Transition-metal-free cross-coupling reactions by single electron transfer (SET)

Article abstract of DOI:10.1002/ejoc.201301246

A facile, efficient, single-step protocol for the synthesis of cinnoline derivatives by a transition-metal-free coupling between amino- and nitroaryl compounds by single electron transfer (SET) has been developed. Direct carbon-carbon bond formation was achieved from nonfunctionalized aromatic carbon atoms. A plausible mechanism has been proposed. Direct carbon-carbon bond formation between nonfunctionalized carbon atoms (C-H) in the presence of KOtBu for the synthesis of cinnoline derivatives was achieved. Copyright

Full text of DOI:10.1002/ejoc.201301246

SHORT COMMUNICATION
DOI: 10.1002/ejoc.201301246
Transition-Metal-Free Cross-Coupling Reactions by Single Electron Transfer
(SET)
Suresh Kumar Sythana,[a,b] Santhosh Unni,*[a] Yogesh M. Kshirsagar,[a] and
Pundlik R. Bhagat*[b]
Keywords: C–H activation / C–C coupling / Synthetic methods / Electron transfer / Arylation
A facile, efficient, single-step protocol for the synthesis of
cinnoline derivatives by a transition-metal-free coupling be-
tween amino- and nitroaryl compounds by single electron
transfer (SET) has been developed. Direct carbon–carbon
bond formation was achieved from nonfunctionalized aro-
matic carbon atoms. A plausible mechanism has been pro-
posed.
Introduction
There is growing interest among the scientific community
in developing catalysts for the synthesis of complex mo-
lecules from nonfunctionalized precursors. Selective C–H
bond functionalization has attracted the attention of a
number of research groups over the past two decades.[1–5]
In particular, the use of KOtBu for direct C–H arylation
reactions has attracted many in the scientific com-
munity.[6–16] These research groups have independently
demonstrated the construction of biaryl compounds from
aryl halides by using KOtBu (Figure 1).
A. Studer and D. P. Curran suggested that these results
are not related to C–H activation or organocatalysis but
should be viewed as base-promoted homolytic aromatic
substitution (HAS) reactions.[17] The suggested mechanism
for these reactions is shown in Figure 2.
The aryl halide undergoes reduction by single electron
transfer in the presence of KOtBu, giving rise to a tert-
butoxy radical species and the potassium salt of the radical
anion (Figure 2, Step 1). The radical anion thus generated
diffuses further to form an aryl radical species through eli-
mination of a halide ion (Step 2). Addition of benzene or
substituted benzene to this aryl radical leads to the forma-
tion of a HAS radical (Step 3), which undergoes an oxi-
dation process either through proton transfer (PT) followed
by electron transfer (ET) (Path 1) or vice versa (Path 2)
leading to the formation of carbon–carbon bonds.[17]
Figure 1. KOtBu-mediated cross-coupling reactions between aryl
halides and aryl substrates.
[a] Pharmaceutical Development, AstraZeneca India Pvt. Ltd,
Bellary Road, Bangalore, Karnataka 560024, India
E-mail: Santosh.unni@astrazeneca.com
http://www.astrazenecaindia.com/
To the best of our knowledge, there are no reports avail-
able on carbon–carbon bond formation between nonfunc-
tionalized aryl carbon atoms by KOtBu-mediated SET re-
actions. For the first time, herein we report KOtBu-medi-
ated intermolecular carbon–carbon cross-coupling reac-
tions for the synthesis of biologically active cinnolines and
their derivatives from nitroaryl compounds and arylamines
[b] Chemistry Division, School of Advanced Sciences,
VIT University,
Vellore, Tamilnadu 632014, India
E-mail: drprbhagat111@gmail.com
http://www.vit.ac.in/
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301246
Eur. J. Org. Chem. 2014, 311–314
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. K. Sythana, S. Unni, Y. M. Kshirsagar, P. R. Bhagat
SHORT COMMUNICATION
(Entries 3 and 4). Interestingly, a remarkable difference was
observed on using K+ as the counter cation (Entry 5). To
understand the role of the K+ cation, the reaction was per-
formed with the addition of a stoichiometric amount of 18-
crown-6 to trap the K+ cation during the course of the reac-
tion; under these conditions, no product formation was ob-
served (Entry 6). This observation suggests that the alkali
metal cation plays a role in this transformation. It should
be noted that the basicity of KOtBu is higher than that
of NaOtBu and LiOtBu. Moreover, the electron density of
KOtBu is higher than of other bases, which enhances its
ability to participate in single electron transfer. These obser-
vations show that tert-butoxide acts as a single electron do-
nor, and the results are consistent with the SET mechanism.
Table 1. Base screening.[a]
Figure 2. Carbon–carbon bond formation between Ar–X and
Ar–H.
Entry
Base
Product 3a [%]
1
2
3
4
5
6
7
NaOH
KOH
LiOtBu
NaOtBu
KOtBu
0
0
1.6
10.6
86.4
trace
trace
(Scheme 1). This alternative chemical reaction affords
benzo[c]cinnoline N-oxides under mild reaction conditions
from substituted anilines and nitrobenzenes. The existing
synthetic protocols involve a multistep strategy utilizing
transition-metal catalysts such as palladium(0) (Suzuki cou-
pling) or copper (Ullmann coupling) for the construction
of cinnoline derivatives.[18–23]
18-crown-6[b] and KOtBu
KOtBu and TEMPO[c]
[a] Reaction conditions: nitrobenzene (10.75 mmol), toluene
(10 mL), aniline (10.75 mmol), base (10.75 mmol), 80–85 °C, 3 h.
[b] 18-Crown-6 (11 mmol) was added. [c] TEMPO (11 mmol) was
added.
Preliminary screenings showed that a minimum of
1.25 equiv. KOtBu was required for maximum reaction con-
version. We observed a drop in yield on reducing the
amount of base, which can be attributed to quenching of
KOtBu by water formed during the reaction as byproduct.
To understand the importance of solvent and its influence
on the formation of product 3a, we performed reactions
in different solvents; the results are summarized in Table 2.
Aprotic nonpolar and ethereal solvents were found to be
Scheme 1. KOtBu-mediated synthesis of benzo[c]cinnoline N-ox-
ides.
Table 2. Solvent screening.[a]
Entry
Solvent
Product 3a [%][b]
Results and Discussion
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
n-hexane
toluene
xylene
86.3[c]
93.0
78.8
87.4[d]
85.5[e]
73.8
88.0
0
0
0
0
0
The design of our study was based on a well-known phe-
nomenon that nitrobenzene reacts with KOtBu through sin-
gle electron transfer (SET) to generate the corresponding
potassium salt of the nitrobenzene radical anion[24–26] and
a tert-butoxy radical. Based on this consideration, we be-
lieved that in the presence of a suitable substrate the nitro-
benzene radical anion might react further leading to some
interesting compounds.
To visualize our theory, we chose aniline as a model sub-
strate. The reaction was carried out in toluene using 1 equiv.
of KOtBu at 80–85 °C for 2–3 h. Monitoring of the reaction
by TLC confirmed the formation of a new product
(Scheme 1), which was isolated and characterized as 3a.
Reactions employing other bases such as KOH and
NaOH did not give rise to any products (Table 1, Entries 1
and 2). Trace amounts of product 3a were observed on
tetrahydrofuran
2-methyl-THF
cyclopentyl methyl ether
1,4-dioxane
acetonitrile
isopropyl acetate
N,N-dimethylacetamide
dimethyl sulfoxide
N-methylpyrrolidone
n-butanol
0
0
78
2-propanol
tert-amyl alcohol
[a] Reaction conditions: nitrobenzene (10.75 mmol), solvent
(10 mL), aniline (10.75 mmol), potassium tert-butoxide
(13.43 mmol). [b] Yields are based on the reaction conversion as
monitored by HPLC (see the Supporting Information for details).
[c] Including intermediate 4 (19.9area-%). [d] Reaction performed
using alkoxides bearing a counter cation such as Li+ or Na+ at 50–55 °C for 20 h. [e] Reaction performed at 70–75 °C for 5 h.
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Cross-Coupling Reactions by Single Electron Transfer (SET)
suitable solvents; reactions performed in more polar sol- nucleophilic reaction between nitrobenzene and aniline to
vents such as N-methylpyrrolidone gave rise to a different produce an intermediate, followed by intramolecular C–C
product profile.[27] This experiment clearly indicates that the bond formation, because we did not observe any related
nature of the solvent controls the formation of the required intermediates or byproducts. Our findings suggest that the
product 3a. By using this protocol we were able to synthe- reaction proceeds via radical intermediates, which is also
size several benzo[c]cinoline N-oxide derivatives as shown confirmed by the addition of common radical scavengers
in Table 3.
such as 2,2,6,6-tetramethylpiperidine-1-oxyl (TEMPO;
Table 1, Entry 7), which halted the reaction. The possibility
of a benzyne intermediate is ruled out, because the reaction
predominantly afforded a single regioisomeric product.
Table 3. Synthesis of benzo[c]cinnoline N-oxides.
Entry
R11
R12
R21 Product 3
Yield [%]
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
H
H
Br
H
H
H
H
H
Cl
H
H
H
CH3
CH3
H
H
H
H
H
OCH3
SCH3
D
H
Cl
H
H
F
H
H
H
Cl
Cl
H
H
OCH3
SCH3
H
H
H
3a
3b
3c
3d
3e
3f
3g
3h
3i
3j
3k
3l
3m
3n
3o
3p
3q
77
90
53
63 (3d), 23 (3a)
66
72
79
72
49
73
76
64
76
72
78
84
76
CH(CH3)2
N(CH3)2
OCH3
OCH3
CH(CH3)2
OCH3
SCH3
H
H
H
H
D
Substrates with an electron-withdrawing fluoride, chlor-
ide, bromide group or an electron-donating moiety such as
methyl, isopropyl, methoxy, thiomethoxy, or substituted
amines on the aryl ring are well tolerated under the reaction
conditions.
An interesting feature of our reaction system with sub-
strates bearing a halogen atom at the para position is that
the electron transfer process initiated between nitrobenzene
and KOtBu does not propagate further to a carbon–halide
bond. In contrast, when the halo group is replaced at the
ortho position we do observe formation of the dehaloge-
nated product with 23% yield (Table 3, Entry 4). This can
be attributed to high electron spin density at the ortho posi-
tion, which undergoes first-order decay leading to the deha-
logenated product.[28–30]
Scheme 2. Proposed reaction mechanism.
In addition, reactions were performed with [D5]aniline to
gain further insight into the mechanism, because the rate
of reaction is expected to differ from non-deuterated to deu-
terated anilines. However, monitoring of the reaction by
HPLC and NMR spectroscopic analysis have shown that
both reactions proceed at similar rates towards the forma-
tion of products 3a and 3q via intermediates 4 and 5,
thereby pointing to a concerted mechanism in which kH/kD
= 1 (see the Supporting Information).
To understand the reaction pathway, the progress of the
reaction was monitored by HPLC. The reaction was appar-
ently spontaneous at higher temperature (80–85 °C) with no
reactive intermediates being observed from the analysis of
Conclusions
We have demonstrated a simple and high-yielding, single-
samples at various time intervals. On other hand, when step procedure for the synthesis of diverse tricyclic scaffolds
samples were analyzed from reactions performed at 25 and bearing a central pyridazine motif. In addition, the N-ox-
50 °C, an intermediate was observed to form that later con- ides produced by this ring-closure method are of interest,
verts into the required product on continuing the reaction. because they give rise to the regioselective N-oxidation of
However, it was also observed that the reaction did not pro- diazines. This newly discovered KOtBu-mediated reaction is
gress at temperatures below 20 °C. Encouraged by this re- of scientific interest because of the non-functionalized car-
sult, we isolated the intermediate and confirmed it as 4, bon–carbon bond formation involved. These types of reac-
which undergoes dehydration in the presence of base to give tions have gained much importance among the wider scien-
3a.
tific community as is evident from recent reports.[31] Their
A representative example of our proposed mechanism is findings are consistent with the observation that these reac-
shown in Scheme 2. Control experiments have shown that tions involve radical intermediates. Further exploration of
in the absence of base, intermediate 4 was stable under the this methodology as well as its application towards the syn-
reaction conditions. We can rule out the possibility of a thesis of complex molecules is underway.
Eur. J. Org. Chem. 2014, 311–314
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313

S. K. Sythana, S. Unni, Y. M. Kshirsagar, P. R. Bhagat
SHORT COMMUNICATION
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Experimental Section
Synthesis of 3. General Procedure: To a solution of nitrobenzene 2
(10.75 mmol) and aniline 1 (10.75 mmol) in toluene (10 mL) was
added KOtBu (13.43 mmol), and the mixture was heated at 80–
85 °C for 3 h. The reaction was quenched by the addition of
aqueous acetic acid, then the organic layer was separated, and the
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Supporting Information (see footnote on the first page of this arti-
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1
HRMS, H and 13C NMR spectra for 3a–q, 4 and 5; DEPT and
1
Hetero Cosy for 4.; HPLC chromatograms and H NMR spectra
for the reaction monitoring of deuterium-labeling experiments.
HPLC chromatograms of the reaction mixtures at various time in-
tervals and reactions performed in different solvents.
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Received: August 19, 2013
Published Online: November 26, 2013
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Eur. J. Org. Chem. 2014, 311–314