Quaternary N-(2-Pyridyl)-DABCO Salts: One-Pot in Situ Formation from Pyridine-N-oxides and Reactions with Nucleophiles: A Mild and Selective Route to Substituted N-(2-Pyridyl)-N′-ethylpiperazines

Article abstract of DOI:10.1021/acs.joc.6b02952

The N-(2-pyridyl)-N′-ethylpiperazines are important structural motifs in several medicinally relevant compounds. Known synthetic methods toward these structures are multistep and generally based on the S_NAr-chemistry; their applicability is significantly limited to substrates containing electron-withdrawing groups. Here, we describe a new methodology for a rapid and modular access to this privileged scaffold. Importantly, the developed protocol proved to be very general and efficient for the substrates containing substituents of different electronic nature. An operationally simple, metal-free, one-pot synthetic procedure involves the initial reaction of activated heterocyclic N-oxides with DABCO, followed by in situ treatment of the resultant quaternary N-(2-pyridyl)-DABCO salts with nucleophiles, resulting in ring-opening. The method features mild reaction conditions, high positional selectivity, and excellent functional-group tolerance. The utility of our approach is demonstrated by the late-stage site-selective functionalizations of complex molecules; a rapid modular assembly of MC2050, a potent PARP-1 inhibitor; and gram-scale preparations.

Full text of DOI:10.1021/acs.joc.6b02952

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Article
Quaternary N-(2-Pyridyl)-DABCO Salts: One-Pot in Situ Formation
from Pyridine-N-Oxides and Reactions with Nucleophiles – A Mild
and Selective Route to Substituted N-(2-Pyridyl)-N'-ethylpiperazines.
Dmitry I. Bugaenko, Marina A. Yurovskaya, and Alexander V. Karchava
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b02952 • Publication Date (Web): 20 Jan 2017
Downloaded from http://pubs.acs.org on January 20, 2017
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Quaternary Nꢀ(2ꢀPyridyl)ꢀDABCO Salts: OneꢀPot in Situ Formation from
PyridineꢀNꢀOxides and Reactions with Nucleophiles – A Mild and Selective
Route to Substituted Nꢀ(2ꢀPyridyl)ꢀN'ꢀethylpiperazines.
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Dmitry I. Bugaenko, Marina A. Yurovskaya, and Alexander V. Karchava*
Department of Chemistry, Moscow State University, Moscow 119992, Russia
karchava@org.chem.msu.ru
ABSTRACT:
The Nꢀ(2ꢀpyridyl)ꢀN'ꢀethylpiperazines are important structural motifs in several medicinally
relevant compounds. Known synthetic methods toward these structures are multistep and
generally based on the S Arꢀchemistry; their applicability is significantly limited to substrates
N
containing electronꢀwithdrawing groups. Here we describe a new methodology for a rapid and
modular access to this privileged scaffold. Importantly, the developed protocol proved to be very
general and efficient for the substrates containing substituents of different electronic nature. An
operationally simple, metalꢀfree, oneꢀpot synthetic procedure involves the initial reaction of
activated heterocyclic Nꢀoxides with DABCO, followed by in situ treatment of the resultant
quaternary Nꢀ(2ꢀpyridyl)ꢀDABCO salts with nucleophiles, resulting in ringꢀopening. The method
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features a mild reaction conditions, high positional selectivity, and excellent functionalꢀgroup
tolerance. The utility of our approach is demonstrated by the lateꢀstage siteꢀselective
functionalizations of complex molecules; a rapid modular assembly of MC2050, a potent PARPꢀ
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inhibitor; as well as gramꢀscale preparations.
INTRODUCTION
Pyridines and piperazines are among the most frequently utilized nitrogen heterocycles in
1
, 2
3
4ꢀ6
FDA approved drugs. Also, substituted pyridines and piperazines have found widespread
application as experimental drugs, agrochemicals, ligands and functional materials. Due to their
important role in many fields, methods to access diversely functionalized derivatives of these
7
privileged heterocycles have been highly sought after.
The NꢀheteroarylꢀN'ꢀethylpiperazine motif is an essential structural component of several
8
4
marketed drugs and drug candidates. Among them, Spycel™ and Geodon™ , the approved
drugs for treatments of cancer and schizophrenia respectively. Particularly, the Nꢀ(2ꢀpyridyl)ꢀN'ꢀ
9, 10
11
12
ethylpiperazine fragment can be found in potent PARPꢀ1,
SMO, PI3K inhibitors, and a
1
3
promising experimental drug for treatment of neurodegenerative disorders (Figure 1) .
Traditional synthetic strategies toward these compounds rely upon a nucleophilic substitution in
electron deficient heterocyclic halides with the appropriate piperazine precursors. However, the
scope of this approach is often dramatically restricted owing to costly substituted heteroaryl
halides and the lack of Nꢀmonosubstituted piperazines; both compounds are usually accessed via
multistep sequences. Another approach to this type of compounds is based on transitionꢀmetalꢀ
catalyzed C–Nꢀbond forming reactions and uses the same difficultly available starting materials
6, 14, 15
and additionally requires expensive and toxic catalysts and supporting ligands.
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Figure 1. Representative examples of marketed drugs and drug candidates containing Nꢀ
heteroarylꢀN'ꢀethylpiperazine core.
Alternatively, reactions between 2ꢀhalopyridines or derivatives thereof and 1,4ꢀ
diazabicyclo[2.2.2]octane (DABCO) could generate the quaternary ammonium salts A (Y=Hal)
(Scheme 1), which would react with nucleophiles affording Nꢀ(2ꢀpyridyl)ꢀN'ꢀethylpiperazines via
a ringꢀopening reaction. From this perspective, the ammonium salts A could be extremely
valuable intermediates to furnish medicinally relevant heterocyclic scaffolds in a modular and
stepꢀeconomical manner. However, owing to harsh reaction conditions required, the salt A has
never been prepared using the S Arꢀbased approach, but instead piperazines B and C comprising
N
substituted Nꢀethylpiperazinyl moiety have reported to be isolated, which presumably originated
1
6–20
from ringꢀopening of the initially formed salts A (Y=Cl, Scheme 1).
Although the use of Nꢀ
(2ꢀchloroethyl)piperazines C as substrates in reaction with nucleophiles has been revealed,
nevertheless, the protocol demands high reaction temperatures (>160 °C) for their generation and
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the further elaboration, resulting in the restricted functional group compatibility.
Finally, this
method is only applicable to pyridines bearing electronꢀwithdrawing groups such as NO , CF ,
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3
CN, and CO R, no reaction products were detected with 2ꢀchloropyridine and 2ꢀchloroꢀ4ꢀ
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picoline as the starting materials. Thus, incorporation of pyridines without electronꢀ
withdrawing groups remains challenging. To address this limitation, obviously, the other type of
reaction should be used to produce the quaternary salts A.
Scheme 1. Strategy for Nꢀ(Hetro)arylꢀNꢀethylpiperazine synthesis using DABCO
PyridineꢀNꢀoxides preꢀactivated with acylating agents are ideal substrates in the reactions
with a broad range of nucleophiles offering a valuable synthetic alternative to the nucleophilic
21–23
substitution in 2ꢀhalopyridines and transitionꢀmetalꢀcatalyzed reactions.
Nucleophilic
displacement in 2ꢀhalopyridines is the strongly substrateꢀdependent reaction and typically
2
4
requires harsh conditions, resulting in limited substrate scope and low functional group
tolerance. To the contrary, addition of a nucleophile to an activated pyridineꢀNꢀoxide (generally
prepared in situ) and the subsequent deoxygenative aromatization usually proceeds efficiently
under mild conditions, which improves functional group tolerance and overall applicability of
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the process. Furthermore, haloꢀpyridines are not easily accessible in a regioselective mode and
normally prepared from the corresponding Nꢀoxides, which in turn can be easily obtained in high
2
4
yields via simple oxidation of commercially available pyridines (Scheme 2).
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Scheme 2. S Arꢀ and NꢀOxideꢀbased Approaches to 2ꢀSubstituted Pyridines
N
23
Although known for almost half a century, the Nꢀoxideꢀbased strategy for the synthesis
of substituted pyridines has received significant attention in recent years. Many reliable synthetic
protocols for preparation of substituted pyridines and fused pyridines from the Nꢀoxide
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29
precursors have been developed. Various nucleophiles including halogenideꢀ,
azideꢀions,
3
0–33
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35,
35
amines,
NHꢀheterocycles,
alcohols and phenols, thiols and thiophenols as well as
3
7
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carbon nucleophiles (enamines, silyl ketene acetals, and azalactones ) were successfully
employed under mild and metalꢀfree reaction conditions with significantly larger scope of
substrates in contrast to the conventional S Arꢀbased approach. An intramolecular version of this
N
4
0
41, 42
process was used for the preparation of fused heterocycles via C–N and C–O
bond
formations. Despite the obvious advantages of this useful strategy, issues of low α/α' and α/γ
25, 27
selectivity as well as lack of generality often arise.
In fact, some methods for the preparation
25, 26
of fused pyridines (quinolines, isoquinolines, etc.) are not suitable to pyridines.
Therefore,
new and broad applicable methods for regioselective conversion of readily available pyridineꢀNꢀ
oxides into substituted pyridines with wide functional group tolerance are of high interest. If
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developed effectively, these methods provide streamlined accesses to valuable scaffolds for
pharmaceutical and agrochemical applications.
RESULTS AND DISCUSSION
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Herein, we present the first synthetic access to Nꢀ(2ꢀpyridyl)ꢀN'ꢀethylpiperazines
applicable to substrates bearing both electronꢀdonating and electronꢀaccepting groups in the
heterocyclic moieties. Our strategy is based on a twoꢀstep sequence comprising the generation of
ꢀ
Nꢀ(2ꢀpyridyl)ꢀDABCO salts A (Y=CF CO , Scheme 1) from pyridineꢀNꢀoxides and DABCO,
3
2
followed by nucleophilic ringꢀopening accomplished in one pot (Scheme 1B). Based on the
literature, two mechanistically distinct plausible pathways for the formation of the quaternary
salt A can be proposed (Scheme 3). In both cases, initial activation of the Nꢀoxide by
trifluoroacetic anhydride leads to enhancing both electrophilicity and CHꢀacidity of the Cꢀ2
position.
Then,
an
attack
of nucleophilic DABCO
and
the subsequent
deprotonation/aromatization provide the Cꢀ2 substituted product A, similar to the ReissertꢀHenze
43
25
reaction (pathway a). Alternatively, the activated Nꢀoxide can be deprotonated by DABCO
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4, 45
to generate a highly active electrophilic species such as a carbene,
which in turns attacks a
lone pair of DABCO. The subsequent aromatization in this case also provides the salt A
2
8
(pathway b, Scheme 3).
Scheme 3. Plausible pathways for the formation of the quaternary salt A
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The key features of our approach include: (1) the mild reaction conditions preventing the
further transformation of the salts A into compounds B and C (in contrast to the S Arꢀbased
N
approach, see Scheme 1A), and (2) the enhanced reactivity of the salts A toward nucleophiles.
Although there have been few reports on the preparation of 2ꢀpyridyltrialkylammonium salts
from pyridineꢀNꢀoxides and tertiary amines, their synthetic application was examined only in
3
1, 46
aromatic nucleophilic displacement of the trialkylammonium groups.
However, no studies
have been reported on nucleophilic ringꢀopenings of quaternary NꢀarylꢀDABCO salts, and in
particular, on using the salts A for a broad scope synthesis of substituted Nꢀ(2ꢀpyridyl)ꢀN'ꢀ
ethylpiperazines.
To optimize the reaction conditions quinoline Nꢀoxide (1a) and thioacetic acid (AcSH)
were selected as a model substrate and a nucleophile respectively. The reaction was design as
oneꢀpot, twoꢀstep transformations toward substituted piperazines 2 including an intermediate
formation of the quaternary ammonium salt A (Table 1). Initially a mixture of the Nꢀoxide 1a
and DABCO was treated with an activating agent to give the salt A, which was afterwards
quenched with AcSH.
Testing of different reaction parameters revealed that the highest yield of the desired
piperazine 2a was obtained when the reaction was performed in MeCN with 7 equiv of DABCO
and trifluoroacetic anhydride (TFAA, 2.5 equiv) as the activating agent. Unacceptably low yields
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were observed with other typically used activating agents (Table 1, entries 1–6). Notably, the
ꢀ
formation of the quaternary salt A (X=CF CO ) was not highly solvent dependent: the starting
3
2
material 1a was completely consumed (TLC) within 1 h at the ambient temperature in all tested
solvents. Although MeCN and DMF were preferred solvents providing near quantitative yields
and high purity (GCꢀMS) of the piperazine 2a even without a column chromatography;
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comparable yields were obtained in benzene and THF, while the yield was moderate in CH Cl2
2
(entries 1, 7–10). Control experiments showed that using less than 7 equiv of DABCO as well as
less than 2 equiv of TFAA resulted in decreasing yield (entries 1, 11–16). It should be mentioned
that DABCO plays a dual role, acting as the nucleophile for the first step as well as a base for
both the first and the second steps. Remarkably, under the mild reaction conditions employed, no
bisꢀpiperazine side product (similar to the salt B, Scheme 1A), arising from a nucleophilic attack
of excess DABCO on the initially formed salt A, was detected even with 12 equiv of DABCO
(entry 17). In a separate set of experiments (entries 18–20) the optimal reaction time for the
1
second step was determined. By monitoring reaction progress with H NMR spectroscopy, we
observed complete product formation within 1 h at room temperature. Finally, the reaction
demonstrated an exceptional regioselectivity: only the 2ꢀsubstituted quinoline 2a (confirmed by
4
7
2
D NMR experiments: NOESY, and HMBC) was obtained and the corresponding 4ꢀisomer
was not detected.
a
Table 1. Optimization the reaction conditions
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Entry DABCO, Activating
AcSH, Solvent Yield,
b
equiv
agent, equiv
equiv
%
Activating agent
1
2
3
4
5
6
7
7
7
7
7
7
TFAA 2.5
4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
98
0
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
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Ac O 2.5
4
4
4
4
4
2
Ts O 2.5
38
26
0
2
ClOCCOCl 2.5
MeOCOCl 2.5
TMSCl 2.5
Solvent
0
7
8
9
1
7
7
7
7
TFAA 2.5
TFAA 2.5
TFAA 2.5
TFAA 2.5
4
4
4
4
CH Cl2
48
86
2
THF
DMF 99 (96)
0
PhH
88
Ratio of DABCO, TFAA, AcSH
1
1
1
2
4.5
6
TFAA 1.5
TFAA 2.5
TFAA 2.5
TFAA 2.5
TFAA 2.5
TFAA 2.0
TFAA 2.5
2
3
3
3
4
4
4
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
57
79
91
13
14
15
16
17
7
c
3
38
81
94
98
6
7
12
Time of the reaction after addition AcSH
d
e
f
18
19
7
7
7
TFAA 2.5
TFAA 2.5
TFAA 2.5
4
4
4
MeCN
MeCN
48
71
20
MeCN 98 (96)
a
Reactions was performed on 1 mmol (1 equiv) of quinoline Nꢀ
b
oxide (1a) in 20 mL of solvent [0.05 M]. Yields were
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1
determined with H NMR using 3,6ꢀdibromoꢀpꢀxylene as an
с
internal standard. Yields in parenthesis are isolated yields. N,Nꢀ
diisopropylethylamine (4 equiv) was added. Time of the reaction
d
e
f
after addition AcSH was 15 min /30 min /60 min .
DABCO=1,4ꢀdiazabicyclo[2.2.2]octane. TFAA=trifluoroacetic
anhydride
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Having established the optimal reaction conditions (Table 1, entries 1 and 9), we next
studied the scope of Nꢀoxides (Table 2). The method showed excellent generality for pyridineꢀ
and quinolineꢀNꢀoxides bearing electronically diverse substituents. Utilizing Nꢀoxides of
unsubstituted pyridine (2b), alkylpyridines (2c and 2e), (hetero)arylpyridines (2d, 2f, and 2l),
and aminopyridines (2g and 2k) as substrates the corresponding products were obtained in good
to high yields as single regioisomers. Importantly, this method provides access to Nꢀ(2ꢀpyridyl)ꢀ
N'ꢀethylpiperazines which are inaccessible through current methods based on the S Ar
N
2
0
chemistry. Apart from two cases, installation of the piperazine moiety in 3ꢀsubstituted pyridineꢀ
Nꢀoxides occurred at the 6ꢀposition with the complete positional selectivity. PyridineꢀNꢀoxides
with alkoxy substituents at the 3ꢀposition 1i and 1j were exceptional substrates, leading under the
standard reaction conditions to mixtures of the amination products at the 6ꢀ and 2ꢀpositions (2i +
2i' and 2j + 2j'). For both substrates, the sterically less hindered 6ꢀregioisomers (2i and 2j) were
47
the major products, as confirmed by 2D NMR experiments (ROESY, and HMBC). Although
the preferential attack of sterically demanding DABCO on the sterically less hindered 6ꢀposition
is not surprising, the 2/6ꢀselectivity observed for 3ꢀalkoxysubstituted Nꢀoxides 1i and 1j was
unexpected and allowed us to assume that the steric hindrance is not the only factor governing
selectivity; stereoelectronic interactions probably also contribute to the reaction outcome.
Conversions of 4ꢀsubstituted pyridineꢀNꢀoxides were less successful. Ethyl isonicotinate Nꢀoxide
(
1n) and 4ꢀbezoylpyridine Nꢀoxide (1o) were unproductive under the standard conditions, only
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starting materials were fully recovered in both cases. When alternative reaction conditions (90
°
C, 24 h) were applied in the first step, the targeted product 2n was formed in a low yield (15%),
with 67% of the starting Nꢀoxide 1n being recovered. Nevertheless, the Nꢀoxide 1o did not
undergo the process even under these forcing reaction conditions. NꢀOxides of 4ꢀpicoline (1r)
and 4,4′ꢀbipyridine (1p) gave only products of the desꢀoxygenation (in 38% and 94% yields,
respectively), whereas neither the targeted piperazine 2q nor the starting material were isolated
when the reaction was performed with 4ꢀmetoxypyridine Nꢀoxide (1q). Diversely substituted
quinolineꢀNꢀoxides reacted smoothly affording the expected products 2s–2x as single Cꢀ2
isomers and in high yields. Notably, the bicyclic substrates 1v and 1w turned into the
corresponding piperidines 2v and 2w in high yields unlike their monocyclic counterparts 1n and
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1q. This difference presumably reflects the known increased reactivity of fused pyridineꢀNꢀ
21c, 25, 26
oxides in reactions of this type on which we have mentioned previously.
In general, many
nucleophileꢀsensitive and synthetically valuable functional groups including halide, ether, ester,
amide, and nitrile were perfectly tolerated under the used reaction conditions.
a
Table 2. Scope of heterocyclic Nꢀoxides
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a
Reactions was performed on 1 mmol (1equiv) of Nꢀoxide 1 in
b
CH CN [0.05 M]. Yields are isolated yields. DMF was used
3
c
instead of MeCN Isolated from the reaction of 1h as a result of
d
transamidation. See text.
Next, other types of sulfur nucleophiles that can be applied for the ring opening step were
examined. Thiophenols, including Nꢀunprotected 2ꢀaminothiophenol, heterocyclic thiols, and
benzylthiol were found to be suitable partners delivering the corresponding piperazines in good
to high yields under mild reaction conditions (Table 3). SHꢀHetrocycles which were investigated
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48, 49
as nucleophiles are common in drugꢀlike molecules.
Sodium benzenesulfinate gave the
sulfone 3s only in a modest yield. Quite surprisingly, the expected piperazine was not obtained
when sodium thiocyanate was used as the nucleophile, the salt 4a was instead isolated in a very
high yield. The structure of 4a was unambiguously confirmed by Xꢀray diffraction analysis
(Table 3). The salt 4a obviously originated from a nucleophilic attack of excess DABCO onto
the initially formed quaternary salt A (Table 1). In this case, thiocyanateꢀion proved to be a
weaker nucleophile compared to DABCO.
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a
Table 3. Scope of Sulfur Nucleophiles
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Reactions was performed on 1 mmol (1equiv) of Nꢀoxide 1 in
b
CH CN [0.05 M]. Yields are isolated yields. 12 equiv of
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c
d
DABCO was used. DMF was used. Sodium pꢀ
toluenesulfinate was employed. 90 °C in the second step.
Based on the above observation, we decided to explore the utility of our starting materials
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for preparation of heterocyclic compounds comprising bis(ethylpiperazine) motif, which can be
50, 51
found in biologically active compounds
(Table 4). We hypothesized that suitable reaction
conditions in the first step of the process would lead to the formation of ammonium salts B that
would be reactive to the further ring opening. Increasing the reaction time and temperature (8 h,
90 °C) in the first and second steps under otherwise identical reaction conditions (compare to
Table 1, entry 1) lead to the formation of bisꢀpiperazine 5a in 83% yield. Other sulfur
nucleophiles as well as sodium azide similarly underwent this process; bisꢀpiperazines 5b–5d
were afforded in good to high yields (61–79%) through a oneꢀpot procedure. It is worth
mentioning, that the preparation of compounds 5, employing the synthetic methods reported to
5
0, 51
date, would require multistep sequences including protection/deprotection operations.
a
Table 4. Synthesis of bisꢀpiperazines
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a
Reactions was performed on 1 mmol (1equiv) of Nꢀoxide 1 in
DMF [0.05 M]. Yields are isolated yields.
Having explored the scope of sulfur nucleophiles in the ringꢀopening reactions of the
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quaternary Nꢀ(2ꢀpyridyl)DABCO salts, we turned our attention to other types of nucleophiles
(
Table 5). Although slightly higher temperature and prolonged reaction time were required, the
quaternary salt A demonstrated high level of reactivity toward nitrogen, carbon and oxygen
nucleophiles. We found that potassium phthalimide, methylhydrazine, morpholine, and sodium
cyanide take part in the ringꢀopening process smoothly to afford the expected piperazine
compounds 6a–6d chemoꢀ and regioselectively in good yields (54–84%). Sodium azide gave
under the same reaction condition an inseparable mixture of piperazine 6e and
tetrazolo[1,5a]quinoline (7e) in a 1:1 ratio. Furthermore, the reaction of sodium 4ꢀ
fluorophenolate failed to produce the expected piperazine 6f and resulted in the formation of 2ꢀ
phenoxyquinoline 7f exclusively. Apparently, the observed reaction outcome can be explaining
5
2
and predicted considering hardꢀsoft properties of the used nucleophiles. For the relatively soft
nucleophiles, such as thiols, amines, and cyanideꢀion, the preference to form piperazines as a
result of the nucleophilic attack on the quaternized DABCO moiety is considerably greater. In
contrast, the harder nucleophiles, such as phenolate, tend to react at the Cꢀ2 position of quinoline
bringing about a nucleophilic displacement of DABCO as a leaving group. The earlier report on
the synthesis of 2ꢀfluoropyridines via nucleophilic substitution in 2ꢀpyridyltrialkylammonium
3
1
salts with “hard” fluorine anion complements our observations.
a
Table 5. Scope of Other Nucleophiles
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a
Reactions was performed on 1 mmol (1 equiv) of Nꢀoxide 1 in
DMF [0.05 M] 1) DABCO (7 equiv), TFAA (2.5 equiv); 2)
b
Nucleophile (4 equiv). Yields are isolated yields. Obtained as a
c
mixture (1:1), 89% total yield. Not optimized
With the developed protocol, we next demonstrated its synthetic utilities. First, we
53
™
applied our method for the late stage functionalization of Quinoxyfen , an active ingredient of
5
4
™
55
many fungicides (Scheme 4A). Quinoxyfen was oxidized and the corresponding Nꢀoxide 1y
was successfully subjected to our standard reaction conditions (Table 1, entry 1) to afford the
™
piperazine 8 in 68% yield (56% yield over two steps starting from Quinoxyfen ). Furthermore,
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our standard reaction conditions were employed for modification of the bisꢀNꢀoxide 1z
containing two alkylated pyridine moieties. Interestingly, the isomerically substituted pyridine
rings reacted in different ways: while the 3ꢀalkylpyridine part reacted in the typical manner,
producing a substituted piperazine, the 2ꢀalkypyridine fragment underwent the Boekelheide
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reaction, to provide after hydrolysis introducing of the hydroxyl group (Scheme 4B). Overall,
utilizing a simple, oneꢀpot procedure, the complex heterocyclic compound 9 was obtained in
excellent yield (76%) and complete regioselectivity. This transformation is a particularly
appealing due to the selectivity and the rapid installation of molecular complexity, gained
through the one pot procedure. Finally, we focused on the streamlined oneꢀpot synthesis of
MC2050 (10), a potent PARPꢀ1 inhibitor, from readily available pyridine Nꢀoxide (1b) and 2ꢀ
mercaptoꢀ4(3H)ꢀquinazolinone. Our innovative approach provided the targeted agent 10 in 65%
yield (Scheme 4C). Previously reported preparation of this compound includes a twoꢀstep
9
sequence, affording MC2050 (10) in 45% overall yield.
a
Scheme 4. Synthetic application
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a
Yields are isolated. Reaction conditions: A 1) Nꢀoxide (1y, 1
mmol, 1 equiv), DABCO (7 equiv), TFAA (2.5 equiv), CH CN
3
[
0.05 M], 0 °C to rt, 1 h; 2) AcSH (4 equiv), rt, 1h. B 1) Nꢀ
oxide (1z, 1 mmol, 1 equiv), DABCO (10 equiv), TFAA (5
equiv), CH CN [0.05 M], 0 °C to rt, 10 h; 2) PhSH (6 equiv),
3
rt, 10 h; 3) 2M Na CO , rt, 3 h. C 1) Nꢀoxide (1b, 1 mmol, 1
2
3
equiv), DABCO (7 equiv), TFAA (2.5 equiv), DMF [0.05 M],
0
°C to rt, 1h; 2) K CO (5 equiv), rt, 0.5 h; 3) RNa (4 equiv),
2 3
rt, overnight.
To highlight the practicality and robustness of the presented method, synthetically useful
thiols 11 and 12 were prepared in gramꢀscale, employing quinoline Nꢀoxide and DABCO as the
common starting materials and slightly different reaction conditions. Thiols 11 and 12 were
obtained in high overall yields (95% and 82% respectively) and purity without chromatography
purification (Scheme 5).
a
Scheme 5. Scaleꢀup preparations
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a
Yields are isolated yields. Conditions: A see Tab.2; B see
Tab.4; C AcCl (6 equiv), MeOH [0,21 M], rt, 24 h; D AcCl (8
equiv), MeOH [0,21 M], rt, 24 h.
CONCLUSION
This work represents the first systematic investigation on generation of quaternary Nꢀ(2ꢀ
pyridyl)DABCO salts from substituted pyridineꢀNꢀoxides and their previously unexplored
reactivity with nucleophiles. Reaction of activated Nꢀoxides with DABCO proceeds rapidly and
in a regioselective manner under mild conditions. In situ generated salts react with sulfur,
nitrogen, and carbon nucleophiles via a ring opening pathway, providing a concise access to
substituted Nꢀethylpiperazines in good to high yields, including compounds inaccessible by other
methods. Overall, the oneꢀpot, twoꢀstep process is applicable to a wide variety of structurally and
electronically diverse substrates and nucleophiles and tolerant to many different functionalities.
The high synthetic potential of the method was proved by synthesis of biologically relevant
compounds, including MC2050, a potent PARPꢀ1 inhibitor, the late stage functionalization of
Quinoxyfen™, as well as gramꢀscale preparations. Interestingly, unlike the aboveꢀmentioned
nucleophiles, phenolateꢀion reacts yielding a product of the nucleophilic displacement of the
DABCOꢀmoiety rather than the ring opening.
Experimental Section
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General Information All commercially available chemicals and solvents of high purity were
used without purification unless otherwise stated. Thioacetic acid was distillated prior to use.
DABCO was used from a freshly opened bottle. Column chromatography was performed in flash
conditions using silica gel (0.040–0.063 mm). Analytical thinꢀlayer chromatography (TLC) was
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1
13
carried out on silica gel 60 F254 plates that were visualized by exposure to UV light. H and C
NMR were recorded at 400MHz or 600MHz and 75MHz, 100MHz or 150MHz respectively for
solutions in CDCl , DMSOꢀd or D O. Chemical shifts are quoted in δ (ppm) and J values are
3
6
2
reported in Hz. Chemical shifts are referenced relative to residual proton signals of the
deuterated solvents. Massꢀspectra were recorded by EI mode with 70 eV. High resolution mass
spectra (HRMS) were measured using electrospray ionization (ESI) on an Orbitrap spectrometer.
FTꢀIR spectra were measured in KBr or as neat compounds. Only characteristically absorption
ꢀ1
bands were described, which are given in wave numbers (cm ). Melting points were determined
in open capillaries and are uncorrected. Reactions to produce product of types 2–11 were run
under an argon atmosphere. Yields refer to chromatographically and spectroscopically pure
compounds.
5
7
Methyl pyridinꢀ3ꢀylacetate was prepared following to the literature procedure.
5
7 13
Characterization data obtained matched those previously reported in the literature . C NMR
(
100 MHz, CDCl ): δ 171.3, 150.5, 148.7, 136.9, 129.8, 123.5, 52.4, 38.4.
3
1
ꢀMethylꢀ2ꢀpyridinꢀ3ꢀylꢀ1Hꢀbenzimidazole. To a stirred solution of 2ꢀpyridinꢀ3ꢀylꢀ1Hꢀ
5
8
benzimidazole (3.90 g, 20 mmol, 1 equiv) in DMF (30 mL, 0.67 M) sodium hydride (60 w/w
dispersion in mineral oil, 960 mg, 24 mmol, 1.2 equiv) was added portionwise over 30 min at 0
°
C. After stirring for 1 h at rt, dimethyl sulfate (2.77 g, 2.1 mL, 22 mmol, 1.1 equiv) was added
dropwise over 30 min. The reaction mixture was stirred for 1 h and the solvent was removed
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under reduced pressure. The residue was dissolved in 60 mL CH Cl and washed with 2 M aq.
2
2
NaOH (2×40 mL) and then with H O (6×40 mL). The organic layers were dried with Na SO ,
2
2
4
and the solvent was removed under reduced pressure to give the desired product as a tan solid,
yield 3.90 g (93%); mp: 140 – 143 °C, Characterization data obtained matched those previously
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reported in the literature.
ꢀChloroꢀ8ꢀmethoxyquinoline was prepared from 5ꢀchloroꢀ8ꢀhydroxyquinoline (3.59 g, 20
5
mmol) using the procedure described for 1ꢀmethylꢀ2ꢀpyridinꢀ3ꢀylꢀ1Hꢀbenzimidazole. Yellow
solid; yield 3.77 g (97%); mp: 60 – 63 °C. Characterization data obtained matched those
60
previously reported in the literature.
6
1
62
3
ꢀPhenylpyridine 1ꢀoxide (1d), 4ꢀ(1ꢀOxidopyridinꢀ2ꢀyl)morpholine (1k), 2ꢀPyridinꢀ2ꢀ
63
64
ylpyridine 1ꢀoxide (1l), Ethyl pyridineꢀ2ꢀcarboxylate 1ꢀoxide (1m), Ethyl isonicotinate 1ꢀ
64
65
oxide (1n), (1ꢀOxidopyridinꢀ4ꢀyl)(phenyl)methanone (1o), 4ꢀMethoxypyridine 1ꢀoxide
6
6
55
60
(
1q), 6ꢀBromoquinoline 1ꢀoxide (1s), 5ꢀChloroꢀ8ꢀmethoxyquinoline 1ꢀoxide (1t), Methyl
6
7
68
quinolineꢀ4ꢀcarboxylate 1ꢀoxide (1v), 1,10ꢀPhenanthroline 1ꢀoxide (1x), 5,7ꢀDichloroꢀ4ꢀ
55
(4ꢀfluorophenoxy)quinoline 1ꢀoxide (1y)
were prepared using reported procedures.
Characterization data obtained for these compounds matched those previously reported in the
literature.
General Procedure for the Synthesis of Heterocyclic NꢀOxides (General Procedure A).
To a cooled to 0 °C and stirred solution of a heterocyclic compound (15 mmol, 1 equiv) in
CH Cl (40 mL, 0.375 M), mꢀCPBA (75%, 4.14 g, 18 mmol, 1.2 equiv) was slowly added,
2
2
stirring was continued for 24 h at rt. Saturated aqueous solution of K CO was slowly added and
2
3
the resulting mixture was stirred for 30 min, then the layers were separated and the water layer
was extracted well with CHCl (5 × 30 mL). The combined organic layers were dried with
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Na SO , and the solvent was removed under reduced pressure to give the desired product in a
2
4
high purity. The products were used in the next step without additional purification.
Do not remove under reduced pressure the solvent immediately after the end of the reaction, it is
very dangerous!
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1
Methyl (1ꢀoxidopyridinꢀ3ꢀyl)acetate (1e): yield 2.23 g (89%); amorphous; light yellow. H
NMR (400 MHz, CDCl ): δ 8.15 (s, 1H), 8.10 – 8.12 (m, 1H), 7.18 – 7.24 (m, 2H), 3.70 (s, 3H),
3
1
3
3
.57 (s, 2H). C NMR (100 MHz, CDCl ): δ 169.5, 139.2, 137.3, 133.0, 127.3, 125.3, 51.9,
3
+
+
37.0. MS, m/z (I, %): 167 (100, M ), 151 (63), 92 (96). HRMS (ESI) m/z: [M+H] Calcd for
C H NO 168.0655; Found 168.0657.
8
10
3
1
ꢀMethylꢀ2ꢀ(1ꢀoxidopyridinꢀ3ꢀyl)ꢀ1Hꢀbenzimidazole (1f): yield 3.44 g (76%); amorphous;
1
light yellow. H NMR (400 MHz, CDCl ): δ 8.63 (s, 1H), 8.33 (d, J = 6.6 Hz, 1H), 7.84 (d, J =
3
13
8
.1 Hz, 1H), 7.76 (d, J = 8.0 Hz, 1H), 7.35 – 7.48 (m, 4H), 3.93 (s, 3H). C NMR (100 MHz,
CDCl ): δ 147.6, 142.5, 139.5, 139.0, 136.5, 129.9, 126.3, 126.0, 123.9, 123.0, 120.1, 109.9,
3
+
+
3
1.7. MS, m/z (I, %): 225 (M , 83), 209 (53), 208 (100), 156 (63). HRMS (ESI) m/z: [M + H]
Calcd for C H N O 226.0975; Found 226.0979.
1
3
12
3
1
Nꢀ(1ꢀOxidopyridinꢀ3ꢀyl)acetamide (1h): yield 2.98 g (98%); white solid; mp: 208 – 211 °C. H
NMR (400 MHz, CDCl ): δ 9.90 (br, 1H), 8.63 (s, 1H), 7.74 (d, J = 6.4 Hz, 1H), 7.49 (d, J = 8.3
3
1
3
Hz, 1H), 7.00 – 7.04 (m 1H), 1.97 (s, 3H). C NMR (150 MHz, DMSOꢀd ): δ 169.1, 138.3,
6
+
133.4, 129.8, 126.1, 115.6, 23.8. MS, m/z (I, %): 152 (M , 100), 110 (54), 94 (32), 93 (44).
+
HRMS (ESI) m/z: [M + H] Calcd for C H N O 153.0659; Found 153.0657.
7
9
2
2
3
ꢀ{[1ꢀ(Methylsulfonyl)piperidinꢀ4ꢀyl]oxy}pyridine 1ꢀoxide (1i): yield 5.16 g (95%); white
1
solid; mp: 118 – 121 °C. H NMR (400 MHz, CDCl ): δ 8.20 (s, 1H), 7.95 (d, J =6.1 Hz, 1H),
3
7
.18 – 7.23 (m, 1H), 6.95 (d, J =8.4 Hz, 1H), 4.47 – 4.53 (m, 1H), 3.22 – 3.33 (m, 4H), 2.76 (s,
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13
3
H), 1.83 – 2.05 (m, 4H). C NMR (100 MHz, CDCl ): δ 155.5, 132.5, 129.0, 125.9, 116.6,
3
7
2.3, 42.1, 34.8, 29.5. MS, m/z (I, %): 272 (M+, 33), 162 (100), 112 (27), 84 (44), 55 (33).
+
HRMS (ESI) m/z: [M + H] Calcd for C H N O S 273.0904; Found 273.0907.
11
17
2
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0
1
2
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6
7
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0
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4
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2
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4
5
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7
8
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0
1
3
ꢀPropoxypyridine 1ꢀoxide (1j): yield 2.89 g (94%); yellow viscous liquid. H NMR (400 MHz,
CDCl ): δ 8.08 (s, 1H), 7.96 – 7.98 (m, 1H), 7.17 – 7.21 (m, 1H), 6.93 – 6.95 (m, 1H), 3.92 –
3
13
3
.96 (m, 2H), 1.77 – 1.86 (m, 2H), 1.01 – 1.04 (m, 3H). C NMR (100 MHz, CDCl ): δ 156.6,
3
+
1
31.1, 127.1, 125.1, 114.6, 69.8, 21.2, 9.30. MS, m/z (I, %): 153 (M , 81), 139 (47), 111 (100).
+
HRMS (ESI) m/z: [M + H] Calcd for C H NO 154.0863; Found 154.0860.
8
12
2
1
Quinolineꢀ4ꢀcarbonitrile 1ꢀoxide (1u): yield 2.40 g (94%); yellow solid; mp: 183 – 185°C. H
NMR (400 MHz, CDCl ): δ 8.73 (d, J = 8.4, 1H), 8.51 (d, J = 6.4, 1H), 8.22 (d, J = 8.4, 1H),
3
1
3
7.83 – 7.90 (m, 2H), 7.67 (d, J = 6.4 Hz, 1H). C NMR (150 MHz, CDCl ): δ 142.1, 135.1,
3
+
1
1
1
6
31.8, 131.1, 129.0, 126.3, 125.9, 120.2, 115.5, 106.3. MS, m/z (I, %): 170 (M , 100), 154 (22),
+
42 (26), 115 (70), 114 (25). HRMS (ESI) m/z: [M + H] Calcd for C H N O 171.0553; Found
10
7
2
71.0549.
ꢀChloroꢀ4ꢀmethoxyquinoline 1ꢀoxide (1w): yield 3.06 g (97%); lightꢀbrown solid; mp: 209 –
1
212 °C. H NMR (400 MHz, CDCl ): δ 8.69 (d, J = 9.3 Hz, 1H), 8.46 (d, J = 6.4 Hz, 1H), 8.18
3
13
(
d, J = 2.0, 1H), 7.72 (dd, J = 9.3, 2.0 Hz, 1H), 6.66 (d, J = 6.4 Hz, 1H), 4.06 (s, 3H). C NMR
(
100 MHz, CDCl ): δ 152.9, 139.0, 135.9, 133.9, 131.1, 122.9, 121.4, 121.3, 100.4, 56.1. MS,
3
+
+
m/z (I, %): 211, 209 (M ; 39, 100), 196, 194 (31, 96). HRMS (ESI) m/z: [M + H] Calcd for
C H ClNO 212.0287 and 210.0316; Found 212.0287 and 210.0315.
10
9
2
2
ꢀ[2ꢀ(1ꢀOxidopyridinꢀ3ꢀyl)ethyl]pyridine 1ꢀoxide (1z): prepared using 2.4 equiv mꢀCPBA in
1
8
8% yield (2.85 g); offꢀwhite solid; mp: 184 – 187 °C. H NMR (600 MHz, CDCl ): δ 8.27 (d, J
3
=
6.1 Hz, 1H), 8.03 – 8.09 (m, 2H), 7.09 – 7.19 (m, 5H), 3.18 – 3.21 (m, 2H), 3.06 – 3.08 (m,
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9
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H). C NMR (100 MHz, CDCl ): δ 149.6, 139.9, 139.6, 138.8, 137.0, 126.2, 126.1, 125.5,
3
+
1
25.4, 124.2, 31.8, 28.4. MS, m/z (I, %): 216 (M , 10), 199 (100), 181 (56). HRMS (ESI) m/z:
+
[
M + H] Calcd for C H N O 217.0972; Found 217.0970.
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60
General Procedure for the Synthesis of Compounds 2 (Table 2, General Procedure B).
To a solution of heterocyclic Nꢀoxide 1a–y (1 mmol, 1 equiv) in 20 mL (0.05 M) of CH CN (or
3
DMF for Nꢀoxides insoluble in CH CN: 1f, 1h, 1p, 1s, 1t, 1u, 1w) 1,4ꢀdiazabicyclo[2.2.2]octane
3
(DABCO, 784 mg, 7 mmol, 7 equiv) was added in one portion. To the mixture cooled to 0 °C a
solution of trifluoroacetic anhydride (525 mg, 350 µL, 2.5 mmol, 2.5 equiv) in CH CN (5 mL)
3
was added dropwise. The resulted mixture was stirred for 1 h at rt. A solution of a thioacetic acid
(
304 mg, 4 mmol, 4 equiv) in CH CN (5 mL) was slowly added, and the resulting mixture was
3
stirred for 1 h at rt. The solvent was removed under reduced pressure and the residue was
dissolved in 20 mL CH Cl and was washed with saturated solution of NaHCO (3×20 mL),
2
2
3
water layers were combined and extracted CH Cl (4×20 mL), all organic layers were combined
2
2
and dried with Na SO , the solvent was removed under reduced pressure. The crude residue was
2
4
purified by flash chromatography on silica gel using gradient mixtures of EtOAc – nꢀhexane (1:4
to 1:0) or CH Cl – MeOH (20:1 to 2:1) as eluent.
2
2
Sꢀ[2ꢀ(4ꢀQuinolinꢀ2ꢀylpiperazinꢀ1ꢀyl)ethyl] ethanethioate (2a): yield 0.303 g (96%); also was
prepared following the general procedure using 2 g (13.8 mmol) of Nꢀoxide 1a; yield 4.17 g
1
(96%); offꢀwhite solid; mp: 98 – 101 °C; R = 0.33 (EtOAc/nꢀhexane = 1/1). H NMR (400 MHz,
f
CDCl ): δ 7.88 (d, J = 9.1 Hz, 1H), 7.70 (d, J = 8.3 Hz, 1H), 7.59 (dd, J = 7.8, 1.2 Hz, 1H), 7.53
3
(t, J = 7.7, 1H), 7.22 (t, J = 7.5, 1H), 6.97 (d, J = 9.1 Hz, 1H), 3.75 – 3.79 (m, 4H), 3.06 – 3.10
13
(
m, 2H), 2.60 – 2.66 (m, 6H), 2.35 (s, 3H). C NMR (100 MHz, CDCl ): δ 195.7, 157.3, 147.8,
3
137.6, 129.6, 127.3, 126.7, 123.2, 122.5, 109.6, 57.6, 52.9, 45.0, 30.7, 26.2. FTꢀIR (KBr): νmax
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−1
+
(
cm ): 1691 (C=O). MS, m/z (I, %): 315 (M , 8), 240 (99), 171 (52), 157 (100), 128 (33).
+
+
HRMS (ESI) m/z: [M + H] Calcd for C H N OS 316.1478; Found 316.1480.
17 22
3
Sꢀ[2ꢀ(4ꢀPyridinꢀ2ꢀylpiperazinꢀ1ꢀyl)ethyl] ethanethioate (2b): yield 0.142 g (54%); amorphous;
0
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0
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0
1
2
3
4
5
6
7
8
9
0
1
brown; R = 0.17 (EtOAc/nꢀhexane = 1/1). H NMR (400 MHz, CDCl ): δ 8.17 (d, J = 6.0 Hz,
f
3
1H), 7.45 – 7.49 (m, 1H), 6.60 – 6.65 (m, 2H), 3.54 – 3.57 (m, 4H), 3.04 – 3.08 (m, 2H), 2.59 –
1
3
2
.64 (m, 6H), 2.34 (s, 3H). C NMR (100 MHz, CDCl ): δ 195.7, 159.4, 147.9, 137.5, 113.4,
3
−1
1
07.1, 57.5, 52.7, 45.1, 30.6, 26.3. FTꢀIR (thin film): νmax (cm ): 1690 (C=O). MS, m/z (I, %):
+
+
265 (M , 6), 190 (100), 147 (36), 121 (56), 107 (78). HRMS (ESI) m/z: [M + H] Calcd for
+
C H N OS 266.1322; Found 266.1332.
13
20
3
Sꢀ{2ꢀ[4ꢀ(5ꢀMethylpyridinꢀ2ꢀyl)piperazinꢀ1ꢀyl]ethyl} ethanethioate (2c): yield 0.175 g (63%);
1
amorphous; brown; R = 0.19 (EtOAc/nꢀhexane = 1/1). H NMR (400 MHz, CDCl ): δ 7.97 (s,
f
3
1
2
1
H), 7.26 (d, J = 8.6 Hz, 1H), 6.54 (d, J = 8.6 Hz, 1H), 3.43 – 3.46 (m, 4H), 2.99 – 3.03 (m, 2H),
1
3
.53 – 2.58 (m, 6H), 2.29 (s, 3H), 2.14 (s, 3H). C NMR (100 MHz, CDCl ): δ 195.7, 158.0,
3
−
1
47.6, 138.4, 122.3, 107.0, 57.5, 52.7, 45.6, 30.6, 26.3, 17.3. FTꢀIR (thin film): νmax (cm ): 1690
+
(
C=O). MS, m/z (I, %): 279 (M , 16), 204 (92), 190 (30), 135 (40), 121 (100). HRMS (ESI) m/z:
+
+
[M + H] Calcd for C H N OS 280.1478; Found 280.1483.
1
4
22
3
Sꢀ{2ꢀ[4ꢀ(5ꢀPhenylpyridinꢀ2ꢀyl)piperazinꢀ1ꢀyl]ethyl} ethanethioate (2d): yield 0.276 g (81%);
1
beige solid; mp: 107 – 110 °C; R = 0.27 (EtOAc/nꢀhexane = 1/1). H NMR (400 MHz, CDCl ):
f
3
δ 8.44 (d, J = 2.3 Hz, 1H), 7.73 (dd, J = 8.8, 2.3 Hz, 1H), 7.52 – 7.53 (m, 2H), 7.40 – 7.44 (m,
2
2
1
H), 7.30 – 7.33 (m, 1H), 6.72 (d, J = 8.8 Hz, 1H), 3.62 – 3.70 (m, 4H), 3.09 – 3.11 (m, 2H),
1
3
.64 – 2.72 (m, 6H), 2.35 (s, 3H). C NMR (100 MHz, CDCl ): δ 195.6, 158.6, 146.1, 138.3,
3
−
1
36.1, 128.9, 126.8, 126.3, 126.2, 106.8, 57.5, 52.6, 45.1, 30.6, 26.2. FTꢀIR (KBr): νmax (cm ):
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+
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686 (C=O). MS, m/z (I, %): 341 (M , 18), 266 (63), 197 (36), 183 (100). HRMS (ESI) m/z: [M
+
+
+
H] Calcd for C H N OS 342.1635; Found 342.1641.
19 24 3
Methyl (6ꢀ{4ꢀ[2ꢀ(acetylthio)ethyl]piperazinꢀ1ꢀyl}pyridinꢀ3ꢀyl)acetate (2e): yield 0.152 g
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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56
57
58
59
60
1
(
45%); brown solid; mp: 77 – 80 °C; R = 0.13 (EtOAc/nꢀhexane = 1/1). H NMR (400 MHz,
f
CDCl ): δ 8.05 (d, J =2.3 Hz, 1H), 7.42 (dd, J = 8.8, 2.3 Hz, 1H), 6.62 (d, J = 8.8 Hz, 1H), 3.67
3
(
s, 3H), 3.52 – 3.57 (m, 4H), 3.48 (s, 2H), 3.04 – 3.08 (m, 2H), 2.59 – 2.64 (m, 6H), 2.34 (s, 3H).
1
3
C NMR (100 MHz, CDCl ): δ 195.7, 172.1, 158.7, 148.2, 138.5, 118.8, 107.0, 57.6, 52.7, 52.1,
3
−1
45.2, 37.5, 30.7, 26.3. FTꢀIR (KBr): νmax (cm ): 1739 (C=O), 1680 (C=O). MS, m/z (I, %): 337
+
+
+
(
M , 2), 193 (52), 179 (100), 162 (67). HRMS (ESI) m/z: [M + H] Calcd for C H N O S
16 24 3 3
3
38.1533; Found 338.1531.
Sꢀ(2ꢀ{4ꢀ[5ꢀ(1ꢀmethylꢀ1Hꢀbenzimidazolꢀ2ꢀyl)pyridinꢀ2ꢀyl]piperazinꢀ1ꢀyl}ethyl) ethanethioate
(
2f): yield 0.197 g (50%); lightꢀbrown solid; mp: 118 – 120 °C; R = 0.15 (EtOAc/nꢀhexane =
f
1
1
–
3
/1). H NMR (600 MHz, CDCl ): δ 8.55 (d, J =2.3 Hz, 1H), 7.99 (dd, J = 8.9, 2.3 Hz, 1H), 7.80
3
7.81 (m, 1H), 7.37 – 7.39 (m, 1H), 7.30 – 7.32 (m, 2H), 6.78 (d, J = 8.9 Hz, 1H), 3.89 (s, 3H),
13
.72 – 3.75 (m, 4H), 3.10 – 3.12 (m, 2H), 2.66 – 2.70 (m, 6H), 2.36 (s, 3H). C NMR (100
MHz, CDCl ): δ 195.6, 159.1, 151.9, 148.3, 142.8, 138.5, 136.5, 122.5, 122.3, 119.2, 115.0,
3
−
1
1
09.5, 106.4, 57.4, 52.5, 44.7, 31.7, 30.6. 26.2. FTꢀIR (KBr): νmax (cm ): 1689 (C=O). MS, m/z
+
+
+
(
I, %): 395 (M , 28), 320 (100), 237 (90). HRMS (ESI) m/z: [M + H] Calcd for C H N OS
21 26 5
396.1853; Found 396.1840.
Sꢀ[2ꢀ(4ꢀ{5ꢀ[(2,2,2ꢀTrifluoroacetyl)amino]pyridinꢀ2ꢀyl}piperazinꢀ1ꢀyl)ethyl]
ethanethioate
(
2g): was obtained from Nꢀoxide 1h together with 2h. Yield 0.266 g (71%); lightꢀbrown solid;
1
mp: 149 – 152 °C; R = 0.13 (EtOAc/nꢀhexane = 1/1). H NMR (400 MHz, CDCl ): δ 8.23 (s,
f
3
1
H), 7.81 – 7.85 (m, 2H), 6.66 (d, J = 9.3, 1H), 3.56 – 3.66 (m, 4H), 3.08 – 3.12 (m, 2H), 2.66 –
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5
5
5
5
5
5
5
6
13
2
.74 (m, 6H) , 2.35 (s, 3H). C NMR (100 MHz, CDCl ): δ 196.4, 156.5 (q, J = 36.9 Hz),
3 CF
1
55.2, 140.9, 131.4, 123.0, 115.9 (q, JCF = 288.3 Hz), 106.8, 57.3, 52.4, 45.0, 30.5, 26.1. FTꢀIR
−
1
+
(
KBr): νmax (cm ): 3295 (NH), 1713 (C=O), 1668 (C=O), 1141 (CF ). MS, m/z (I, %): 376 (M ,
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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5
6
7
8
9
0
1
2
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
6
) 301 (100), 287 (50), 258 (46), 232 (96), 218 (80), 116 (55). HRMS (ESI) m/z: [M + H] Calcd
+
for C H F N O S 377.1254; Found 377.1242.
1
5
20
3
4
2
Sꢀ(2ꢀ{4ꢀ[5ꢀ(Acetylamino)pyridinꢀ2ꢀyl]piperazinꢀ1ꢀyl}ethyl) ethanethioate (2h): was obtained
from Nꢀoxide 1h together with 2g. Yield 0.040 g (12%); lightꢀbrown solid; mp: 129 – 132° C; Rf
1
= 0.38 (CHCl /C H OH = 10/1). H NMR (400 MHz, CDCl ): δ 8.09 (d, J = 2.3, 1H), 7.83 (dd, J
3
2
5
3
=
9.2, 2.3 Hz, 1H), 7.18 (br, 1H), 6.63 (d, J = 9.2 Hz, 1H), 3.51 – 3.58 (m, 4H), 3.06 – 3.09 (m,
1
3
2
H), 2.60 – 2.66 (m, 6H), 2.34 (s, 3H), 2.15 (s, 3H). C NMR (75 MHz, CDCl ): δ 195.8, 168.8,
3
−
1
157.0, 140.5, 131.7, 125.7, 107.2, 57.6, 52.7, 45.6, 30.7, 26.3, 24.2. FTꢀIR (KBr): νmax (cm ):
+
3
304 (NH), 1683 (C=O), 1655 (C=O). MS, m/z (I, %): 322 (M , 4), 247 (68), 207 (34), 178 (56),
+
+
1
64 (100). HRMS (ESI) m/z: [M + H] Calcd for C H N O S 323.1536; Found 323.1527.
15 23
4
2
Sꢀ{2ꢀ[4ꢀ(5ꢀ{[1ꢀ(Methylsulfonyl)piperidinꢀ4ꢀyl]oxy}pyridinꢀ2ꢀyl)piperazinꢀ1ꢀyl]ethyl}
ethanethioate (2i), and Sꢀ{2ꢀ[4ꢀ(3ꢀ{[1ꢀ(methylsulfonyl)piperidinꢀ4ꢀyl]oxy}pyridinꢀ2ꢀ
yl)piperazinꢀ1ꢀyl]ethyl} ethanethioate (2i′): obtained as an inseparable mixture, 0.328 g (74%
1
total yield); brown amorphous; R = 0.32 (CHCl /C H OH = 10/1). H NMR (400 MHz, CDCl ):
f
3
2
5
3
δ 7.83 –7.87 (m, 1H), 7.10 (dd, J = 9.1, 2.9, 0.76H), 7.02 (dd, J = 7.8, 1.1 Hz, 0.24H), 6.75 (dd, J
= 7.8, 4,9 Hz, 0.24H), 6.57 (d, J = 9.1 Hz, 0.76H), 4,45 – 4.51 (m, 0.24H), 4.23 – 4.39 (m,
0
2
1
5
.76H), 3.36 – 3.43 (m, 4H), 3.19 – 3.33 (m, 4H), 2.97 –3.03, m, 2H), 2,76 (s, 0.72H), 2.74 (s,
1
3
.28H), 2.53 – 2.65 (m, 6H), 2.27 (s, 3H), 1.83 –1.84 (m, 4H). C NMR (100 MHz, CDCl ): δ
3
95.6, 195.5, 155.4, 153.2, 145.9, 143.5, 140.3, 137.1, 127.6, 123.1, 116.7, 108.0, 72.4, 71.2,
7.5, 57.4, 53.5, 53.0, 52.6, 47.8, 45.9, 42.3, 42.2, 34.8, 34.7, 30.6, 29.89, 29.86, 26.1, 25.9. FTꢀ
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The Journal of Organic Chemistry
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9
−1
+
IR (thin film): νmax (cm ): 1689 (C=O); 1326, 1158 (SO ). MS, m/z (I, %): 442 (M , 15), 367
2
+
+
(
100), 284 (44), 123 (30). HRMS (ESI) m/z: [M + H] Calcd for C H N O S 443.1781; Found
19 31 4 4 2
443.1785.
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Sꢀ{2ꢀ[4ꢀ(5ꢀPropoxypyridinꢀ2ꢀyl)piperazinꢀ1ꢀyl]ethyl} ethanethioate (2j), and Sꢀ{2ꢀ[4ꢀ(3ꢀ
propoxypyridinꢀ2ꢀyl)piperazinꢀ1ꢀyl]ethyl} ethanethioate (2j′): obtained as an inseparable
1
mixture, 0.207 g (64% total yield); brown amorphous; R = 0.23 (EtOAc/nꢀhexane = 1/1). H
f
NMR (400 MHz, CDCl ): δ 7.92 (d, J = 3.0 Hz, 0.84H), 7.84 (dd, J = 4.9, 1.5 Hz, 0.16H), 7.13
3
(dd, J = 9.1, 3.0 Hz, 0.84H), 7.00 (dd, J = 8.1, 1.5 Hz, 0.16H), 6.79 (dd, J = 8.1, 4.9 Hz, 0.16H),
6.61 (d, J = 9.1 Hz, 0.84H), 3.86 – 3.93 (m, 2H), 3.41 –3.48 (m, 4H), 3.03 – 3.09 (m, 2H), 2.57 –
1
3
2
.69 (m, 6H), 2.33 (s, 3H), 1.71 – 1.88 (m, 2H), 0.98 – 1.07 (m, 3H). C NMR (100 MHz,
CDCl ): δ 195.1, 174.1, 154.5, 148.4, 145.9, 138.4, 134.1, 125.3, 118.1, 116.6, 108.0, 70.4, 69.4,
3
57.3, 57.1, 52.6, 52.4, 52.3, 45.8, 30.3, 25.6, 22.4, 22.3, 21.4, 10.6, 10.2. FTꢀIR (thin film): νmax
−
1
+
(
cm ): 1692 (C=O). MS, m/z (I, %): 323 (M , 28), 248 (76), 179 (32), 165 (100). HRMS (ESI)
+
+
m/z: [M + H] Calcd for C H N O S 324.1740; Found 324.1742.
16
26
3
2
Sꢀ{2ꢀ[4ꢀ(6ꢀMorpholinꢀ4ꢀylpyridinꢀ2ꢀyl)piperazinꢀ1ꢀyl]ethyl} ethanethioate (2k): yield 0.201
1
g (57%); dark viscous liquid; R = 0.15 (EtOAc/nꢀhexane = 1/1). H NMR (400 MHz, CDCl ): δ
f
3
7.30 (t, J = 8.1 Hz, 1H), 5.99 (d, J = 8.1 Hz, 1H), 5.94 (d, J = 8.1 Hz, 1H), 3.74 – 3.77 (m, 4H),
3.46 – 3.48 (m, 4H), 3.39 – 3.42 (m, 4H), 3.00 – 3.03 (m, 2H), 2.53 – 2.55 (m, 6H), 2.30 (s, 3H).
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C NMR (150 MHz, CDCl ): δ 195.4, 158.3, 158.0, 139.1, 96.3, 95.8, 66.7, 57.2, 52.3, 45.5,
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−1
+
4
4.5, 30.5, 25.5. FTꢀIR (thin film): νmax (cm ): 1697 (C=O). MS, m/z (I, %): 350 (M , 19), 192
+
+
(
100). HRMS (ESI) m/z: [M + H] Calcd for C H N O S 351.1849; Found 351.1847.
17 27 4 2
Sꢀ{2ꢀ[4ꢀ(2,2'ꢀBipyridinꢀ6ꢀyl)piperazinꢀ1ꢀyl]ethyl} ethanethioate (2l): yield 0.302 g (88%);
1
yellow viscous liquid; R = 0.21 (EtOAc/nꢀhexane = 1/1). H NMR (400 MHz, CDCl ): δ 8.64 (d,
f
3
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