Vasicine catalyzed direct C-H arylation of unactivated arenes: Organocatalytic application of an abundant alkaloid

Article abstract of DOI:10.1016/j.tetlet.2013.06.125

Vasicine, a quinazoline alkaloid isolated from Adhatoda vasica, has been employed as an organocatalyst for direct C-H arylation of unactivated arenes with aryl iodides/bromides without the assistance of any transition metal catalyst. A number of sensitive functional groups such as methyl, methoxy, O-benzyl, acetyl, and amino were well tolerated under present reaction conditions. Mechanistic investigation supported the involvement of radical intermediates.

Full text of DOI:10.1016/j.tetlet.2013.06.125

Tetrahedron Letters 54 (2013) 4868–4871
Contents lists available at SciVerse ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Vasicine catalyzed direct C–H arylation of unactivated arenes:
organocatalytic application of an abundant alkaloid
Sushila Sharma a,b, Manoranjan Kumar a,b, Vishal Kumar , Neeraj Kumar
b
a,b,
⇑
a
Academy of Scientific and Innovative Research, CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176 061, India
CSIR-Institute of Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176 061, India
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Vasicine, a quinazoline alkaloid isolated from Adhatoda vasica, has been employed as an organocatalyst
for direct C–H arylation of unactivated arenes with aryl iodides/bromides without the assistance of
any transition metal catalyst. A number of sensitive functional groups such as methyl, methoxy, O-benzyl,
acetyl, and amino were well tolerated under present reaction conditions. Mechanistic investigation sup-
ported the involvement of radical intermediates.
Received 13 April 2013
Revised 25 June 2013
Accepted 26 June 2013
Available online 4 July 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Alkaloid
Biaryls
C–H activation
Organocatalyst
Vasicine
Biaryl moiety is a key component in many biologically active
natural products, pharmaceuticals, liquid crystals, light emitting
diodes, and polymers. A number of methods have been developed
activation.12 Rueping et al. further extended this metal-free ap-
proach to intramolecular Heck cyclization/isomerisation.13
The use of organic molecules from natural sources and their
derivatives such as cinchona alkaloids, phenylethylamine, and pro-
line as organocatalyst is a rapidly growing area for selective chem-
1
for the synthesis of biaryl compounds, however, direct arylation of
unactivated aromatic C–H bonds using transition metal based cat-
2
14
alysts is one of the predominant strategies. A number of transition
ical synthesis. Inertness toward moisture and oxygen, relatively
metals such as Pd, Rh, Ru, Ir, Cu, Ni, Fe, and Co have been employed
as catalysts for C–H activation,3 the presence of inherent toxicity
with most of the transition metals demands an alternative
approach.
inexpensive, and easy handling make the organocatalyst an
attractive alternative to transition metals. Recently, Tanimori and
co-workers reported proline catalyzed direct C–H arylation of
unactivated arenes.
1
5
Transition metal-free direct arylation of unactivated arenes
with aryl halides catalyzed by organic molecules has recently
gained much interest among chemists after the initial efforts by
The abundance of a natural product is an important criterion to
promote it as organocatalyst. Vasicine is an abundantly available
quinazoline alkaloid mainly isolated from Adhatoda vasica (present
Itami and co-workers. Shi and co-workers,5 Kwong/Lei, and
4
6
upto 1%). Despite its medicinal importance in Ayurveda, its
16
7
Shira-kawa/Hayashi have utilized DMEDA, 1,10-phenanthroline,
organocatalytic potential was not known before. Herein, we first
time report vasicine catalyzed direct arylation of unactivated are-
nes with aryl bromides and iodides.
To optimize the best reaction conditions, the direct C–H aryla-
tion of benzene with 4-iodotoluene was carried out in the presence
of different natural ligands (L1–L6, Fig. 1) and bases. Among the
different ligands, (±) vasicine and (±) vasicinone (L1, L2, 0.5 equiv)
were found to be the most active at 110 °C in the presence of
KOt-Bu (Table 1, entries 5 and 12).
and its derivatives to promote transition metal-free synthesis of
biaryl motifs through homolytic aromatic substitution mechanism
involving aryl radical intermediates. Some other groups utilized
0
8
2
,3-biimidazo[1,2-a]pyridin-2 -one radical, Al(OH)(bpydc) metal
9
10
organic framework, porphyrin, and quinoline-1-amino-2-car-
1
1
boxylic acid for this transformation. Recently, Charette and co-
workers have reported transition metal-free KOt-Bu mediated
intramolecular arylation of aryl halide derivatives via C–H
Though, both ligands showed comparable yields of the desired
product, the best result was obtained with L1. In the presence of
(
ꢀ) vasicine (L1a) as ligand, no effect on yield of the product was
observed (Table 1, entry 7). However, same amount of other tested
natural ligands (L3–L6) did not give the desired yield (Table 1,
entries 13–16).
⇑
Corresponding author. Tel.: +91 1894 230426; fax: +91 1894 230433.
E-mail addresses: neerajnpp@rediffmail.com, neeraj@ihbt.res.in (N. Kumar).
0
040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.06.125

S. Sharma et al. / Tetrahedron Letters 54 (2013) 4868–4871
4869
Table 1
Table 2
a
a
Arylation of benzene with 4-iodotoluene
Direct C–H arylation of arene with aryl iodides
Catalyst, base,
N2 atmosphere
Entry
Aryl iodide
Arene
Product
Yieldb (%)
I
+
I
R1
R1
Entry Catalyst (equiv) Base (equiv) Time (h) Temp (°C) Yieldb (%)
1
2
3
4
5
6
7
8
9
R1 = H
94
93
74
50
94
50
73
70
79
82
R
R
R
R
R
R
R
R
R
1
1
1
1
1
1
1
1
1
= 4-CH
3
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
L1 (0.1)
L1 (0.2)
L1 (0.3)
L1 (0.4)
L1 (0.5)
L1 (0.6)
L1a (0.5)
L1 (0.5)
L1 (0.5)
L1 (0.5)
L1 (0.5)
L2 (0.5)
L3 (0.5)
L4 (0.5)
L5 (0.5)
L6 (0.5)
L1 (0.5)
L1 (0.5)
L1 (0.5)
L1 (0.5)
L1 (0.5)
L1 (0.5)
—
KOt-Bu (4)
KOt-Bu (4)
KOt-Bu (4)
KOt-Bu (4)
KOt-Bu (4)
KOt-Bu (4)
KOt-Bu (4)
KOt-Bu (1)
KOt-Bu (2)
KOt-Bu (3)
KOt-Bu (5)
KOt-Bu (4)
KOt-Bu (4)
KOt-Bu (4)
KOt-Bu (4)
KOt-Bu (4)
NaOt-Bu (4)
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
48
24
48
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
110
80
19
43
70
84
93
94
92
75
85
89
92
72
NR
8
= 2-OCH
= 3-OCH
= 4-OCH
= 4-OBn
3
3
3
= 4-COCH
3
= 2-NH
= 4-NH
2
2
1
0
1
= 4-CF
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
I
I
55c,d
1
I
85c,e
12
I
I
8
32
64
NR
NR
NR
NR
NR
NR
NR
47
18
40c,f
K
2
CO
NaOH (4)
Cs CO (4)
DABCO (4)
NaHCO (4)
3
(4)
13
I
2
3
3
14
15
30
95
I
KOt-Bu (4)
—
KOt-Bu (4)
KOt-Bu (4)
L1 (0.5)
L1 (0.5)
L1 (0.5)
N
I
N
CH3
CH3
a
Reaction conditions: 4-iodotoluene (0.5 mmol), benzene (4 ml), KOt-Bu
I
16
35g
75h
(
2.0 mmol) at 110 °C for 48 h.
b
Isolated yield.
N
H C
I
3
17
N
a
Lowering the quantity of catalyst and base below 0.5 and
Reaction conditions: aryl iodide (0.5 mmol), arene (4 mL), KOt-Bu (2.0 mmol),
4
equiv, respectively, led to a decrease in yield and no significant
change was observed with higher amount of catalyst or base
Table 1, entries 1–11). No reaction occurred in the presence of
other bases such as CO NaOH, Cs CO 1,4-diazabicy-
clo[2.2.2]octane (DABCO), and NaHCO , while NaOt-Bu afforded
vasicine (0.25 mmol), 110 °C, under N
2
atmosphere 48 h.
b
Isolated yield.
Reaction carried out for 72 h.
c
(
d
p-Iodobiphenyl was observed in 29% yield.
m-Iodobiphenyl was observed in 11% yield.
o-Iodobiphenyl was observed in 31% yield.
K
2
3
,
2
3
,
e
f
3
g
h
1
o:m:p = 1:0.5:0.37; as determined by HNMR.
lower yield of the product (Table 1, entries 17–22).
o:m = 1:0.25; as determined by 1HNMR.
As expected, no reaction occurred in the absence of base or cat-
alyst (Table 1, entries 23 and 24). Lower yield of the desired prod-
uct was observed when the reaction was carried out at lower
temperature or for shorter reaction time (Table 1, entries 25 and
comparatively lower yields (Table 2, entries 3 and 8). Electron defi-
cient aryl iodide, 4-iodoacetophenone gave the desired product in
good yield without affecting the acetyl group (Table 2, entry 7). 4-
Iodotrifluoromethylbenzene afforded the coupling product in good
yield (Table 2, entry 10). 1,3- and 1,4-diiodobenzene gave ter-
phenyl as major product in 72 h along with iodobiphenyl as minor
product (Table 2, entries 11 and 12). In the reaction of 1,2-diiodo-
benzene with benzene, a typically challenging substrate combina-
2
6). Further to rule out the involvement of any trace impurities
of transition metal, the reaction was carried out in the presence
of metal salts (FeCl , CuSO O, and CoSO O). KOt-Bu from
3
4
ꢁ5H
2
4
ꢁ6H
2
different sources and vasicine isolated from different batches were
also utilized. No change in the reaction rate was observed.
With the best reaction conditions in hand, the scope of the reac-
tion was extended to various substituted aryl iodides. Coupling of
most substrates gave moderate to high yield. Iodobenzene coupled
smoothly with benzene to afford the product in excellent yield
6
tion, o-terphenyl was obtained in moderate yield (Table 2, entry
13). The coupling reaction of 2-iodofluorene with benzene afforded
the desired product in 32% yield (Table 2, entry 14). Also 2-iodo-
pyridine coupled smoothly to afford the desired product in excel-
lent yield. The scope of the reaction was also investigated for
coupling of different arenes with aryl iodide. Coupling of toluene
with iodobenzene provided ortho isomer as major product (Table 2,
entry 16). Pyridine coupled efficiently with 4-iodotoluene to afford
ortho isomer as major product (Table 2, entry 17).
Further, the scope of the method was extended by coupling
reaction of aryl bromides with benzene (Table 3).
Bromobenzene and 4-bromotoluene coupled efficiently and
gave the desired products in excellent yield (Table 3, entries 1
and 2). 4-Bromoacetophenone and 4-bromoaniline afforded
(
Table 2, entry 1). Aryl iodides with electron-donating substituents
such as 4-CH , 4-OCH , 2-NH , and 4-NH gave good to excellent
yield of the product (Table 2, entries 2, 5, 8, and 9).
The –NH group is considered very reactive in coupling reac-
3
3
2
2
2
17
tions and leads to C–N bond formation. Coupling of haloanilines
and benzene through organocatalytic approach has not been re-
ported before. However, in the present case C–C coupling took
place without affecting the –NH
Moderate yields of the products were obtained in the reactions
of 3-OCH and 4-OBn substituted iodobenzenes (Table 2, entries
and 6). The effect of steric hindrance was seen in the reaction
of o-substituted aryl iodides giving the desired product in
2
group (Table 2, entries 8 and 9).
3
4

4
870
S. Sharma et al. / Tetrahedron Letters 54 (2013) 4868–4871
Table 3
Direct C–H arylation reactions of benzene with aryl bromides
corresponding biphenyls in good yields which were lower as com-
a
pared to iodoarenes (Table 3, entries 4 and 5). High yield of the
product was obtained in case of 3-bromopyridine, however, 3-ami-
no-6-bromopyridine afforded lower yield (Table 3, entry 9 and 10).
Entry
Aryl bromide
Product
Yieldb (%)
Br
1
,4-Dibromobenzene provided terphenyl as major product in 48 h
R
R1
along with 4-bromobiphenyl as minor product, whereas 1,3-dibro-
mobenzene gave terphenyl in lower yield and full conversion was
not observed even after 72 h (Table 3, entries 6 and 7).
1
2
3
4
5
R = H
92
94
12
65
64
R = 4-CH
R = 4-OCH
R = 4-COCH
3
3
3
Interestingly, in case of 1,2-dibromobenzene, 2-bromobiphenyl
was obtained as major product (Table 3, entry 8) as reported earlier
the homolytic aromatic radical substitution mechanism is involved
R = 4-NH
2
6
Br
Br
64c
1
8
in such organocatalytic coupling reactions. To verify this, the
model reaction was carried out in the presence of TEMPO as a rad-
ical scavenger (Scheme 1). The significant decrease in the rate of
the reaction and yield of the product clearly indicates the involve-
Br
7
24d,e
Br
Br
Br
6
ment of aryl radical intermediate.
8
9
60d,f
Further, kinetic isotope effect (KIE) studies were carried out by a
competition reaction between C H and C D (Scheme 2). A small
6 6 6 6
Br
Br
N
KIE value of 1.7 revealed that C–H bond cleavage is not the rate
88
35
determining step (for details see Supplementary data).6
N
N
Also, high ortho selectivity in case of substituted arenes sup-
ports the radical mechanism. Taking into account all these obser-
vations a radical mechanism was proposed to be involved in the
coupling reaction. To further confirm this, a competition reaction
was carried out between an equimolar mixture of electron rich
haloarene and electron deficient haloarene with benzene
(Scheme 3). High yield of the product obtained with electron defi-
cient substrate as compared to electron rich substrate indicates
that aryl radical is generated through SET (single electron transfer)
mechanism as electron deficient aryl halides have higher
Br
N
NH2
H N
2
1
0
a
Reaction conditions: aryl bromide (1.0 mmol), benzene (4 mL), KOt-Bu
(
4.0 mmol), vasicine (0.5 mmol), 110 °C, under N
2
atmosphere 48 h.
b
Isolated yield.
c
p-Bromobiphenyl was observed in 14% yield.
Reaction carried out for 72 h.
m-Bromobiphenyl was observed in 19% yield.
o-terphenyl was observed in 6% yield.
d
e
f
7
,19
reactivities.
O
O
NH
On the basis of the above observations, the proposed mecha-
nism involves initial interaction of vasicine with potassium tert-
butoxide, which helps in one electron reduction of aryl halide
(Fig. 2). The aryl halide radical anion then undergoes C–halogen
bond cleavage to give aryl radical, which adds to benzene molecule
N
N
O
N
HO
HO
N
N
O
OH
OH
(
(
± ± Vasicine (L1±
-± Vasicine (L1a±
(± ± Vasicinꢀne (L2±
(± ± Thymidine (L3±
OH
HO
O
O
O
HO
O
OH
HO
HO
CF3
OCH3
HO
OH
O
OH
OH
I
I
L-(+±-Ascꢀrbicacid (L5±
Maltꢀl (L6±
D-(+±-Glucꢀse (L4±
Vasicine (0.5 equiv), 110 o
KOt-Bu (4 equiv.), 2 h
C
+
+
+
Figure 1. Structure of tested natural ligands.
N atmosphere
2
CF3
OCH3
Vasicine (0.5equiv.)
KOt-Bu (4 equiv.)
TEMPO (1 equiv.)
Yield
yield
I + H
0
.5 equiv 0.5 equiv
36%
80%
---
2%
---
1
10 oC, 48 h
N atmosphere
1.0 equiv
equiv
0 equiv
2
No scavanger = >99% (GC yield)
TEMPO = 15%
0
1.0 equiv
40%
Scheme 1. Effect of radical inhibitor.
Scheme 3. Competition reaction between aryl iodides.
I
(
30 equiv)
Vasicine (0.5 equiv.), 110 o
C
+
+ D
D
D
KOt-Bu (4 equiv.), 48 h
D
D
D
N atmosphere
D
2
D
D
D
D
(
30 equiv)
Scheme 2. Kinetic isotopic effect experiment.

S. Sharma et al. / Tetrahedron Letters 54 (2013) 4868–4871
4871
t-BuOH
H
.
Ar
.
_
K+
N
ArX (X = I, Br)
.
_
X
Ar
KOt-Bu
Ar
ArX
N
X-
O
H
K
O
t-Bu
Ar
Figure 2. Proposed reaction mechanism.
+ KX
to generate aryl substituted cyclohexadienyl radical intermediate
which is followed by deprotonation to form biaryl radical anion.
This radical anion undergoes single electron transfer to other aryl
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1
halide to form biaryl product and generating aryl radical.
In conclusion, vasicine, a natural product has been established
as an efficient catalyst for transition metal-free direct coupling of
unactivated arenes with aryl iodides/bromides. The present
method reports the catalytic potential of abundantly available
vasicine, which can further be explored for other chemical
transformations.
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