Silver/Palladium Relay Catalyzed Cross-Coupling of N'-Acetyl-8-quinolinesulfonylhydrazide with Alcohols: An Easy Access to 8-Quinolinesulfinate Esters

Article abstract of DOI:10.1002/ejoc.202000911

An efficient strategy for the synthesis of unexplored 8-quinolinesulfinate esters has been reported. The method involves in situ generation of quinoline sulfinate from N'-acetylquinoline-8-sulfonohydrazide via silver mediated cleavage followed by palladium-catalyzed cross-coupling with 1° and 2° alcohols to yield sulfinate esters. A variety of substituted alcohols were successfully employed in the reaction. Control experiments performed to understand the mechanism, revealed that the transformation follows a radical pathway and the alcohol oxygen get incorporated in the resulting sulfinate esters. Two of the chirally pure alcohols were also used in the transformation to study the diastereoselectivity in the reaction. In order to demonstrate the synthetic utility, a representative allyl-quinoline-8-sulfinate 3f was successfully converted into the 8-(allylsulfonyl)-quinoline 4 via palladium(II) acetate mediated isomerization.

Full text of DOI:10.1002/ejoc.202000911

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Silver/palladium relay catalyzed cross-coupling of N'-acetyl-8-
quinolinesulfonylhydrazide with alcohols: An easy access to 8-
quinolinesulfinate esters
Authors: Aanamika Yadav, Mayur D. Ambule, Ruchir Kant, and Ajay
Kumar Srivastava
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000911
Link to VoR: https://doi.org/10.1002/ejoc.202000911
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000911
Silver/palladium relay catalyzed cross-coupling of N'-acetyl-8-
quinolinesulfonylhydrazide with alcohols: An easy access to 8-
quinolinesulfinate esters
Anamika Yadav,[a] [c] Mayur D. Ambule, [a] [c] Ruchir Kant[b] and Ajay K. Srivastava*[a] [c]
[
a] A. Yadav, M. D, Ambule, Dr. A. K. Srivastava
Medicinal and Process Chemistry Division
CSIR-Central Drug Research Institute
Lucknow-226031, India
E-mail: ajayk.srivastava@cdri.res.in
Homepage URL: https://cdri.res.in/1868.aspx?id=1868
[
[
b]
c]
Dr. R. Kant
Molecular and Structural Biology Division
CSIR-Central Drug Research Institute
Lucknow-226 031, India
Academy of Scientific and Innovative Research (AcSIR), Ghaziabad- 201 002, India
Supporting information for this article is given via a link at the end of the document.
Abstract: An efficient strategy for the synthesis of unexplored
-quinolinesulfinate esters has been reported. The method
discovery, we became interested to develop a viable method for
8
the synthesis of quinolinesulfinates that were not much explored.
A review of available methods to synthesize sulfinates reveals
that the required starting materials (I-VIII, Figure 1) to prepare
quinolinesulfinates are either not stable or require multiple steps
for their synthesis (Figure 1).Therefore, we planned to use the
involves in situ generation of quinoline sulfinate from N'-
acetylquinoline-8-sulfonohydrazide via silver mediated cleavage
followed by palladium-catalyzed cross-coupling with 1° and 2°
alcohols to yield sulfinate esters. A variety of substituted alcohols
were successfully employed in the reaction. Control experiments
performed to understand the mechanism, revealed that the
transformation follows a radical pathway and the alcohol oxygen
get incorporated in the resulting sulfinate esters. Two of the
chirally pure alcohols were also used in the transformation to
study the diastereoselectivity in the reaction. In order to
demonstrate the synthetic utility, a representative allyl-quinoline-
stable
and
readily
available
N'-acetylquinoline-8-
sulfonohydrazide 1 that can be prepared in single step without
column purification and can be used as the sulfinylating source
for the preparation of desired sulfinate esters by coupling with
alcohols.
8
-sulfinate 3f was successfully converted to the 8-(allylsulfonyl)-
quinoline 4 via palladium (II) acetate mediated isomerization.
Sulfinate esters are versatile sulfinylating source for the
construction of various organosulfur compounds including
1
-4
sulfoxides, sulfinamides and sulfones. Umpolung character of
sulfinate makes them more attractive species for many coupling
1,
5-7
reactions.
In the recent past, a sulfinate ester probe was
8
reported by Chakrapani’s group for thiol bioimaging, whereas Wu
et al. reported that certain sulfinates exhibit antibiotic activity
9
against a human leukemia cell line HL-60. Sulfinates are mainly
1
0-15
synthesized by substitution reactions with alcohols.
In the
year 2016, Jang et al. reported a copper-catalyzed aerobic
16
oxidative coupling of thiols and alcohols to form sulfinates.
Another report in the same year appeared from the Prapurna’s
group for the synthesis of sulfinates from alcohols reacting with
1
7
TosMIC under Mitsunobu conditions. Subsequently Pan and
Liu’s group used sulfonylhydrazide for the copper-catalyzed
1
8-20
aerobic oxidative reaction with alcohols to prepare sulfinates.
Very recently, Basak et al.used N-sulfonylhydrazones to prepare
Figure 1. Analysis of starting material required for the synthesis of
quinolinesulfinates.
2
1
sulfinates using Wittig ylide. Regarding the quinoline sulfinate
esters, there is only one report by Sharpless et al., wherein they
could prepare mentholquinoline-8-sulfinate from sulfonyl chloride
1
5
and menthol in moderate yields. Furthermore, the method is not
At the outset of this investigation, N'-acetylquinoline-8-
sulfonohydrazide 1 was reacted with ethanol 2a using AgOAc
under different reaction conditions (Table 1). To our delight, the
formation of desired ethylquinoline-8-sulfinate 3a was observed
albeit in low yield with poor conversion of 60% and formation of
side desulfonylated product quinoline 3' (entry 1, Table 1). Higher
well suited for the primary alcohols and generate undesired side
1
5
products. A careful analysis of reported methods, it was
observed that the heterocyclic sulfinates are not much explored
and most of the synthetic methods were limited to alkyl/aryl
sulfinates. In our ongoing interest in exploring quinolines for drug
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000911
equivalents of AgOAc afforded 3a with increased yields along with
the side product 3' (entries 2 and 3, Table 1).To avoid the
formation of quinoline 3' and to afford the desired sulfinate ester
On performing the reaction in absence of AgOAc, starting material
was found to be intact in the reaction mixture (entry 13, Table 1).
Different catalysts like Cu(OAc)
2
, Co(OAc)
2
, Ni(OAc)
2
.4H
2
O were
3
a in higher yield, Pd(OAc)
yielded sulfinate 3a in 40% yield with 100% conversion (entries
and 5, Table 1). Furthermore, the use of 1.5 equivalents of
afforded the desired sulfinate
2
was used along with AgOAc, which
screened but there is the formation of side product along with
desired product in low yield (entry 14-16, Table 1). Thus, 1.5
4
equivalents of AgOAc and 30 mol% Pd(OAc)
2
in THF was found
to be the most suited reaction condition for this transformation
AgOAc and 30 mol% Pd(OAc)
2
ester 3a in 55% yield without formation of quinoline 3' (entry 6,
Table 1). After screening various solvents for this transformation,
THF was found to be the best yielding 3a in 59%yield (entries 7-
(entry 10, Table 1). The ethylquinoline-8-sulfinate 3a was fully
1
13
characterized by H and C NMR spectral analysis in which the
characteristic peaks of diastereotopic protons of 3a appeared at
1
1, Table 1). However, the reaction did not proceed in DMSO
δ 4.29 ppm (dq, J = 10.0, 7.1 Hz, 1H) and 3.91 ppm (dq, J =
1
(
entry 7, Table 1). Also, the reaction did not proceed at room
10.0, 7.1 Hz, 1H) ( H NMR, 400 MHz, CDCl
3
).
temperature (entry 12, Table 1).
With the optimized reaction condition in hand, the substrate scope
for this transformation was examined using a variety of alcohols
(Table 2). On using primary aliphatic alcohols, quinolinesulfinates
Table 1. Optimization of the reaction conditionsa
3
a-3e formed smoothly in 51-64% yields in compare to secondary
alcohols whereas tertiary alcohols did not afford the desired
product 3v (Table 2). In the case of allylic alcohols, reaction
condition is well suited for synthesizing allylsulfinates 3f and 3g in
5
5% and 54% respectively. Whereas with the benzyl alcohol,
entry
AgOAc
equiv.)
Catalyst
Solvent
t
(h)
3a
Yield
3’
sulfinate ester 3h was obtained in 50% yield.
b
Yieldb
[%]
(
[
%]
Table 2. Substrate scope,b
1
1.0
2.0
3.0
3.0
2.0
1.5
1.5
1.5
1.5
1.5
1.5
1.5
-
DCE
DCE
40
40
40
20
26
18
25
40
30
18
40
18
20
32
35
40
40
55
0
18
29
2
-
3
-
DCE
35
4c
5d
6
DCE
25
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
Pd(OAc)
2
2
2
2
2
2
DCE
19
DCE
-
7
DMSO
ACN
-
8
22
55
59
20
9
Toluene
THF
trace
-
1
1
1
0
Pd(OAc)
2
1
Pd(OAc)
Pd(OAc)
2
2
DCM
THF
trace
Trace
-
trace
Trace
2e
13
14
15
-
Pd(OAc)
2
THF
THF
THF
18
18
18
-
1.5
1.5
Cu(OAc)
Co(OAc)
2
2
34
36
42
44
Ni(OAc) .4
2
1
6f
1.5
THF
18
34
40
2
H O
a
Reaction Conditions: 1 (0.19 mmol), 2 (0.38 mmol), AgOAc (0.28mmol),
a
Reaction Conditions: All reactions were carried out using 1 (0.19 mmol), 2
Pd(OAc)
2
(30 mol%), with substituted benzylic alcohols AgOAc (0.38 mmol),
b
(
0.38 mmol), catalyst (30 mol%) and solvent (2.0 mL) at 60 °C under nitrogen.
anhydrous THF (2.0 mL) at 60 °C under nitrogen atmosphere. Isolated yields.
b
c
d
e
Isolated yields. Pd(OAc)
2
(10 mol%). Pd(OAc)
2
(20 mol%). At room
f
temperature. In presence of 4 Å MS DCE = 1, 2-dichloroethane, DMSO =
Dimethyl sulfoxide, ACN
= Acetonitrile, THF = Tetrahydrofuran, DCM =
Effect of substituents on benzylic alcohols was explored by
utilizing the substituted benzyl alcohols in the reaction (Table 2).
The electron-rich benzyl alcohols reacted well and afforded the
Dichloromethane.
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000911
corresponding sulfinates 3j-3l in 51-53% yields. Benzyl alcohols
with halogen substituents such as fluoro, bromo and iodo, reacted
well resulting the corresponding sulfinates 3m-3q in good to
moderate yields of 50-60%. m-Nitrobenzyl alcohol produced the
corresponding sulfinate 3r in 68% yield.In case of 2-amino benzyl
alcohol, the reaction did not work. α-Naphthyl alcohol afforded
the desired sulfinate ester 3t, however in low yield of 40%.
Secondary alcohol such as isopropyl alcohol also reacted well
providing the corresponding ester 3u in 52% yield. Tertiary
alcohol such as 2-methylbutan-2-ol and phenol did not give the
desired sulfinate esters (3v, 3w) limiting the reaction scope to
Scheme 2. Conversion of allyl sulfinate to allyl sulfone.
Further, investigations were carried out to get the mechanistic
insight of the reaction (Scheme 3). In order to confirm, whether
acetylation of alcohol was the first step in the reaction, pre-
acetylated benzyl alcohol 5 was used in the reaction but no
formation of sulfinate ester 3h was observed (Scheme 3a). After
primary and secondary alcohols.
A
single crystal X-ray
crystallographic analysis of the representative sulfinate 3n
unambiguously confirmed the structural identity of prepared
sulfinates.
18
18
that, O-labelled benzyl alcohol O-2h was reacted with 1 under
the standard reaction condition (Scheme 3b). The analysis of
Mass data of the product 18O-3h, it was found that the major peak
Next, to check the diastereoselectivity in the sulfinate
formation, two of the representative enantiomerically pure
alcohols, (-)-menthol 2x and naproxen-derived alcohol 2y were
reacted under the standard reaction conditions (Scheme 1).
Naproxen is a marketed nonsteroidal anti-inflammatory drug
1
8
appeared at 286.0781 (m/z) for O-labelled sulfinate confirming
the incorporation of oxygen from the benzyl alcohol.
2
2
(
NSAID) for the management of pain. Using (-)-menthol 2x, an
inseparable mixture of diastereomers 3x was obtained in the ratio
1
15
of 1:0.7 as per the crude H NMR analysis. Interestingly, with
the naproxen-derived alcohol 2y, better diastereoselectivity was
observed and the corresponding mixture of sulfinate 3y was
obtained in 2:1 diastereomeric ratio (Scheme 1).
Scheme 1. Reaction with chiral alcohols.
In an effort to convert the allyl-quinolinesulfinate 3f to allyl-
quinolinesulfone 4, sulfinate 3f was treated with Pd(OAc)
2
in
2
3,24
dioxane (Scheme 2).
To our delight the conversion took place
1
efficiently yielding 4 in 80% yield but the H NMR spectral
analysis showed it to be a mixture of two Regioisomers 4a and 4b
in the ratio of 3:1 (Scheme 2).Formation of regioisomer 4b might
have occurred from 4a by 1,3-H shift in presence of K
2
CO
3
.
However, the rearrangement of benzyl quinolinesulfinate 3h to
benzyl quinolinesulfone did not take place in the same reaction
conditions and the starting material remained unreacted.
Scheme 3. Mechanistic investigations.
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000911
Reactions performed in presence of radical scavengers such Experimental Section
as
2,2,6,6-tetramethylpiperidin-1-oxyl
(TEMPO)
and
butylatedhydroxytoluene (BHT) reduced the yield drastically or
prevented the formation of desired sulfinate, confirming the
reaction to follow a radical pathway (Scheme 3c). On performing
the reaction in absence of alcohol, formation of intermediate D
was observed via crude ESMS analysis in Scheme 3d (see ESI
Page No. 24). However, efforts to isolate the stable form of B for
further characterization was futile. It was also observed that the
reaction did not take place with N’-acetyl-tosylhydrazide 6,
reflecting the role of quinoline nitrogen in the formation of the
sulfinate esters (Scheme 3e).
An oven-dried 10 mL round bottom flask equipped with
magnetic bar was charged with N'-acetylquinoline-8-
sulfonohydrazide 1 (50.0 mg, 0.19 mmol), alcohol 2 (0.38 mmol),
AgOAc (47.0 mg, 0.28 mmol) and Pd(OAc) (13.0 mg, 30 mol%),
2
anhydrous THF (2.0 mL) was then added under nitrogen
atmosphere with constant stirring. After addition, the reaction was
heated to 60 °C on a pre-heated oil bath for 15-18 h. After
completion of the reaction (based on TLC), the reaction mixture
was filtered through celite pad and the filtrate was evaporated
under reduced pressure. The crude was purified by silica gel
column chromatography to afford the desired quinoline sulfinate
Based on the previous reports18, 25, 26 and results obtained in
the present investigations, a plausible reaction mechanism is
proposed in Scheme 4. It is postulated the radical intermediate A
is generated from the N’-acetyl sulfonohydrazide 1 by reacting
3
. The structure of 3n (CCDC 1859571) was unambiguously
confirmed X-ray crystallography.
with silver acetate. Intermediate
A
undergoes through
Acknowledgements
McFadyen-Stevens type cleavage to generate the sulfone radical
2
7-29
C that isomerises to sulfinate radical Cʹ.
Sulfinate radical Cʹ
Financial support from SERB, New Delhi [Grant No.
CRG/2018/001897 (GAP0320)] is highly acknowledged. AY and
AMD thank CSIR for providing fellowship. Authors are grateful to
SAIF, CSIR-CDRI for analytical support. This manuscript bears
CDRI communication number 100000.
can convert to the sulfinate anion D via single electron transfer.
Formation of intermediate D was confirmed through ESMS
analysis of the reaction mixture performed in the absence of
alcohol (see ESI Page No. 24). Further, palladium (II) acetate
coordinates with sulfinate D to form intermediate E, and facilitates
the addition of alcohol resulting the formation of desired sulfinate
2
5
ester 3.
Keywords: Sufinate ester; Quinoline sulfinate,
Sulfonohydrazide, Sulfone
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5
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European Journal of Organic Chemistry
10.1002/ejoc.202000911
Entry for the Table of Contents
Key topic: Quinoline sulfinates
An efficient strategy for the synthesis of unexplored quinoline-8-sulfinate esters has been reported via silver and palladium-catalyzed cross-
coupling of readily available N'-acetylquinoline-8-sulfonohydrazide with a range of 1° and 2° alcohols. Substrate scope, mechanistic studies
and synthetic applications have been explored in detail.
Institute twitter handle:@CSIR_CDRI
Dr. Ajay K Srivastava twitter handle @AksOrg
6
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