2,2′-Homocoupled Azine N,N′-Dioxides or Azine N-Oxides: CDC- or SNAr-Controlled Chemoselectivity

Article abstract of DOI:10.1002/ejoc.201700504

An unprecedented Cu(OAc)₂- and LiOtBu-mediated homocoupling of azine N-oxides to yield 2,2′-azine N,N′-dioxides is reported. This is the first instance in which copper has been used to catalyze the homodimerization reaction, especially of 2-phenylpyridine N-oxides. In the absence of catalytic copper, the reaction follows an alternative pathway, and instead of dioxides it yields 2,2′-azine N-monoxides. This latter protocol works efficiently with a range of N-heterocyclic oxides of pyridine, 2-phenylpyridine, quinoline and N-aryl-1,2,3-triazole. It is scalable, offers high regioselectivity and gives the products in moderate to high yields. The observed chemoselectivity between the copper-assisted and copper-free protocols is routed through oxidative cross-dehydrogenative coupling (CDC) and nucleophilic aromatic substitution of hydrogen (S_NAr) pathways, respectively.

Full text of DOI:10.1002/ejoc.201700504

A Journal of
Accepted Article
Title: 2,2'-homocoupled azine N,N'-dioxides or azine N-oxides: CDC or
SNAr controlled chemoselectivity
Authors: Abadh Kishor Jha and Nidhi Jain
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10.1002/ejoc.201700504
European Journal of Organic Chemistry
FULL PAPER
2,2’-homocoupled azine N,N’-dioxides or azine N-oxides: CDC or
SNAr controlled chemoselectivity
Abadh Kishor Jha[a] and Nidhi Jain[a]*
Abstract: An unprecedented Cu(OAc)2 and LitOBu mediated
homocoupling of azine N-oxides to yield 2,2’-azine N,N’-dioxides is
reported. This is the first instance where copper has been used to
catalyze the homodimerization reaction, especially with N-oxides of
2-phenyl pyridine. In the absence of catalytic copper, the reaction
follows an alternative pathway, and instead of dioxide yields the 2,2’-
azine N-monoxides. This protocol works efficiently with a range of N-
heterocyclic oxides of pyridine, 2-phenyl pyridine, quinoline, and N-
aryl-1,2,3-triazole. It is scalable, offers high regioselectivity, and
gives the products in moderate to high yields. The observed
chemoselectivity between copper-assisted and copper-free protocols
is routed through an oxidative cross-dehydrogenative coupling
(CDC), and nucleophilic aromatic substitution of hydrogen (SNAr)
respectively.
involving direct C-H activation through transition-metal catalyzed
oxidative cross-coupling between two hetero(arenes)[6] have
lifted the limitation of working with pre-functionalized substrates,
and have also been accomplished with heterocyclic N-oxides as
the starting material.[7] As shown in Scheme 1, Kuang et al
reported the first oxidative CH/CH direct coupling of azine N-
oxides using a Pd-Ag system.[8] The strategy allowed an access
to homocoupled pyridine N-oxides and 1,2,3-triazole N-oxides,
in addition to the hetero- linked N,N’-dioxide products. This was
followed by the work of Zhu and Liu who reported a similar Pd-
Ag mediated homodimerization of azine N-oxides.[9] However, to
the best of our knowledge, homocoupling of N-oxides with a
copper catalyst still does not exist. Cognizant of the importance
of these molecules, and driven by our interest in developing
copper as a cheap catalyst for C-H functionalizations,[10] we
initiated the work on homocoupling reactions.
Introduction
Bipyridines, biquinolines, biisoquinolines and bitriazoles
constitute an important class of biheterocycles with numerous
applications in drug discovery,[1] and functional materials.[2] Not
only the biheterocycles, but their N-oxides as well as N,N’-
dioxides are important synthetic intermediates, often used as
organocatalysts[3] and ligands[4] in metal-catalyzed reactions
(Figure 1).
Scheme 1. Synthesis of symmetrical azine N, N’-dioxides.
A literature search on homocoupled 2,2’-azine N-oxides
revealed that they have been synthesized starting from azine N-
oxides via a) palladium catalyzed coupling with halogenated
azine (Scheme 2a),[11] b) coupling with 2-pyridyllithium prepared
from 2-bromopyridine and tert-butyl lithium at -78 °C (Scheme
2b),[12] and c) coupling with another molecule of azine N-oxide in
the presence of an organocatalyst (Scheme 2c).[13] However,
each of these reactions suffered from limitations of pre-
functionalized substrate, or expensive Pd catalyst, or drastic
reaction conditions.
In view of above literature, and in continuation of our on-going
interest in chemistry of azine N-oxides,[10(a)] we embarked upon a
Cu(OAc)2 and LitOBu promoted oxidative homocoupling to
synthesize 2,2’-azine N,N’-dioxides in moderate to good yields.
Interestingly, in absence of catalytic copper, the reaction
furnished 2,2’-azine N-monoxides selectively. The observed
chemo-selectivity under the two sets of conditions has been
rationalized based on the CDC and SNAr pathways.
Figure 1. Synthetically useful heterocyclic N,N’-dioxides and N-oxides.
The general synthetic approach to access these biheterocycles
relies on palladium or nickel catalyzed cross-coupling reactions
of
halogenated
N-heterocycles
with
the
heteroaryl
organometallic reagents, which are activated site selectively by
transmetallating groups like SnR3, ZnX, BR2, MgX, or SiR3.[5] Of
late, strategies
aDepartment of Chemistry, Indian Institute of Technology, New Delhi-110016; *E-
mail: njain@chemistry.iitd.ac.in; http://web.iitd.ac.in/~njain/#/home; Fax: +91
11 26581102; Tel: +91 11 26591562.
†Electronic Supplementary Information (ESI) available: copies of 1H NMR, 13C
NMR and X-ray crystallographic data for compounds 2b
& 3d.
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10.1002/ejoc.201700504
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Table 1. Optimization of reaction conditions for homocoupling of 2-phenyl
pyridine N-oxide.[a]
Temp. Catalyst
(o C)
Yield (%)
2a
Entry
Solvent
Base
3a
0
1
2
PhCl
LitOBu
LitOBu
120
120
CuI
CuI
70
Toluene
78,83[b]
0
97,72[c]
,
Scheme 2. Synthesis of azine N-oxides through different methods.
3
Toluene
LitOBu
0
120
120
90
Cu(OAc)2
10[d],20[e]
4
5
6
7
Toluene
Toluene
o-Xylene
m-Xylene
LitOBu
LitOBu
LitOBu
LitOBu
Cu(OAc)2
0[f]
0
0
Results and Discussion
-
-
-
-
18
21
39
We chose to start the work with 2–phenyl pyridine N-oxide (1a),
since no prior literature on its homocoupling through a dual C-H
activation strategy existed. 1a was heated at 120 °C in presence
of LitOBu (3 equiv.) and copper iodide (20 mol%) in
chlorobenzene as the solvent. After allowing the reaction to
continue for 72 h, we were delighted to see the formation of
6,6'–diphenyl-[2,2'-bipyridine] 1,1'-dioxide (2a) in 70% yield
(Table 1, Entry 1). The finding was encouraging since the
previous report on Pd catalyzed homocoupling was
unsuccessful with 2–phenyl pyridine N-oxide as the substrate.[8]
Replacing chlorobenzene with toluene, and reducing the amount
of LitOBu to 2.5 equiv. led to an increase in the yield of 2a to
83% (Table 1, Entry 2). The yield increased further to 97% when
Cu(OAc)2 was used as the catalyst (Table 1, Entry 3). Further
optimizations by reducing the amount of Cu(OAc)2 to 10 mol%,
or reducing the reaction time to 50 h, or carrying out the reaction
in absence of LitOBu resulted in a drastic drop in the product
yield (Table 1, Entry 3). Notably, the reaction did not take place
under nitrogen atmosphere (Table 1, Entry 4). Hence, the best
conditions to synthesize homocoupled 2–phenyl pyridine N,N’-
dioxide were found to be with Cu(OAc)2 (20 mol%) and LitOBu
(2.5 equiv.) in toluene at 120 °C for 72 h. Interestingly, when we
examined the reaction in absence of copper salt; a new product,
6,6'–diphenyl-[2,2'-bipyridine] 1-oxide (3a) was exclusively
formed in 18% yield after 24 h (Table 1, Entry 5). To improve
the yield, optimization of reaction with respect to solvent,
base, temperature, and time was carried out (Table 1, Entries
6-15). Solvents such as o-xylene, m-xylene and chlorobenzene
were screened, and chlorobenzene was found to give the
highest yield of 3a (Table 1, Entries 6-8). Replacement of LitOBu
with other bases such as K2CO3, Cs2CO3, KtOBu and NatOBu
affected the reaction negatively, and no product formation was
seen (Table 1, Entries 9-12). Also, reducing the amount of
LitOBu to 2.5 and 2.0 equivalents dropped the yield to 40 and
25% respectively, suggesting that base had an important role in
the reaction (Table 1, Entry 8). Variation in temperature and time
was carried out next. Raising the temperature to 100 and 120 °C
increased the yield to 85 and 91% respectively, while
90
0
90
0
90
44,40[b]
25[g]
,
8
PhCl
LitOBu
0
9
PhCl
PhCl
PhCl
PhCl
PhCl
K2CO3
Cs2CO3
KtOBu
NatOBu
LitOBu
90
90
-
-
-
-
-
-
0
0
0
0
0
-
-
10
11
12
13
90
-
90
-
100
120
85
91,70[h]
82[i],89[f]
,
14
15
PhCl
PhCl
LitOBu
LitOBu
0
0
130
-
80
[a] Reaction conditions: 1a (1.0 equiv., 0.06 mmol), LitOBu (3.0 equiv., 14.41
mmol) and catalyst (0.2 equiv.) taken in a solvent and heated for 72 h in a
sealed tube; Yields are based on % conversions as determined by HPLC, [b]
LitOBu (2.5 equiv.), [c] Cu(OAc)2 (0.1 equiv.), [d] Time 50 h, [e] No base, [f]
Reaction done under N2 atmosphere [g] LitOBu (2.0 equiv.), [h] Time 15 h, [i]
Time 44 h; For entry 5 to 15, reaction time was 24 h and reaction was done in
absence of catalyst.
increasing it further to 130 °C dropped the yield (Table 1,
Entries 13-15). Lowering the reaction time to 15 h decreased the
yield to 70% while increasing it to 44 h did not help in improving
the yield (Table 1, Entry 14). Thus, the best reaction conditions
to synthesize homocoupled 2–phenyl pyridine N-oxide were
found to be using 3.0 equiv. of LitOBu in chlorobenzene at 120
°C for 24 h.
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Table 2. Homocoupling of 2-phenyl pyridine N-oxide derivatives in presence of
copper catalyst.[a]
Table 3. Homocoupling of 2-phenyl pyridine N-oxide derivatives in absence of
copper catalyst.[a]
[a] Reaction conditions: Isolated yield, 1a-1i (0.53 mmol, 1.0 equiv.), LitOBu
(1.59 mmol, 3.0 equiv.) taken in chlorobenzene solvent and heated at 120 oC
in a sealed tube for 24 h.
[a] Reaction conditions: Isolated yield, 1a-1g (0.23 mmol, 1.0 equiv.), LitOBu
(0.69 mmol, 3.0 equiv.) taken in toluene solvent and heated at 120 oC in a
sealed tube for 72 h.
With the optimized reaction condition in hand, the scope
of copper catalyzed homocoupling for various derivatives of
2–phenyl pyridine N-oxide was explored, and the results are
summarized in Table 2. Reaction with ortho-, meta-, and
para-methyl substituted 2-phenylpyridine N-oxides gave the
corresponding N,N’-dioxides (2b-2d) in 78-84% yields. With
para-ethyl derivative, however, slightly lower yield of the
corresponding product 2e was obtained. Phenyl ring substituted
with electron withdrawing fluoro- group gave the corresponding
products 2f and 2g in 68 and 74% yields respectively. As a
general observation, yield with meta-substituted derivatives (2c
and 2f) was lower compared to the ortho- and para-
counterparts (2b, 2d, 2g). It is noteworthy to reiterate that there
are no prior reports on synthesizing these molecules directly
through dual CH activation.
Table 4. Scope of other N-heterocyclic oxides in absence of copper catalyst.[a]
During the reaction optimization studies (Table 1), we
found that in absence of catalytic amount of copper acetate, the
reaction furnished homocoupled 2-phenyl pyridine N-oxide (3a)
as the only product instead of the dioxide 2a which was formed
under metal-catalyzed conditions. To confirm the generality of
this observation, the reaction was explored with various
derivatives of 2-phenyl pyridine N-oxide. As shown in Table 3,
the desired products (3a-3i) were obtained in moderate to good
yields. It was found that 2-phenylpyridine N-oxide
substituted with electron donating methyl/ethyl group on
phenyl ring gave higher yield of products (3b-3e) compared
to those bearing electron withdrawing fluoro/chloro-
substituents at similar positions (3f-3h). Notably, changing
the position of phenyl substituent on pyridine N-oxide from
[a] Reaction conditions: Isolated yield, 1j-1s (0.23 mmol, 1.0 equiv.), LitOBu
(0.69 mmol, 3.0 equiv.) taken in chlorobenzene solvent and heated at 120 C
in a sealed tube for 24 h.
°
corresponding 2,2’-homocoupled N-oxide products (4a-4d) in
60-86% yields. The lower yield with meta-substituted methyl
derivative (4c, 60%) was in accordance to the earlier
observation with meta-substituted phenyl pyridine N-oxide (3i,
Table 2). The reaction was found to be equally facile with
quinoline and substituted quinoline N-oxides, and gave the
products (4e-4g) in 82-90% yields. Surprisingly, reaction with
isoquinoline N-oxide resulted in complete deoxygenation of the
product, and 1,1’-biisoquinoline (4h) was obtained in 50% yield.
Notably, even N-aryl-1,2,3-triazole N-oxides sustained the
reaction conditions, and the corresponding 5,5’-coupled triazole
N-oxides (4i, 4j) were obtained albeit in lower yields. To
establish synthetic utility of the developed protocol, the reaction
was tested on a gram scale. We were pleased to find that
reaction with 10.5 mmol of 1j under the standard reaction
conditions afforded [2.2'-bipyridine] 1-oxide (4a) in 86% yield
(1.56 g).
2- to 3-, dropped the yield of the corresponding product 3
phenyl pyridine N-oxide 3i) significantly to 50%.
-
(
The scope of metal-free homocoupling was extended to other N-
heterocyclic oxides (Table 4). Pyridine N-oxide (1j), and methyl
substituted pyridine N-oxides were tried, and gave the
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Further, the synthesized biheteroaryl N-oxides could be
transformed to the corresponding biheteroaryls by carrying out
reduction with Zn-dust. As shown in Scheme 3, treatment of
6,6'-bis(4-fluorophenyl)-[2,2'-bipyridine] 1-oxide (3g) with an
excess of Zn-dust in THF:NH4Cl(sat.) for 2 h yielded the
dioxides. The coupled products are obtained in moderate to
good yields with high regio- and chemo-selectivity. The reactions
are highly efficient, and work with a variety of heterocyclic N-
oxides. The methodology is scalable, and provides a practical
access to symmetrical biheterocyclic frameworks. The observed
chemo-selectivity in the reaction is speculated to arise out of the
two mechanistic pathways that might be invoked under copper-
catalyzed and copper-free conditions.
deoxygenated
product,
6,6'-bis(4-fluorophenyl)-[2,2'-
bipyridine] (5a) in quantitative yield.
Experimental Section
All the chemicals were purchased from commercial sources and used as
received. The products were purified by flash column chromatography on
Scheme 3. Deprotection of 6,6'-bis(4-fluorophenyl)-[2,2'-bipyridine] 1-oxide.
1
silica gel using 230-400 mesh. H and 13C NMR spectra were measured
on a Bruker DPX-300 MHz spectrometer (1H 300 MHz, 13C 75MHz),
using CDCl3 as the solvent with tetramethylsilane (TMS) as the internal
standard at room temperature. Chemical shifts are given in δ (ppm)
relative to TMS, the coupling constants (J) are given in Hz. High-
resolution mass spectra were recorded with a Q-TOF instrument, using
electrospray ionization (ESI) as the ionization method.
General experimental procedure for preparation of N-Oxides:
A solution of nitrogenous compound (7.8 mmol) in dichloromethane was
taken in 100 ml round bottom flask. To this solution, 70% mCPBA (1.0
equiv.) was added portion wise at 0 °C. The reaction mixture was stirred
at room temperature for 12 h. The progress of reaction was monitored
through TLC. The reaction mixture was diluted with dichloromethane, 4.0
equiv. of K2CO3 was added, and the contents were stirred for another 10
minutes. The desired product was purified on flash column
chromatography using methanol-dichloromethane solvent.
Scheme 4. Plausible mechanism(s) for homocoupling of heterocyclic N-oxides.
Based on our observations and previous literature,[14] a plausible
mechanism for homocoupling of N-heterocyclic oxides with and
without copper salt is given in Scheme 4. We noticed that the
copper acetate catalyzed coupling did not proceed under
nitrogen atmosphere (Table 1, Entry 4), while it had no influence
when the reaction was carried out under metal-free conditions
(Table 1, Entry 14). This indicated that air was necessary only
under copper catalyzed conditions, and that the reaction
probably followed an oxidative cross-dehydrogenative coupling
(CDC) pathway. In light of this, we propose that the reaction is
initiated by deprotonation of the C2-H by LitOBu to generate the
lithium salt of azine N-oxide (A). This is followed by trans-
metallation with Cu(OAc)2 to give an intermediate B, which
undergoes oxidative coupling in presence of air to yield the
homocoupled 2,2’-azine N,N’-dioxide. In absence of copper
acetate, the reaction follows an alternate nucleophilic aromatic
substitution pathway (SNAr), where intermediate A attacks
another molecule of azine N-oxide to yield an intermediate C
which undergoes loss of LiOH to produce the homocoupled 2,2’-
azine N-oxide.
General experimental procedure for homocoupling of 2-phenyl
pyridine N-oxide derivatives in presence of copper catalyst (2a-2g):
2-phenyl pyridine N-oxide derivatives (0.23 mmol, 1.0 equiv.), LitOBu
(0.69 mmol, 3.0 equiv.) and Cu(OAc)2 (0.2 equiv.) were taken in sealed
tube in 2 ml toluene solvent. The contents were heated at 120 °C for 72
hours. The solvent was evaporated on rotary evaporator. The desired
product was purified through flash column chromatography using
dichloromethane and methanol solvent.
General experimental procedure for homocoupling of azine/azole N-
oxide derivatives in absence of copper catalyst (3a-3i & 4a-4j):
Azine/azole N-oxides (0.53 mmol, 1.0 equiv.) and LitOBu (1.59 mmol, 3.0
equiv.) were taken in sealed tube in 2 ml chlorobenzene solvent. The
contents were heated at 120 °C for 24 hours. The solvent was
evaporated on rotary evaporator. The desired product was purified
through flash column chromatography using ethyl acetate-hexane
solvent.
Experimental
fluorophenyl)pyridine 1-oxide (3g):
procedure
for
deoxygenation
of
2-(4-
Conclusions
In conclusion, we demonstrate for the first time a Cu(OAc)2
-
Compound 1g (0.03 mmol) was dissolved in THF: NH4Cl(aq.) (0.03 M) (1:1
v/v). An excess of zinc dust was added to this solution, and it was stirred
at 70 °C for 2 hours. The reaction was filtered over celite, and the solvent
was evaporated on rotary evaporator at low pressure to get the pure
desired product (5a).
LitOBu mediated oxidative CDC of 2-phenyl pyridine N-oxides to
yield the 2,2’-homocoupled N,N’-dioxides. In contrast, under
copper-free conditions, the homocoupling is routed through an
SNAr pathway, and yields azine N-oxides instead of the N,N’-
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6,6'–diphenyl-[2,2'-bipyridine] 1, 1'-dioxide (2a): Light yellowish
amorphous solid, melting point = 154-156 °C, 179 mg, 90%; IR: (ʋmax/cm-
1) = 1249 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 7.84 (d, J = 5.1 Hz, 4H),
CDCl3) δ 156.7, 150.2, 149.9, 148.2, 139.1, 136.8, 133.4, 129.5, 129.4,
129.1, 128.8, 128.2, 127.1, 126.9, 126.8, 125.2, 124.2, 120.7; HRMS
ESI: [M+H]+, Calculated for C22H17N2O 325.1335; found 325.1323.
7.60 (d, J = 6.9 Hz, 2H), 7.53 (d, J = 7.2 Hz, 2H), 7.37-7.44 (m, 7H); 13
C
NMR (75 MHz, CDCl3) δ 149.8, 143.7, 139.3, 132.5, 129.6, 128.1, 127.7,
127.0, 124.8, 114.1; HRMS ESI: [M+H]+, Calculated for C22H17N2O2
341.1285; found 341.1283.
6,6'-di-o-tolyl-[2,2'-bipyridine] 1-oxide (3b): Brick red crystalline solid,
melting point = 147-149 °C, 152 mg, 80%; IR: (ʋmax/cm-1) = 1259 (R3N+-O-
); 1HNMR (300 MHz, CDCl3) δ 8.91 (d, J = 7.8 Hz, 1H), 8.28 (d, J = 6.0
Hz, 1H), 7.84 (t, J = 7.5 Hz, 1H), 7.46 (bs, 2H), 7.31-7.37 (m, 9H), 2.46
(s, 3H), 2.26 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 159.5, 151.5, 149.4,
147.9, 140.2, 137.8, 136.4, 135.9, 133.7, 130.9, 130.0, 129.8, 129.3,
128.4, 127.3, 127.0, 126.0, 125.9, 124.7, 124.5, 123.6, 20.6, 19.6; HRMS
ESI: [M+H]+, Calculated for C24H21N2O 353.1648; found 353.1660.
6,6'-di-o-tolyl-[2,2'-bipyridine] 1, 1'-dioxide (2b): Light yellowish
amorphous solid, melting point = 184-185 °C, 167 mg, 84%; IR: (ʋmax/cm-
1) = 1245 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 7.66 (d, J = 4.5 Hz, 2H),
7.33 (bs, 5H), 7.27 (s, 7H), 2.28 (s, 6H); 13C NMR (75 MHz, CDCl3) δ
151.2, 143.4, 138.4, 133.1, 130.0, 129.4, 129.3, 128.0, 127.2, 125.7,
123.7, 19.7; DEPT 135 NMR (75 MHz, CDCl3) δ 130.0, 129.4, 129.3,
128.0, 127.2, 125.7, 123.7, 19.7; HRMS ESI: [M+H]+, Calculated for
C24H21N2O2 369.1598; found 369.1610.
6,6'-di-m-tolyl-[2,2'-bipyridine] 1-oxide (3c): colourless crystalline solid,
melting point = 120-121 °C, 160 mg, 84%; IR: (ʋmax/cm-1) = 1257 (R3N+-O-
1
); HNMR (300 MHz, CDCl3) δ 8.80 (d, J = 7.5 Hz, 1H), 8.28 (t, J = 6.0
Hz, 1H), 7.82-7.90 (m, 3H), 7.77 (d, J = 7.8 Hz, 1H), 7.64 (s, 1H), 7.55 (d,
J = 7.2 Hz, 1H), 7.36-7.43 (m, 4H), 7.26 (s, 2H), 2.46 (s, 3H), 2.42 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 156.9, 150.4, 149.9, 148.2, 139.1,
138.4, 137.8, 136.7, 133.3, 130.1, 130.0, 129.8, 128.6, 128.2, 127.6,
127.1, 126.8, 126.5, 125.2, 124.1, 124.0, 120.8, 21.6, 21.4; HRMS ESI:
[M+H]+, Calculated for C24H21N2O 353.1648; found 353.1649.
6,6'-di-m-tolyl-[2,2'-bipyridine] 1, 1'-dioxide (2c): Light brown
amorphous solid, melting point = 160-164 °C, 155 mg, 78%; IR: (ʋmax/cm-
1) = 1247 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 7.75 (s, 2H), 7.62 (t, J =
10.2 Hz, 4H), 7.55 (d, J = 5.7 Hz, 2H), 7.37 (t, J = 6.6 Hz, 4H), 7.29 (bs,
2H); 13C NMR (75 MHz, CDCl3) δ 150.0, 143.6, 137.7, 132.4, 130.3,
130.1, 128.0, 127.5, 126.9, 126.6, 124.4, 21.4; HRMS ESI: [M+H]+,
Calculated for C24H21N2O2 369.1598; found 369.1591.
6,6'-di-p-tolyl-[2,2'-bipyridine] 1-oxide (3d): Colourless amorphous
°
solid, melting point = 172-174 C, 164 mg, 86%; IR: (ʋmax/cm-1) = 1252
6,6'-di-p-tolyl-[2,2'-bipyridine] 1, 1'-dioxide (2d): Light brown
amorphous solid, melting point = 209-210 °C, 163 mg, 82%; IR: (ʋmax/cm-
1) = 1244 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 7.76 (d, J = 5.1 Hz, 4H),
7.51-7.56(m, 4H), 7.26 (bs, 6H), 2.39 (s, 6H); 13C NMR (75 MHz, CDCl3)
δ 150.0, 143.8, 139.7, 129.6, 129.5, 128.7, 127.3, 126.6, 124.6, 21.4;
HRMS ESI: [M+Na]+, Calculated for C24H20N2NaO2 391.1417; found
391.1414.
(R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.79 (d, J = 7.5 Hz, 1H), 8.26 (d, J
= 3.6 Hz, 1H), 7.99 (d, J = 6.9 Hz, 2H), 7.83 (t, J = 7.8 Hz, 1H), 7.70-7.76
(m, 3H), 7.41 (s, 2H), 7.30 (d, J = 7.2 Hz, 4H), 2.42 (s, 6H); 13C NMR (75
MHz, CDCl3) δ 156.7, 150.2, 149.9, 148.2, 139.4, 139.1, 136.7, 136.4,
130.4, 129.5, 129.4, 128.9, 126.9, 126.7, 126.6, 125.1, 123.9, 120.4;
HRMS ESI: [M+H]+, Calculated for C24H21N2O 353.1648; found
353.1648.
6,6'-bis(4-ethylphenyl)-[2,2'-bipyridine] 1, 1'-dioxide (2e): Light brown
viscous liquid, 139 mg, 70%; IR: (ʋmax/cm-1) = 1232 (R3N+-O-); 1HNMR
(300 MHz, CDCl3) δ 7.85 (dd, J’ = 2.1 Hz, J” = 8.1 Hz, 2H), 7.71 (d, J =
8.1 Hz, 4H), 7.40 (dd, J’ = 2.1 Hz, J” = 7.8 Hz, 2H), 7.29 (d, J = 8.1 Hz,
4H), 6.95 (t, J = 7.8 Hz, 2H), 2.70 (q, J = 7.5 Hz, 4H), 1.26 (s, 6H); 13C
NMR (75 MHz, CDCl3) δ 149.7, 146.2, 135.7, 130.4, 129.3, 127.6, 126.8,
125.2, 113.1, 28.7, 15.3, DEPT 135 NMR (75 MHz, CDCl3) δ 135.7,
129.3, 127.6, 126.8, 125.2, 28.8, 15.3; HRMS ESI: [M+H]+, Calculated for
C26H25N2O2 397.1911; found 397.1908.
6,6'-bis(4-ethylphenyl)-[2,2'-bipyridine] 1-oxide (3e): colourless
amorphous solid, melting point = 154-155 °C, 168 mg, 88%; IR: (ʋmax/cm-
1) = 1238 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.80 (t, J = 4.5 Hz, 1H),
8.27 (q, J = 3.6 Hz, 1H), 8.00 (t, J = 5.4 Hz, 2H), 7.81-7.87 (m, 1H), 7.72-
7.75 (m, 3H), 7.40-7.43 (m, 2H), 7.33 (d, J = 6.0 Hz, 4H), 2.72 (t, J = 2.1
Hz, 4H), 1.26-1.31 (m, 6H); 13C NMR (75 MHz, CDCl3) δ 156.7, 150.2,
149.9, 148.2, 145.7, 145.4, 136.7, 136.7, 130.6, 129.5, 128.3, 127.7,
126.9, 126.9, 126.6, 125.1, 123.9, 120.4, 28.8, 28.7, 15.5, 15.5; HRMS
ESI: [M+H]+, Calculated for C26H25N2O 381.1961; found 381.1961.
6,6'-bis(3-fluorophenyl)-[2,2'-bipyridine] 1, 1'-dioxide (2f): Colorless
viscous liquid, 135 mg, 68%; IR: (ʋmax/cm-1) = 1248 (R3N+-O-); 1HNMR
(300 MHz, CDCl3) δ 7.68 (d, J = 10.2 Hz, 2H), 7.54-7.60 (m, 6H), 7.39-
7.49 (m, 4H), 7.11-7.22 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 162.3 (d,
6,6'-bis(3-fluorophenyl)-[2,2'-bipyridine] 1-oxide (3f): Colourless
amorphous solid, melting point = 174-176 °C, 130 mg, 68%; IR: (ʋmax/cm-
1) = 1240 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.84 (d, J = 7.2 Hz, 1H),
8.31 (bs, 1H), 7.85 (q, J = 9.3 Hz, 4H), 7.54-7.62 (m, 2H), 7.47 (d, J = 4.2
Hz, 4H), 7.16 (d, J = 8.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ 163.3 (d,
3
1JCF = 244.2 Hz), 148.5, 143.8, 134.2, 129.6 (d, JCF = 8.2 Hz), 127.6,
2
1
4
127.3, 125.3, 124.5, 116.8 (d, JCF = 23.7 Hz), 116.7, 116.5; HRMS ESI:
1JCF = 241.3 Hz), 162.4 (d, JCF = 244.5 Hz), 155.3 (d, JCF = 2.8 Hz),
[M+Na]+, Calculated for C22H14F2N2NaO2 399.0916; found 399.0946.
149.8, 148.9, 148.1, 141.3, 141.2, 137.0, 135.1, 135.0, 130.2 (d, JCF
=
3
3
4
8.1 Hz), 129.8 (d, JCF = 8.2 Hz), 127.5, 126.9, 125.2 (d, JCF = 3.5 Hz),
124.7, 122.3 (d, JCF = 2.6 Hz), 120.8, 116.7 (d, JCF = 23.6 Hz), 116.3,
116.0 (d, JCF = 21.2 Hz), 114.0, 113.7; HRMS ESI: [M+H]+, Calculated
4
2
6,6'-bis(4-fluorophenyl)-[2,2'-bipyridine] 1,1'-dioxide (2g): Colorless
viscous liquid, 147 mg, 74%; IR: (ʋmax/cm-1) = 1249 (R3N+-O-); 1HNMR
(300 MHz, CDCl3) δ 7.86-7.90 (m, 4H), 7.54 (t, J = 8.1 Hz, 4H), 7.37 (t, J
= 7.2 Hz, 2H), 7.14 (t, J = 8.7 Hz, 4H); 13C NMR (75 MHz, CDCl3) δ 163.3
2
for C22H15F2N2O 361.1147; found 361.1142.
1
3
(d, JCF = 248.7 Hz), 148.82, 143.9, 131.7 (d, JCF = 8.4 Hz), 128.4,
6,6'-bis(4-fluorophenyl)-[2,2'-bipyridine] 1-oxide (3g): Colourless
amorphous solid, melting point = 184-185 oC, 137 mg, 72%; IR:
(ʋmax/cm-1) = 1256 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.77 (d, J = 7.5
Hz, 1H), 8.26 (t, J = 4.5 Hz, 1H), 8.06-8.10 (m, 2H), 7.74-7.89 (m, 4H),
7.44 (d, J = 4.5 Hz, 2H), 7.18 (t, J = 8.1 Hz, 4H); 13C NMR (75 MHz,
127.4, 126.8, 124.6, 115.1 (d, JCF = 21.6 Hz); HRMS ESI: [M+Na]+,
2
Calculated for C22H14F2N2NaO2 399.0916; found 399.0912.
6,6'–diphenyl-[2,2'-bipyridine] 1-oxide (3a): Light yellowish amorphous
1
1
°
solid, melting point = 129-130 C, 178 mg, 94%; IR: (ʋmax/cm-1) = 1256
CDCl3) δ 163.2 (d, JCF = 247.1 Hz), 163.2 (d, JCF = 248.1 Hz), 155.8,
4
3
(R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.82 (d, J = 5.4 Hz, 1H), 8.27 (bs,
149.9, 149.2, 148.2, 136.9, 135.2 (d, JCF = 3.4 Hz), 131.6 (d, JCF = 8.3
Hz), 129.5 (d, JCF = 3.8 Hz), 128.7 (d, JCF = 8.2 Hz), 127.1, 126.7,
4
3
1H), 8.07 (bs, 2H), 7.78 (bs, 4H), 7.40-7.46 (m, 8H); 13C NMR (75 MHz,
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700504
European Journal of Organic Chemistry
FULL PAPER
125.1, 124.0, 120.4, 115.6 (d, 2JCF = 21.4 Hz), 115.3 (d, 2JCF = 21.7 Hz);
HRMS ESI: [M+H]+, Calculated for C22H15F2N2O 361.1147; found
361.1165.
129.8, 129.5, 128.9, 128.1, 128.0, 127.5, 127.4, 125.2, 123.7, 122.8,
120.2; HRMS ESI: [M+H]+, Calculated for C18H13N2O 273.1022; found
273.1020.
6,6'-bis(4-chlorophenyl)-[2,2'-bipyridine] 1-oxide (3h): Colourless
amorphous solid, melting point = 189-190 °C, 134 mg, 70%; IR: (ʋmax/cm-
1) = 1253 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.78 (d, J = 5.7 Hz, 1H),
8.26 (bs, 1H), 8.03 (d, J = 5.4 Hz, 2H), 7.86 (d, J = 5.7 Hz, 1H), 7.76 (bs,
3H), 7.46 (d, J = 7.2 Hz, 6H); 13C NMR (75 MHz, CDCl3) δ 155.5, 149.9,
149.1, 148.2, 137.4, 137.0, 135.4, 135.3, 131.6, 130.9, 128.9, 128.5,
128.1, 127.3, 126.7, 125.2, 124.3, 120.5; HRMS ESI: [M+H]+, Calculated
for C22H15Cl2N2O 393.0556; found 393.0552.
6,6'-dimethyl-[2,2'-biquinoline] 1-oxide (4f): Yellowish crystalline solid,
melting point = 170-172 °C, 170 mg, 90%; IR: (ʋmax/cm-1) = 1257 (R3N+-O-
); 1HNMR (300 MHz, CDCl3) δ 8.89 (d, J = 8.7 Hz, 1H), 8.75 (d, J = 8.7
Hz, 1H), 8.20 (t, J = 9.3 Hz, 2H), 8.06 (d, J = 8.7 Hz, 1H), 7.72 (d, J = 8.7
Hz, 1H), 7.62 (s, 2H), 7.58 (d, J = 2.7 Hz, 1H), 7.55 (bs, 1H), 2.54 (s, 6H);
13C NMR (75 MHz, CDCl3) δ 150.7, 146.6, 143.2, 140.6, 139.1, 137.4,
134.9, 132.6, 131.8, 130.3, 129.4, 128.1, 127.0, 126.4, 125.0, 123.6,
122.9, 119.9, 21.7, 21.4; HRMS ESI: [M+Na]+, Calculated for
C20H16N2NaO 323.1155; found 323.1148.
5,5'-diphenyl-[2,2'-bipyridine] 1-oxide (3i): Light yellowish crystalline
°
solid, melting point = 159-162 C, 95 mg, 50%; IR: (ʋmax/cm-1) = 1260
6,6'-dimethoxy-[2,2'-biquinoline] 1-oxide (4g): Yellowish crystalline
(R3N+-O-);1HNMR (300 MHz, CDCl3) δ 9.12 (d, J = 8.4 Hz, 1H), 8.98 (d, J
= 1.8 Hz, 1H), 8.61 (d, J = 1.5 Hz, 1H), 8.37 (d, J = 8.4 Hz, 1H), 8.05 (dd,
J’ = 2.4 Hz, J” = 8.4 Hz, 1H), 7.59-7.68 (m, 5H), 7.42-7.54 (m, 6H); 13C
NMR (75 MHz, CDCl3) δ 148.1, 147.7, 145.4, 139.1, 138.8, 137.3, 136.9,
135.0, 134.5, 129.3, 129.3, 129.1, 128.4, 127.5, 127.1, 126.9, 125.3,
124.5; HRMS ESI: [M+H]+, Calculated for C22H17N2O 325.1335; found
325.1326.
solid, melting point = 202-204 C, 156 mg, 82%; IR: (ʋmax/cm-1) = 1263
°
(R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.96 (d, J = 8.7 Hz, 1H), 8.79 (d, J
= 9.6 Hz, 1H), 8.28 (d, J = 8.7 Hz, 1H), 8.17 (d, J = 8.7 Hz, 1H), 8.06 (d, J
= 9.0 Hz, 1H), 7.71 (d, J = 9 Hz, 1H), 7.37-7.42 (m, 2H), 7.13-7.14 (m,
2H), 3.96 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 159.6, 158.5, 148.9,
144.2, 142.3, 137.7, 134.2, 131.6, 131.2, 129.2, 124.5, 124.1, 123.2,
122.4, 122.4, 121.9, 106.0, 104.8, 55.7, 55.6; HRMS ESI: [M+H]+,
Calculated for C20H17N2O3 333.1234; found 333.1247.
[2.2'-bipyridine] 1-oxide (4a): Dark brown viscous liquid, 156 mg, 86%;
IR: (ʋmax/cm-1) = 1245 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.99 (d, J =
6.0 Hz, 1H), 8.72 (bs, 1H), 8.33 (d, J = 6.3 Hz, 1H), 8.18 (d, J = 9.9 Hz,
1H), 7.83 (t, J = 7.8 Hz, 1H), 7.35-7.40 (m, 2H), 7.29 (d, J = 5.1 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 149.6, 149.3, 147.3, 140.6, 136.2, 127.8,
125.6, 125.4, 125.2, 124.2; HRMS ESI: [M+H]+, Calculated for C10H9N2O
173.0709; found 173.0710.
1,1'-biisoquinoline (4h): Dark brown liquid, 88 mg, 50%; IR: (ʋmax/cm-1)
= 1262 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.71 (d, J = 5.7 Hz, 1H),
7.94 (d, J = 8.1 Hz, 1H), 7.81 (d, J = 5.4 Hz, 1H), 7.67-7.76 (m, 2H),
7.44-7.49 (m, 1H); 13C NMR (75 MHz, CDCl3) δ 158.1, 141.9, 136.8,
130.4, 127.8, 127.6, 127.1, 126.9, 121.1; DEPT 135 NMR (75 MHz,
CDCl3) δ 141.9, 130.3, 127.5, 127.1, 126.9, 121.0; HRMS ESI: [M+Na]+,
Calculated for C18H12N2Na 279.0893; found 279.0901.
6,6'–dimethyl-[2, 2'-bipyridine] 1-oxide (4b): Dark brown amorphous
°
solid, melting point = 174-175 C, 128 mg, 70%; IR: (ʋmax/cm-1) = 1252
2,2'-diphenyl-2H,2'H-[4,4'-bi(1,2,3-triazole)] 3-oxide (4i): Light brown
crystalline solid, melting point = 97-100 °C, 83 mg, 44%; IR: (ʋmax/cm-1) =
1224 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 7.79 (s, 1H), 7.55-7.57 (m,
4H), 7.46 (d, J = 8.4 Hz, 3H), 7.29-7.35 (m, 3H), 7.02-7.06 (m, 1H), 6.47
(s, 1H); 13C NMR (75 MHz, CDCl3) δ 149.7, 138.9, 136.2, 130.2, 129.5,
129.2, 128.9, 124.4, 122.7, 121.2, 121.1, 117.9; Elemental analysis
(Calculated): C, 63.15; H, 3.97; N, 27.62; Found: C, 71.65; H, 8.18; N,
11.29.
(R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.56 (d, J = 7.8 Hz, 1H), 7.95-
7.98 (m, 1H), 7.68 (t, J = 7.8 Hz, 1H), 7.22-7.25 (m, 2H), 7.17 (d, J = 7.5
Hz, 1H), 2.60 (s, 3H), 2.57 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 157.9,
149.7, 149.6, 147.6, 136.1, 125.5, 125.5, 124.7, 123.4, 122.3, 24.5, 18.3;
HRMS ESI: [M+Na]+, Calculated for C12H12N2NaO 223.0842; found
223.0850.
5,5'–dimethyl-[2, 2'-bipyridine] 1-oxide (4c): Dark brown amorphous
°
solid, melting point = 113-114 C, 110 mg, 60%; IR: (ʋmax/cm-1) = 1268
2,2'-bis(4-fluorophenyl-2H,2'H-[4,4'-bi(1,2,3-triazole)] 3-oxide (4j):
Light brown crystalline solid, melting point = 107-109 °C, 99 mg, 52%; IR:
(ʋmax/cm-1) = 1221 (R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 7.75 (s, 1H),
7.51-7.56 (m, 2H), 7.39-7.43 (m, 2H), 7.29 (s, 1H), 7.23 (s, 1H), 7.02 (t, J
(R3N+-O-); 1HNMR (300 MHz, CDCl3) δ 8.81 (d, J = 8.4 Hz, 1H), 8.53 (s,
1H), 8.16 (s, 1H), 8.07 (d, J = 8.1 Hz, 1H), 7.60-7.64 (m, 1H), 7.18 (d, J =
8.4 Hz, 1H), 2.40 (s, 3H), 2.34 (s, 3H); 13C NMR (75 MHz, CDCl3) δ
149.7, 147.1, 144.8, 140.3, 136.6, 135.6, 133.9, 127.2, 126.9, 124.8,
18.4, 18.0; HRMS ESI: [M+Na]+, Calculated for C12H12N2NaO 223.0842;
found 223.0841.
= 8.7 Hz, 2H), 6.26 (s, 1H); 13C NMR (75 MHz, CDCl3) δ 162.4 (d, 1JCF
=
1
4
248.8 Hz), 158.7 (d, JCF = 240.7 Hz), 150.9, 149.6, 134.9 (d, JCF = 2.6
Hz), 132.1 (d, 4JCF = 3.1 Hz), 126.7 (d, 3JCF = 8.8 Hz), 120.0 (d, 3JCF = 7.9
Hz), 117.2 (d, JCF = 22.9 Hz), 115.9 (d, JCF = 22.6 Hz); Elemental
analysis (Calculated): C, 56.47; H, 2.96; N, 24.70; Found: C, 63.64; H,
5.82; N, 13.40.
2
2
4,4'–dimethyl-[2, 2'-bipyridine] 1-oxide (4d): Dark brown viscous liquid,
136 mg, 74%; IR: (ʋmax/cm-1) = 1243 (R3N+-O-); 1HNMR (300 MHz,
CDCl3) δ 8.71 (s, 1H), 8.57 (d, J = 4.8 Hz, 1H), 8.20 (q, J = 6.6 Hz, 1H),
7.93 (d, J = 2.4 Hz, 1H), 7.17 (d, J = 4.2 Hz, 1H), 7.05-7.08 (m, 1H), 2.44
(s, 3H), 2.40 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 149.5, 149.0, 147.4,
146.5, 139.9, 137.3, 128.2, 126.4, 126.0, 125.2, 21.2, 20.3; HRMS ESI:
[M+H]+, Calculated for C12H13N2O 201.1022; found 201.1016.
6,6'-bis(4-fluorophenyl)-2,2'-bipyridine (5a): colourless crystalline
solid, melting point = 154-155 °C, 9 mg, 99 %; 1HNMR (300 MHz, CDCl3)
δ 8.56 (d, J = 7.8 Hz, 1H), 8.16 (q, J = 3.3 Hz, 2H), 7.91 (t, J = 7.8 Hz,
1H), 7.74 (d, J = 7.8 Hz, 1H), 7.17-7.26 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 163.6 (d, 1JCF = 249.5 Hz), 155.8, 155.3, 137.7, 135.5 (d, 4JCF
=
2
3.1 Hz), 128.7 (d, 3JCF = 8.2 Hz), 119.9, 119.4, 115.6 (d, JCF = 21.4 Hz);
[2,2'-biquinoline] 1-oxide (4e): Dark brown amorphous solid, melting
point = 152-154 °C, 154 mg, 82%; IR: (ʋmax/cm-1) = 1253 (R3N+-O-);
1HNMR (300 MHz, CDCl3) δ 8.88-8.96 (m, 2H), 8.29 (d, J = 8.7 Hz, 2H),
8.19 (d, J = 8.4 Hz, 1H), 7.89 (d, J = 7.5 Hz, 2H), 7.82 (d, J = 9.6 Hz, 2H),
7.72-7.77 (m, 1H), 7.68 (d, J = 7.5 Hz, 1H), 7.61 (q, J = 7.5 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 151.5, 148.1, 143.8, 142.3, 135.6, 130.4, 130.3,
3
DEPT 135 NMR (75 MHz, CDCl3) δ 137.7, 128.74 (d, JCF = 8.3 Hz),
2
120.0, 119.4, 115.6 (d, JCF = 21.4 Hz); HRMS ESI: [M+H]+, Calculated
for C22H15F2N2 345.1198; found 345.1198.
This article is protected by copyright. All rights reserved.

10.1002/ejoc.201700504
European Journal of Organic Chemistry
FULL PAPER
Keywords: CDC
•
SNAr
•
Homocoupling
•
Azine N-oxides
•
Acknowledgements
Chemoselective
This work has been financially supported by CSIR, India
(
02/0180/14/EMR-II). AKJ thanks CSIR for graduate fellowship. The
authors thank DST-FIST for funding the ESI-HRMS facility at IIT
Delhi.
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10.1002/ejoc.201700504
European Journal of Organic Chemistry
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An unprecedented copper acetate-
catalyzed and copper-free
CDC vs SNAr
Abadh Kishor Jha[a] and Nidhi Jain[a]*
homocoupling of 2-phenyl pyridine N-
oxides to yield N,N’-dioxides or N-
monoxides in the presence of LitOBu
is reported. The chemoselectivity is
governed through an oxidative CDC
and SNAr pathways respectively.
Page No. – Page No.
2,2’-homocoupled azine N,N’-dioxides
or azine N-oxides: CDC or SNAr
controlled chemoselectivity
CDC vs SNAr controlled homocoupling of heterocyclic N-oxides.
This article is protected by copyright. All rights reserved.