Catalyst and solvent-free alkylation of quinoline N-oxides with olefins: A direct access to quinoline-substituted α-hydroxy carboxylic derivatives

Article abstract of DOI:10.1039/c5ob02600h

A catalyst/solvent-free, one-pot and operationally simple method for the synthesis of quinoline-substituted α-hydroxy carboxylic derivatives by the hydroxyheteroarylation of olefins with quinoline N-oxides is reported. The reaction features a high atom-economy, mild and reagent/solvent-free conditions, broad substrate scope and good selectivity with high yields. A preliminary mechanistic study to shed light into the reaction pathway was also carried out.

Full text of DOI:10.1039/c5ob02600h

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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
View Article Online
DOI: 10.1039/C5OB02600H
Journal Name
Communication
Catalyst and Solvent-Free alkylation of Quinoline N-oxides with
Olefins: Direct Access to Quinoline Substituted α–Hydroxy
Carboxylic Derivatives
Received 00th January 20xx,
Accepted 00th January 20xx
ab
ab
ab
ab
Rakesh Kumar, Inder Kumar, Ritika Sharma and Upendra Sharma*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A catalyst/solvent-free, one-pot and operationally simple method for the synthesis of quinoline substituted α-hydroxy
carboxylic derivatives by hydroxyheteroarylation of olefins with quinoline N-oxides is reported. The reaction features high
atom-economy, mild and reagent/solvent-free conditions, broad substrate scope and good selectivity with high yields.
Preliminary mechanistic study to shed light into the reaction pathway was also carried out.
[
16]
Quinoline scaffold is one of the important heterocycle, carboxylic acid derivatives (Scheme 1b).
These derivatives can
[
1]
[2]
commonly encountered in natural products, medicinal and also be synthesized by addition of 2-methyl quinoline to ethyl
[3]
[17]
material chemistry. In medicinal chemistry, beside other activity, glyoxylate by using either Cu(OTf) /1,10-phen/THF
or
catalytic systems (Scheme 1a). Current
since the discovery of quinine. As a result considerable efforts has method holds various advantages over the earlier reported
2
[18]
quinolines are extensively explored for their anti-malarial potential Fe(OAc) /1,4-dioxane
2
[4]
[
5]
[6]
been made for their synthesis and functionalization at different methods: (i) Metal-free (ii) solvent-free (iii) ligand-free (iv) use of
positions. Traditionally, prefunctionalized quinolines and abundantly available olefins for alkylation (v) no-requirement for 2-
transitional metal catalyst were employed for achieving susbtituted quiolines. Overall the current method is conceptually
[7]
functionalization
at
different
position.
To
avoid different and proceeds through 1,3-dipolar cycloaddition followed
prefunctionalization, installation of N-oxide as directing group in by cleavage of N-O bond leading to the formation of new C-C and C-
the quinoline moiety has emerged as an alternative approach for O bond in contrast to Lewis acid promoted addition of 2-
[8]
the transition metal catalyzed as well as for the transition metal- alkylquinoline to ethyl glyoxylate.
[
9]
free direct functionalization of quinoline. Quinoline N-Oxides
were also employed successfully in 1,3-dipolar cycloaddition leading
quinoline substituted -hydroxy carboxylates
[10]
to various heterocycles as well as C-2 functionalization.
So we
via
(
a) metal catalyzed C-C bond formation
(b) C-C and C-O bond formation
thought to utilize acrylates for C-2 alkylation of quinoline via 1,3-
dipolar cycloaddition of quinoline N-oxides with acrylates,
Previous work
ref17
This work
neat
[8b, 11]
surprisingly, which has not yet been explored.
Cu(OTf)2
1,10-phen
N
N
Me
Functionalization under transition-metal-free condition is highly
significant considering the economic and environmental effect of
THF
OH
CO R
O
+
+
Fe(OAc)2
[12]
CO R
N
CO R
2
O
2
2
transition metals. Ideal green synthesis of organic compound is
one which can be achieved simply by reacting the starting material
1,4-dioxane
1
8
ref
metal-, catalyst-, ligand- and solvent-free
[
13]
without the requirement for any catalyst, promoter and solvent.
These types of reactions are more practical as they follow most of
Scheme 1. Synthesis of Quinoline Substituted α–Hydroxy
[
14]
Carboxylates.
the green chemistry principles.
In continuation of our research
[15]
interest for quinoline functionalization, we wish to report herein
direct C-2 alkylation of quinoline N-oxides with olefins leading to
direct access of important quinoline substituted α–hydroxy
Preliminary studies involved the reaction of quinoline N-oxide (1a)
with ethylacrylate (2a) in N-methyl pyrolidine (NMP) as solvent for
4h (Table 1, entry 2). Although, quinoline functionalization at C-2
position with simultaneous transfer of oxygen atom was observed,
-olefinated quinoline and 2-methyl quinoline were observed as the
2
2
a
major side products. The structure of the isolated compound 3a
was established by spectroscopic analysis and finally confirmed by
Natural Product Chemistry and Process Development Division, CSIR-Institute of
Himalayan Bioresource Technology, Palampur, Himachal Pradesh 176 061, INDIA
[19]
single-crystal X-ray diffraction.
Solvents such as N-methyl
b
Academy of Scientific and Innovative Research, CSIR-IHBT, Palampur, Himachal
pyrolidone, N-methyl morpholine, DMF, toluene, and other polar
and non-polar solvents failed to provide the desired product in
Pradesh 176 061, INDIA.
Email: upendra@ihbt.res.in;
Home page: http://www.ihbt.res.in/php/cv/sctInfo.php?id=34049
This journal is © The Royal Society of Chemistry 20xx
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Journal Name
higher yield (Table 1; entries 1; Table S1 entries 3-10). The efficiency good yield (3q-s). Reaction proceeded smoothly in cVaiesweAroticflehOanlildinee
of the reaction was increased significantly when solvents-free
conditions were employed while using 20 equiv. of acrylate (Table 1
entry 3). Further, we optimized temperature, time and quantity of
acrylate critically to get the better selectivity and yield (Table 1;
entries 4-12). Use of 4 equiv of acrylate at 100 C leads to higher
product yield with milder selectivity (Table 1; entry 9). Decrease in
DOI: 10.1039/C5OB02600H
substituents such as F, Cl and Br, thus providing further opportunity
for functionalization (3t-v). Functional group such as CO Me and
2
N(Boc) were well compatible (3w and 3x). Current method is not
limited to only quinoline as polyaromatics heterocycles such as
phenanthridine and benzo[f]quinoline were also alkylated
2
0
time to 15h provided product in good selectivity and yield (Table 1; successfully (3z and 3za). Unfortunately, 6-Nitroquinoline N-oxide
[20]
entry 12).
failed to provide any product.
a
a
Table 1. Optimization Study
Table 2. Substrate Scope
OH
CO2R
N
+
solvent
OR
+
3a
t °C, 24h
N
O
H
O
1a
2a
N
CO2R
4a
entry
2a
t
Solvent
(0.5 ml)
conv yield
3a/4a
0
b
(
equiv) ( C)
(%)
1
5
110
110
N- methyl
pyrrolidone
<5
n.d.
46
-
c
2
5
N- methyl
100
94:6
pyrrolidine
3
4
5
6
7
8
20
20
20
15
10
5
4
20
4
110
r.t.
90
110
110
110
100
100
100
100
-
-
-
-
-
-
-
-
65
<5
35
91
58
n.d.
33
64
63
43
53
67
66
94:6
-
100:0
82:18
81:19
55:45
66:34
71:29
78:22
86
100
100
100
100
84
9
d
1
1
1
0
1
2
e
f, g
4
80 (78) 95:5
a
b
reaction conditions: 1a (0.10 mmol), 2a (x equiv), 24h; NMR yield using
c
tetrachloroethane (TCE) as an d internal standard; 2-methylquinoline
e
f
g
detected as side product (<5%); reaction time 48h; 20h; 15h; isolated
yield in parentheses.
Thereafter, we studied the substrate scope with respect to
quinoline N-oxides and olefins (Table 2). Various activated olefins
provided the desired product selectively in milder to good yield (3a-
h). Current method is also applicable for tri-substituted olefin such
as methacrylate providing the desired product in good yield and
excellent selectivity (3h). A derivative of vitamin E was also
converted into the desired product 3zb in milder yield. Methyl-
substituent in N-heteroaromatic oxide at C-3, C-4 and C-6 did not
affect the outcome of reaction (3i-k). Low yield of product in case of
8
-methyquinoline N-oxide may be due to steric hinderance (3l).
Sterically demanding substituents like hemiacetal, -COMe and
a
Unless otherwise stated reaction conditions: 1 (0.30 mmol), 2 (1.2 mmol),
0
phthalimide at C-3 position were well tolerated (3m-o). Reaction
1
00 C, 15h, isolated yield reported; in parenthesis 3 to C-2 olefinated
proceeded well in case of protected methyl alcohol at C-4 position product (4) ratio calculated on the basis of 1H NMR analysis of crude
b
c
d
0
(
3p).
reaction mixture is reported; reaction time 12h; 36h; at 110 C for 24h,
e 0 f g h
solvent N-methyl pyrrolidine; at 90 C for 15h; 9h; NMR yield; 5h.
Further, to examine the functional group tolerance of current
method, variety of 6-substituted quinoline N-oxide were reacted
with butylacrylate under developed reaction condition. Satisfyingly,
Further to check the applicability of the developed method at larger
scale, the gram scale reaction was carried out (Scheme 2).
[20]
i
t
substituent’s such as – Pr, Bu and OMe provided the product in
2
| Journal Name, 2015, 00, 1-3
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Org aP nl ei ca s &e dB oi o nmo to al ed cj uu sl at rm Ca hr ge imn si stry
Journal Name
Scheme 5. Deuterium labelling experiments.
OH
CO Et
View Article Online
+
CO Et
2
DOI: 10.1039/C5OB02600H
100 °C, 15h
N
O
N
2
OH
+
CO R
2
6
.0 mmol
4 equiv.
3a, 69% (1.01 g)
N
N
CO2R
O
Scheme 2. Gram scale reaction.
N-O
clevage
H
1,3-cycloaddition
N
For preliminary understanding of the reaction pathway, few
experiments were carried out. Use of quinoline instead of quinoline
N-oxide failed to provide any product confirming the requirement
of later (Scheme 3a). To probe the O-atom transfer course,
O
CO R
2
Scheme 6. Probable reaction pathway.
18
Quinoline substituted α–hydroxy carboxylic acid derivatives (3a) can
be converted into corresponding C-2 olefinated quinoline by simply
heating at 100 C for 24h without using any additive or solvent
standard reaction was carried out in the presence of 99% H2
O
(
Scheme 3b). HRMS and GC-MS analysis of the isolated product (3a)
0
18
revealed no O incorporation, thus suggesting that O-atom transfer
is probably intramolecular.
[23]
[8h, 20]
albeit in low yield (scheme 7).
OH
+
+
CO Et
2
100 °C, 15h
OH
CO Et
1
00 °C, 15h
(a)
(b)
N
N
CO Et
2
metal and solvent
free process
N
2
3
a, not detected
CO Et
3a
2
1
00 °C, 24h 46%
H218O (5 equiv.)
N
O
OH
ref.23
CO Et
2
1
00 °C, 15h
N
O
N
CO Et
2
Pd (OAc)2 (5 mol%)
NMP, 110 °C, 20h
N
CO Et
2
3
a, 65%
4a
no 18O incorporation as HRMS observed for 3a = 246.1112
8
6%
Scheme 7. Conversion of 3a to 4a.
Scheme 3. Control experiments.
In summary, we have demonstrated that valuable quinoline
substituted α-hydroxy carboxylic derivatives can be synthesized
directly by reacting quinoline N-oxides with olefins under catalyst,
and solvent-free conditions. Broad substrate scope with milder to
good yield and high selectivity define the importance of current
method. Mechanistic study suggested that reaction probably
proceeds through 1,3-dipolar cycloaddition followed by N-O bond
cleavage.
Competition experiments with electronically different quinoline N-
oxide suggested that quinoline N-oxide with electron donating
group are favoured, which implies that reaction may proceed
through nucleophilic attack of quinoline N-oxide (Scheme 4).
R1
R1
OH
CO Et
N
O
N
2
CO Et
2
+
1
00 °C, 15h
+
R2
OH
CO2Et
Acknowledgement
R2
N
N
O
The authors would like to thank, the Director of the institute for
providing necessary facilities during the course of this research
activity. This activity is supported by Science and Engineering
Research Board, India (EMR/2014/001023). RK and IK acknowledge
UGC, New Delhi for Junior Research Fellowship. Authors thank Mr.
Arif Mohammad Ersad and Prof. Debabrata Maiti, Department of
Chemistry for X-ray analysis. CSIR-IHBT communication no. for this
publication is 3962.
R1 = H, R2 = OMe; 1: 1.5
R = H, R = COMe; 1: 0.7
1
2
Scheme 4. Competition experiments.
Competition experiment between 1a and the deuterated analogue
d7-1a revealed a kinetic isotope effect of k /k ≈ 1.50 (Scheme 5c),
indicating that the cleavage of C-H bond of quinoline N-oxide may
or may not be involved in the rate-limiting step. On the basis of
these preliminary mechanistic experiments and literature,
H
D
[
21]
[
22]
a
Keywords: quinoline· olefin · catalyst-free · solvent-free · alkylation·
probable mechanistic pathway is depicted in Scheme 6. Reaction
might involve 1,3-dipolar cycloaddition followed by cleavage of N-O
bond to provide the final product.
Notes and references
1
(a) V. V. Kouznetsov, L. Y. V. Mendez, C. M. M. Gomez, Curr. Org.
Chem. 2005, 9, 141-161; (b) J. P. Michael, Nat. Prod. Rep. 2008,
25, 166-187.
OH/D
(D7)H7
+
CO2Et
6 6
(D )H
100 °C, 5h
N
O
N
2
CO Et
KIE = 1.50
This journal is © The Royal Society of Chemistry 20xx
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