Isopropanol and potassium tert-butoxide promoted intramolecular direct sp2 C-H functionalization: An expedient synthesis of 1,2,3-triazole annulated chromens and quinolones

Article abstract of DOI:10.1016/j.tetlet.2015.09.096

A series of 1,2,3-triazole annulated chromen and quinolone derivatives have been synthesized by means of direct sp² C-H functionalization in the presence of iso-propanol and potassium tert-butoxide. The reaction proceeds through homolytic aroma

Full text of DOI:10.1016/j.tetlet.2015.09.096

Accepted Manuscript
Isopropanol and potassium tert-butoxide promoted intramolecular direct sp2 C-
H functionalization: An expedient synthesis of 1,2,3-triazole annulated chro-
mens and quinolones
Biplab Mondal, Brindaban Roy
PII:
S0040-4039(15)30137-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2015.09.096
TETL 46768
Reference:
Tetrahedron Letters
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Revised Date:
Accepted Date:
29 July 2015
21 September 2015
22 September 2015
Please cite this article as: Mondal, B., Roy, B., Isopropanol and potassium tert-butoxide promoted intramolecular
direct sp2 C-H functionalization: An expedient synthesis of 1,2,3-triazole annulated chromens and quinolones,
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Isopropanol and potassium tert-butoxide
promoted intramolecular direct sp2 C-H
functionalization: An expedient synthesis of
1,2,3-triazole annulated chromens and
quinolones
Leave this area blank for abstract info.
Biplab Mondal and Brindaban Roy*
TS
X
A
A
B
B
iPrOH (40 mol%)
KOtBu
80oC
61-82% yield
N
N
N
R
H
R
N
N
N
R1
18 examples
R1
X = Cl, Br, I

1
Tetrahedron Letters
Isopropanol and potassium tert-butoxide promoted intramolecular direct sp2 C-
H functionalization: An expedient synthesis of 1,2,3-triazole annulated chromens
and quinolones
Biplab Mondal and Brindaban Roy*
University of Kalyani, Department of Chemistry, Kalyani, Nadia-741235, West Bengal, India
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A series of 1,2,3-triazole annulated chromen and quinolone derivatives have been synthesized by
means of direct sp2 C-H functionalization in presence of iso-propanol and potassium tert-
butoxide. The reaction proceeds through homolytic aromatic substitution (HAS). This efficient
as well as simple C-H functionalization methodology offers a straightforward route to 1,2,3-
triazole annulated oxygen and nitrogen heterocycles.
Available online
2009 Elsevier Ltd. All rights reserved.
Keywords:
sp2 C-H functionalization
1,2,3-triazole
intramolecular C-C coupling
heterocycles
iso-propanol
potassium tert-butoxide
Introduction
MDR-TB is growing due to their wide range of activity and even
those drugs can also be taken orally13. Considering all those
biological and pharmaceutical importance, we assumed that the
synthesis of 1,2,3-triazole annulated chromens and quinolones
might be promising.
In recent years, the chemistry of 1,2,3-triazole derivatives has
gained progressive attention in the field of chemical synthesis1,
material science2, and biology3-9. 1,2,3-Triazole derivatives
exhibit potential antibacterial3, antifungal4, anti-HIV5a, b, and
antimicrobial5c activities. Condensed 1,2,3-triazole derivatives
Various reports are available for the synthesis of 1,2,3-triazole
annulated oxygen and nitrogen heterocycles14. However, all of
acts against the hepatitis C virus6a, inhibits benzodiazepine6b and
them followed transition metal-catalysed (Pd14a, d and Cu14b, c, f
)
6c
adenosine6b,
receptors. Some 1,2,3-triazole derivatives are
recognized as DNA cleaving agent7 and potassium channel
activator 8.
methodology. Despite the significant advances in metal catalysed
organic synthesis, the development of economical and
environmentally compassionate protocols are still a challenge. In
this perspective, transition metal-free C-H functionalization
2H-chromene or 2H-benzopyran is a key structural unit of
many biologically and pharmaceutically active compounds. For
example, daurichromenic acid (A) exhibits anti-HIV properties9
and coutareagenin shows antidiabetic activity10. Various 2H-
benzopyran derivative shows potent antifungal activity 11. 6-
Substituted 2H-chromenyl (B)12 shows potential antidiabetic
activity as a Na+-C-glucose co-transporter inhibitor (Fig. 1).
protocols appear to be particularly attractive15-22
.
Previous work
i) Pd-catalysis (X = H, Y = H;
X
ref 14a)
O
O
ii) Pd-catalysis (X = H,
Y = I; ref 14g)
iii) Pd-catalysis (X = I,
N
N
Y
Y = H; ref 14d)
glucose
N
N
N
N
OH
iv) Cu-catalysis (X = I, Y = H;
ref 14b, c)
1
R
R
O
HOOC
Me
O
2
Me
Me
Me
Me
This work
O
iPrOH
O
O
A
B
O
OH
KOtBu
X = Cl, Br, I
Figure 1. Biologically important 2H-chromene derivatives
N
N
X
1
2
N
N
N
N
On the other hand quinolone unit is considered as a big family
of versatile drugs. Recently, fluoroquinolones are accepted as
second-line drugs by the WHO to treat TB and thus their use in
R
R
Scheme 1. Synthesis of 1,2,3-triazole annulated chromens.

2
Tetrahedron Letters
In last few years, C-H functionalization via homolytic
product 2a was isolated, while 45 % conversion of the starting
material (Table 1, entry 1) was observed. Then the use of a
sublimed grade potassium tert-butoxide23 instead of ordinary
potassium tert-butoxide, offered 67 % yield of 2a with 93 %
conversion of the starting material (Table 1, entry 2). With
sodium tert-butoxide a comparable yield (64 %) of 2a was
isolated during a longer reaction period (10 h) (Table 1, entry 3).
Small amount (11 % yield of 2a with 38 % conversion of 1a) of
2a was isolated with less basic lithium tert-butoxide (Table 1,
entry 4). No product was obtained in absence of base, in presence
of Et3N and Na2CO3 (Table 1, entries 5-7) and the starting
material (1a) remain unchanged.
aromatic substitution (HAS)15, 16 has gained immense interest in
chemical synthesis. These methodologies involves radical anion
intermediates16. This low toxic and simple protocol might be
very attractive and valuable alternatives to the transition metal-
catalyzed C-H transformation. In 2006, Rossi et al. reported the
synthesis of homoaporphine alkaloids by tBuOK mediated photo
induced ortho sp2 C-H arylation under transition metal-free
condition17a. After that in 2008, Itami et al. reported BuOK
t
promoted C-H bond arylation of heterocycles using alry iodides
under microwave condition18a. Following these ground breaking
work, different groups developed a number of transition metal-
free protocols e.g. photo induced sp2 C-H functionalization17,
base mediated and organic electron donar ligand (phen, diamine,
Noticing a steep improvement with sublime grade potassium
tert-butoxide, different alcohols were examined under this
NHC etc) catalysed sp2 C-H arylation19-21 and alcohol BuOK
t
n
reaction conditions. The use of BuOH (Table 1, entry 8) and
promoted sp2 C-H functionalization22 for biaryl and heterocycle
synthesis.
iPrOH (Table 1, entry 9) with sublimed potassium tert-butoxide
provided 69 % and 76 % yields of 2a respectively with total
conversion of starting material, whereas with tBuOH (Table 1, of
entry 10) only 5 % yield of 2a was recorded. Increasing of
alcohol (iPrOH) loading from 20 mol % to 40 mol % the yield of
the reaction increased to 82 % (Table 1, entry 11). During
optimization, different polar and non polar solvents were also ee
continuened under this reaction conditions. With MeCN, only a
trace amount of 2a was obtained (Table 1, entry 12), but with
1,4-dioxane, toluene and mesitylene no sign of formation of 2a
To the best of our knowledge, though there are few examples
of base and ligand catalysed synthesis of heterocycles via sp2
functionalization20, base and acohol catalysed heterocycle
synthesis is rare22b which must be a topic of immanse interest. In
the continuation of our project, transition metal-free synthesis of
heterocycles18d, e; herein, we report the synthesis of 1,2,3-triazole
annulated chromen (2) and quinolone (4) derivatives with the aid
of catalytic amount of iso-propanol in presence of potassium tert-
butoxide through an HAS mechanism.
i
was observed (Table 1, entries 13-15). In absence of PrOH
(Table 1, entry 16) formation of 2a was not found, when PrOH
was used as solvent (Table 1, entry 17) 62 % yield of 2a was
noticed. Only a trace amount of 2a (Table 1, entry 18) was
isolated under open air condition and most of the starting
i
Results and Discussion
Initially, we started our investigation with 1-benzyl-4-((2-
iodophenoxy) methyl)-1H-1,2,3-triazole (1a) (for synthesis of
compound 1 and 3 see experimental section) as a model substrate
and a set of reactions (Table 1) were performed. After surveying
the literature22, we choose 1 mmol of 1a EtOH (20 mol %),
potassium tert-butoxide (3 mmol) in dry DMF at 80 C as initial
reaction conditions for this intramolecular coupling reaction. The
reaction was continued for 6 h and only 5 % of the desired
i
material remain unreacted. Thus 40 mol % PrOH, 3 equiv.
KOtBu in DMF at 80 C under N2 atmosphere for 6 h was
o
accepted as optimized reaction conditions. With the optimized
reaction conditions in hand, we further explored the substrate
scope (1b-k) of this methodology (Scheme 2).
o
Table 1. Optimization of reaction conditions.
O
O
N
N
N
I
N
N
N
Bn
1a
2a
Bn
Yield (%)a
Entry
Cat (mol %)
Base
Solvent
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
EtOH (20)
EtOH (20)
EtOH (20)
EtOH (20)
EtOH (20)
EtOH (20)
EtOH (20)
nBuOH (20)
iPrOH (20)
tBuOH (20)
iPrOH (40)
iPrOH (40)
iPrOH (40)
iPrOH (40)
iPrOH (40)
-
KOtBub
KOtBu
NaOtBu
LiOtBu
-
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
DMF
MeCN
1,4-dioxan
toluene
mesytelene
DMF
-
5
67
64c
11
0
Et3N
0
0
Na2CO3
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
KOtBu
69
76
5
82
trace
0
0
0
0
iPrOH
62d
tracee
iPrOH (40)
DMF
Reaction conditions: 1.0 mmol of 1a, 3.0 mmol base, alcohol and 10 mL solvent were heated for 6 h under N2 atmosphere at 80 oC.
Bold values implies optimized reaction conditions.
a Yields were calculated after flash chromatography
b Ordinary KOtBu was used

3
c Reaction performed for 10 h
d Reaction performed in 10 mL iPrOH, e Reaction performed under open air
Chloro substrate gave very poor yield (10 %, entry-2), while
bromo substrate afforded somewhat lower yield (61 %, entry-7)
than the corresponding iodo compound.
iPrOH (40 mol%)
KOtBu (3 equiv.)
O
O
We also tested the validity of this methodology towards the
synthesis of 1,2,3-triazolo fused quinolone ring systems 4
(Scheme 3). To our delight, the catalytic system also proved to be
fruitful for the synthesis of N-substituted 1H-[1,2,3]triazolo[4,5-
c]quinolin-4(5H)-ones (4).
DMF, 80oC
N2 atm.
R1
R1
N
N
N
N
.
X
N
N
1
2
R2
R2
O
O
O
Me
Me
N
O
N
N
N
N
O
N
N
N
NO2
2c
C8H17
N
N
N
2a
N
Bn
N
N
2b
entry 1: X = I, 82 %
entry 2: X = Cl, 10 %
entry 4: X = I, 79 %
X
N
N
3
entry 3: X = I, 80 %
O
N
Bn
4
Bn
O
O
Me
N
Me
N
O
N
O
tBu
CH3
N
N
N
N
N
2e
2f
N
2d
N
N
N
Bn
CH3
Bn
N
C7H15
entry 6: X = I, 76 %
entry 7: X = Br, 61 %
N
N
N
N
entry 8: X = I, 78 %
4a
4b
Bn
Bn
entry 5: X = I, 80 %
O
entry 3: X = Br, 62 %
entry 1: X = I, 81%
entry 3: X = Br, 64 %
O
O
nBu
Et
N
tBu
Cl
N
N
O
N
O
N
N
N
Br
NO2
N
N
N
2i
N
2h
N
C8H17
2g
Bn
N
N
entry 11: X = I, 69 %
N
N
N
entry 10: X = I, 63 %
entry 9: X = I, 75 %
Cl
Bn
4d Bn
entry 5: X = I, 75 %
4c
entry 4: X = I, 78 %
O
O
Reaction condition: A mixture of 1 mmol 3, 3 mmol KOtBu, 40 mol %
iPrOH in 10 mL DMF was heated at 80 oC for 6 h under N2 atmosphere.
Yields were calculated after flash chromatography.
EtO2C
N
N
Cl
N
N
2k
2j
N
N
Bn
Bn
entry 13: X = I, 62 %
Scheme 3. Synthesis of N-substituted1H-[1,2,3]triazolo[4,5-
c]quinolin-4(5H)-one derivatives.
entry 12: X = I, 65 %
All triazolo fused quinolone derivatives 4a-d were isolated in
good to very good yield (62-81 %). Substrate 3 with iodo group
(3a) gave 81 % yield of 4a, whereas with a bromo group gave 64
% yield of 4a.
Reaction condition: A mixture of 1 mmol 1, 3 mmol KOtBu, 40 mol %
iPrOH in 10 mL DMF was heated for 6 h under N2 atmosphere at 80 oC.
Yields of isolated product based on 1.
Scheme 2. Synthesis of N-substituted 1,4-dihydrochromeno[3,4-
d][1,2,3]triazole.
radical scavenger (I)
TEMPO (3 mmol)
iPrOH (40 mol%)
O
In general, the yield of the reactions were good to very good
(61-82 %). Alkyl and benzyl substitution on triazole nitrogen
atom (1a-d) gave comparable and very good yield of desired
product (2a-d). Alkyl substitution on phenyl ring has no effect on
the yield of this reaction and also gave very good yield of 2e (76
%), 2f (78 %) and 2g (75 %). The starting material (1h, 1i, 1j)
with halogen (Br and Cl) substitution on phenyl ring were well
tolerated and went efficiently under the optimized reaction
conditions with a moderate yield. The phenyl ring with a bromo
group (1h) gave somewhat lower yield (2h: 63%) than the chloro
substituted starting material (2i: 69 %; 2j: 65 %). Substrate 1k
with a strong electron withdrawing carboethoxy group on phenyl
ring went smoothly under this reaction conditions with 62 %
yield of 2k. In case of 1j; single product 2j was isolated (entry-
12) only by the substituting of iodo group and no other product
was obtained corresponding to the substitution of chloro group
was obtained. When X group on the substrate was changed from
iodo to bromo or chloro, the yield of the reaction decreased.
KOtBu (3 mmol)
O
DMF, 80oC
N2 atm.
N
N
I
2a
Bn
1a
N
N
N
N
Bn
radical scavenger
yield (2a)
I =
TEMPO (3 mmol)
BHT (3 mmol)
trace
7 %
Scheme 4. Coupling reaction in presence of radical scavenger
(TEMPO and BHT).
The yield difference between iodo, bromo and chloro substrates
as well as solvent effect (Table 1, entry 12) led us to assume that
the reaction might follow a radical pathway. Consequently we
performed the reaction separately in presence of TEMPO
(2,2,6,6-tetramethylpiperidine 1-oxyl) and BHT (butylated

4
Tetrahedron
hydroxy toluene) (Scheme 4) which produced a trace and 7 %
Compound 1 (1 mmol), iso-propanol (40 mol %) and KOtBu
(3 mmol) were added in preheated Schlenk tubes under N2
atmosphere. 10 mL dry DMF was added into tubes by syringe.
The mixture was stirred under N2 atmosphere in sealed Schlenk
yield of desired product 2a respectively, supporting the radical
pathway of the reaction.
Cosidering all the facts we assumed that aryl radical
generation might be a step in this coupling reaction and following
Murphy et al.22e we propose a plausible mechanistic pathway for
this coupling reaction in Scheme 5.
o
tubes at 80 C for 6 h. The reaction was cooled down to room
temperature. The mixture was filtered through a short plug of
silica gel, washed with copious ethyl acetate. The combined
organic layer was washed with H2O (3 ×10 mL) and saturated
NaCl (aq) (1 ×10 mL). The organic part was dried over Na2SO4,
concentrated under vacuum and purified by flash
chromatography on 230-400 mesh silica gel using ethyl
acetate/petroleum ether (2:8) as the eluent to afford product 2 .
-
I
.
R
R
R
A
A
A
B
B
iPrOH, KOtBu
SET
B
.
N
N
N
N
I
I
6
N
N
N
N
N
1
R1
5
R1
R1
1-Benzyl-1,4-dihydrochromeno[3,4-d][1,2,3]triazole (2a):
R
A
6-endo
B
White solid; Yield: 82 % (X = I), 10 % (X = Cl)
chain transfer
5-exo
1H-NMR (400 MHz, CDCl3, ppm): δ 5.49 (s, 2H); 5.82 (s, 2H);
6.90 (t, J = 7.2 Hz, 1H); 7.01 (d, J = 7.6 Hz, 1H), 7.18-7.23 (m,
4H); 7.29-7.38 (m, 3H).
13C-NMR (100 MHz, CDCl3, ppm): δ 53.0, 64.4, 113.8, 117.9,
122.1, 122.6, 126.5, 127.8, 128.4, 129.2, 130.6, 134.7, 139.7,
153.7.
N
2
N
N
R1
.
R
R
A
R
A
A
rearrangement
B
B
KOtBu
B
.
N
N
N
deprotonation
N
H
.
9
N
N
7
N
N
8
N
R1
R1
R1
HRMS calcd. for C16H14N3O [M + H]+: 264.1137; found:
264.1142
Scheme 5. Plausible mechanistic pathway.
In presence of alcohol and KOtBu, compound 1 generates
anion radical 5 through single electron transfer (SET)22. Radical
anion 5 then transforms to aryl radical 6 through elimination of I-.
This aryl radical 6 then adds to the double bond of triazole ring to
give 5-exo species 7 and/or 6-endo species 8. Species 7 may
rearranges to thermodynamically more stable 8. In presence of
KOtBu radical 8 gives another radical anion 9 via deprotonation.
A radical chain transfer reaction between 9 and 1 result the
desired product 2 along with regeneration of radical anion 5 and
continues the cycle.
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In conclusion, we have demonstrated
a
successful
intramolecular sp2 C-H functionalization methodology towards
the synthesis of 1,2,3-triazolo annulated chromen and quinolone
ring systems. This methodology is efficient, operationally simple
and demands inexpensive iPrOH and tBuOK. Further
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protocol for the synthesis of biologically attractive heterocycles
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NMR data:
General procedure for the preparation of products (2 & 4):

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