8
9
[Fe]
[Fe]
[Fe]
[Ru]
[Ru]
[Ru]
[Ru]
-
EtOH
EtOH
THF
DCE
THF
0.5 h 81
-
-
-
AgOTf
5 h
2
21
72
-
-
-
-
-
1 h
1 h
58 21
65
-
-
-
DMSO 1 h
DMF
2-3
65 10
min
1
1
0
1
[Ru]
[Ru]
-
DME
DME
0.5 h 82
-
84
BF
3
.Et
2
O
2-3
-
-
-
min
2-3
1
1
2
3
[Ru]
-
AgOTf
DME
86
-
min
24 h
AgOTf/
DME
3 2
BF .Et O
1
1
4
5
[Ru]
[Ru]
Bu
Bu
4
NBr
NCl
DME
DME
1 h
1 h
48
41
-
-
4
DME: Dimethoxyethane; DCE: 1,2-Dichloroethane; DMF:
N,N-dimethylformamide; [Fe]: FeCl .4H O (5 mol%)/2-(2-
-diisopropylphenyl)-iminomethylpyridine (dipimp) (6
mol%)/Zn (10 mol%); [Ru]: Cp*Ru(COD)Cl (3 mol%)
2
2
6
[
a]
Optimized reaction conditions for 3aa [Method A]: 1a
0.5 mmol), 2a (0.6 mmol), Cp*Ru(COD)Cl (3 mol%),
DME (0.5 mL), open flask, room temperature, 30 min. 4aa
Method B]: 1a (0.5 mmol), 2a (0.6 mmol),
Cp*Ru(COD)Cl (3 mol%), AgOTf (3 mol%), DME (0.5
mL), open flask, room temperature, 2-3 min.
(
Scheme 2. Chemoselective ruthenium-catalyzed cyclo-
additions leading to arylnitriles 3: 1 (0.5 mmol), 2 (0.6
mmol), Cp*Ru(COD)Cl (3 mol%), DME (0.5 mL), open
flask, room temperature, 30 min.
[
2
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Advanced Synthesis & Catalysis
10.1002/adsc.201800228
reaction as it is one of the widely used precatalyst for lity of this protocol (Scheme 2). In all cases, trace
benzene and pyridine rings construction. Among the amount of dimer (dimerization of diyne) was obtained,
various solvents tested (Table 1, entries 6-10), DME however, no self cyclotrimerization of alkynylnitrile
was found to be best choice for the synthesis of took place.
cyanoarene 3aa in high yield under aerobic conditions
Table 1, entry 10, method A).
We next evaluated the scope for the
chemoselective synthesis of 2-alkynylpyridines 4 by
(
With a set of optimized conditions in mind for the ruthenium catalyzed cycloaddition reactions of diynes
synthesis of cyanoarene 3aa, we further devote our and alkynylnitriles in presence of AgOTf as an
attention to accomplish the suitable reaction additive (method B) and the results are summarized
conditions for the construction of alkynylpyridine 4aa in Scheme 3. It is noteworthy to mention that all the
from the same model substrates 1a and 2a using
Cp*Ru(COD)Cl as a catalyst in DME. Fortunately, various alkyl- and aryl-substituted alkynylnitriles as
when catalytic amount of BF .Et O was added as an well as carbon, oxygen, nitrogen tethered diynes,
additive in the said cycloaddition reaction, 2-alkynyl- indicating the efficiency and novelty of this protocol.
cycloadditions were successfully carried out using
3
2
pyridine 4aa was obtained as the sole cycloadduct in In addition, formation of compounds 4bb and 4bd
high yield (Table 1, entry 11). The yield of the illustrated that the reaction was not limited to terminal
pyridine product was further enhanced when AgOTf diynes but also worked well with internal diynes.
was added as an additive (Table 1, entry 12, method Compound 4aa was isolated as a pure single crystal
B), while none of the products (3aa or 4aa) was and the structure was unequivocally confirmed by
[16]
obtained in the absence of Ru catalyst using either single-crystal X-ray analysis.
AgOTf or BF .Et O (Table 1, entry 13). However, n- To the best of our knowledge, these results
Bu NX (X = Br, Cl) were able to provide demonstrate the first example of the chemoselective
cyanobenzene 3aa in relatively low yields (Table 1, construction of 2-alkynylpyridines (heteroaromatic
entry 14-15). Sonogashira products) via transition metal catalyzed
Under the optimized reaction conditions (method [2+2+2] cycloaddition reactions.
3
2
4
A), the scope and generality of this mild protocol was
After having the optimized conditions for both the
explored. A library of arylnitriles 3 was synthesized cycloadducts in chemoselective manner, we expanded
from the reaction of terminal and internal diynes with
this cycloaddition reaction to non-conjugated
various alkynylnitriles in good to high yields, alkynylnitrile to check the general applicability of the
indicating the remarkable functional group compatibi- protocol. To our delight, our newly developed
chemoselective protocol gave access to the
compounds 6 and 7 in reasonable to good yields
(
Scheme 4).
Scheme 4. Synthesis of 6 and 7 via chemoselective
ruthenium-catalyzed [2+2+2] cycloaddition of 1,6-diyne
and non-conjugated alkynylnitrile 5.
Inspired by these results, we further explored the
chemoselectivity of the ruthenium-catalyzed cycload-
dition reactions of diyne 1a with bromoacetonitrile in
the presence of phenylacetylene (Scheme 5). Much to
our surprise, the desired cycloadducts 8 and 9 were
Scheme 3. Synthesis of 2-alkynylpyridines
4
via
chemoselective ruthenium-catalyzed cycloadditions: 1 (0.5
mmol), 2 (0.6 mmol), Cp*Ru(COD)Cl (3 mol%), AgOTf
Scheme 5. Synthesis of compounds 8, 9, 11 and 13 by
chemoselective ruthenium-catalyzed cycloadditions.
(
3 mol%), DME (0.5 mL), open flask, room temperature,
-3 min.
2
3
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Advanced Synthesis & Catalysis
10.1002/adsc.201800228
obtained in chemoselective manner depending on the
It is clear from the catalytic cycles that intermediate
presence or absence of additive. In the similar way, B is responsible for the formation of cyanobenzenes,
intramolecular cycloaddition of compound 10 was whereas, ruthenacycle K is responsible for the
carried out and interestingly, the compound 11 was formation of 2-alkynylpyridines. It is anticipated that
obtained within 2-3 min as the sole product in the relatively electron rich neutral Ru-complex
B
absence of additive. In presence of additive, the (natural charge on Ru metal 0.692) readily reacts with
reaction did not stop at the stage of compound 12, electron poor triple bond of the alkyne moiety of
double [2+2+2] cycloaddition led to compound 13 as alkynylnitrile to obtain cyanobenzene as the sole
the main product (Scheme 5). These results clearly cycloadduct (Figure 2). This phenomenon was further
indicate that the developed protocol could be easily supported experimentally when the said cycloaddition
implemented as a late stage methodology for various was carried out in the presence of n-Bu
4
NX (Table 1,
natural products synthesis. entries 13-14) to obtain cyanobenzene as the sole
To our delight, we have also found that the present product. On the other hand, relatively electron poor
ruthenium catalyzed cycloaddition protocol can be cationic Ru-complex K (natural charge on Ru metal
applied for the preparation of 2-triazole substituted 0.627) interacts easily with electron rich nitrile moiety
pyridine 15 by a sequential reaction of diyne 1a with of the alkynylnitrile to give 2-alkynylpyridine as the
alkynylnitrile 2a to prepare 4aa under optimized only cycloadduct (Figure 2). Furthermore, it is found
reaction conditions (method B), followed by the that the rate of the reaction is very fast for 2-
addition of benzyl azide 14 in presence of alkynylpyridine formation compared to cyanobenzene.
Cp*Ru(COD)Cl as a catalyst (Scheme 6).
This observation can be explained on the basis of
higher degree of stabilization of intermediate K
compared to B. From the geometrical parameters, it is
evident that the positive charge on Ru complex K
undergoes ring resonance stabilization (as shown in
Figure 2), which is not occurring in B.
Scheme 6. Synthesis of 2-triazole substituted pyridine 15.
In the course of understanding the mechanism, it
was found from the literature that most of the transiti-
on metal complexes coordinate with the triple bond of
2
the acetylene moieties of cyanoacetylenes in η -
fashion (side-on mode).[ On the other hand, only Figure 2. Selected bond lengths (A°) and natural charges
17]
(
shown in color red) for ruthenacycles B and K.
cationic ruthenium complexes prefer to co-ordinate
with alkynylnitrile through the lone pair of nitrogen
1
[18]
DFT calculations to elucidate the role of BF .Et O
3
2
in η (N)-fashion (end-on mode).
Based on this
were also performed (Table 1, entry 11). It was clear
from the calculations that BF .Et O does not generate
cationic Ru species since the free energy of formation
for this reaction was positive (ΔG = 56.09 kcal/mol)
which makes it highly unsuitable for the reaction to
follow the cationic pathway (Scheme 8).
above said information and from energy profile
diagram (shown in Figure 1), possible reaction
mechanisms for the chemoselective formation of
cyanobenzene 3aa and 2-alkynylpyridine 4aa are
depicted in Scheme 7 (detail of the energy profile
diagram is shown in SI).
3
2
Scheme 8. ΔG value in kcal/mol for the formation of P.
Again, calculations were also performed for a
neutral pathway where BF
3
.Et O might coordinate to
2
the nitrogen of alkynylnitrile (Scheme 9). However,
the overall energy released in this process was
observed to be ΔG = - 90.9 kcal/mol, which was not
sufficiently negative (ΔG for the formation of
benzene is -120 kcal/mol) to confirm the
chemoselectivity of pyridines over benzenes. So at
Scheme 7. Possible catalytic cycles for the chemoselective
synthesis of cyanobenzene 3aa and 2-alkynylpyridine 4aa.
4
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Advanced Synthesis & Catalysis
10.1002/adsc.201800228
Figure 1. Potential energy surface (based on ΔG values in kcal/mol) for the formation of 3aa (shown in color blue) and
aa (shown in color red) using chemoselective cycloadditions.
4
this moment, it is difficult to comment on the role of (cyanides and alkynyls) on the rings in a single
BF
3
.Et
2
O for the said reaction.
operation.
Experimental Section
General procedure for ruthenium(II) catalyzed
chemoselective [2+2+2] cycloaddition reactions leading
to the formation of arylnitriles 3: To a round bottom
flask, a solution of alkynylnitrile (0.6 mmol) in DME (0.5
mL) was added. Cp*Ru(COD)Cl (5.7 mg, 3 mol%) and
diyne (0.5 mmol) were added and the reaction mixture was
stirred at room temperature under open flask. After
completion of reaction checked by TLC, the crude reaction
mixture was filtered and purified through column
O as an additive. chromatography over silica gel using hexane/ethyl acetate
as eluents to obtain the desired product.
3 2
Scheme 9. Formation of 4aa using BF .Et
In conclusion, we have developed an additive
dependent Cp*Ru(COD)Cl catalyzed cycloaddition General procedure for ruthenium(II) catalyzed
protocol for the chemoselective construction of chemoselective [2+2+2] cycloaddition reactions leading
functionalized cyanoarenes and 2-alkynylpyridines in to the formation of 2-alkynylpyridines 4: To a round
DME with good to very high yields. Due to bottom flask, diyne (0.5 mmol), alkynylnitrile (0.6 mmol)
impressive functional group compatibility of this and AgOTf (3.8 mg, 3 mol%) were added and dissolved in
protocol, a wide range of cyanobenzenes and 2- DME (0.5 mL) followed by the addition of
alkynylpyridines were achieved. The chemoselective Cp*Ru(COD)Cl (5.7 mg, 3 mol%). The reaction mixture
cycloaddition reactions were further extended to non was stirred at room temperature under open flask. After
conjugated alkynylnitrile to exhibit the general completion of reaction checked by TLC, the crude reaction
applicability of the protocol. It is important to mixture was purified through column chromatography over
mention that we have achieved, for the first time, a silica gel using hexane/ethyl acetate as eluents to obtain the
Ru-based catalytic system which can allow us to con-
struct aromatic and heteroaromatic rings in a chemo-
selective manner and introduce functional groups
desired product.
5
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Advanced Synthesis & Catalysis
10.1002/adsc.201800228
Itoh, J. Am. Chem. Soc. 2005, 127, 605-613; j) J. A.
Varela, L. Castedo, C. Saá, J. Org. Chem. 2003, 68,
Acknowledgements
8
595-8598; k) Y. Yamamoto, R.Ogawa, K. Itoh, J. Am.
Authors are grateful to SERB, DST for its generous
financial support and Dr. C. M. Nagaraja, IIT Ropar
for solving the single crystal structure. DB & HC
would like to thank UGC & IIT Ropar, respectively,
for their fellowships.
Chem. Soc. 2001, 123, 6189-6190.
[
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To benzenes: a) S. Nishigaki, Y. Shibata, K. Tanaka, J.
Org. Chem. 2017, 82, 11117-11125; b) R. Shintani, C.
Takagi, T. Ito, M. Naito, K. Nozaki, Angew. Chem. Int.
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10.1002/adsc.201800228
UPDATE
Additive Controlled Switchable Selectivity from
Cyanobenzenes
to
2-Alkynylpyridines:
Ruthenium(II) Catalyzed [2+2+2] Cycloadditions
of Diynes and Alkynylnitriles
Adv. Synth. Catal. Year, Volume, Page – Page
Divya Bhatt, Neha Patel, Hrishikesh Chowdhury,
Prasad V. Bharatam, Avijit Goswami*
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