Room Temperature Metal-Catalyzed Oxidative Acylation of Electron-Deficient Heteroarenes with Alkynes, Its Mechanism, and Application Studies

Article abstract of DOI:10.1021/acs.joc.8b01475

Herein, we report an original one-step, simple, room-temperature, regioselective Minisci reaction for the acylation of electron-deficient heteroarenes with alkynes. The method has broad functional group compatibility and gives exclusively monoacylated products in good to excellent yields. The mechanistic pathway was analyzed based on a series of experiments confirming the involvement of a radical pathway. The ¹⁸O-labeling experiment suggested that water is a source of oxygen in the acylated product, and head space GC-MS experiment shows the C-C cleavage occurs via release as CO₂.

Full text of DOI:10.1021/acs.joc.8b01475

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Article
Room Temperature, Metal-catalyzed Oxidative Acylation of Electron-
deficient Heteroarenes with Alkynes, its Mechanism and Application Studies
Shweta Sharma, Mukesh Kumar, Ram A. Vishwakarma, Mahendra K. Verma, and Parvinder Pal Singh
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b01475 • Publication Date (Web): 21 Sep 2018
Downloaded from http://pubs.acs.org on September 21, 2018
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Room Temperature, Metal-catalyzed Oxidative Acylation of Electron-
deficient Heteroarenes with Alkynes, its Mechanism and Application
Studies
Shweta Sharma,1 Mukesh Kumar,1 Ram A. Vishwakarma,1Mahendra K. Verma2and
Parvinder Pal Singh1,*
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1Medicinal Chemistry Division, Academy of Scientific and Innovative Research, CSIRꢀ
Indian Institute of Integrative Medicine, Canal Road, Jammuꢀ180001, India
2Analytical Chemistry Division, CSIRꢀIndian Institute of Integrative Medicine, Canal Road,
Jammuꢀ180001, India
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Abstract:
Herein, we report an original oneꢀstep, simple, roomꢀtemperature, regioꢀselective Minisci
reaction for the acylation of electronꢀdeficient heteroarenes with alkynes. The method has
broad functional group compatibility and gives exclusively monoꢀacylated products in good
to excellent yields. The mechanistic pathway has been analyzed based on a series of
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experiments confirming the involvement of a radical pathway. The Oꢀlabeling experiment
suggested that water is a source of oxygen in the acylated product and head space GCꢀMS
experiment shows the CꢀC cleavage occurs via release as CO2.
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Introduction:
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Minisci’s reaction presents an attractive approach for the CꢀH functionalization of electronꢀ
deficient heteroarenes. Over the last decade, this approach has been studied in depth with
respect to its diversity, mechanism and application.1,2 Minisci’s reaction has been
successfully employed for the acylation, alkylation, arylation, carbamoylation,
amidoalkylation, etc. of electronꢀdeficient heteroarenes.3,4 Among these, acylation and
alkylation reactions are considered the most important because of the wide occurrence of the
produced structures in natural products5,6 and bioꢀactive compounds.7, 2a,8 The synthesis of
acylated and alkylated heteroarenes has been achieved using several donor compounds.
Acylation has been performed with oxoꢀacid, aldehyde, methylarene,and selenoester
groups,1a,9,10,11,12 while alkylation has been achieved with acids, alcohols, alkyl boronic acids
and their salts, xanthates, acetals, and alkyl halides (Figure 1).3,13 Under oxidative conditions,
these donors are converted into nucleophilic carbonꢀcentered radicals and subsequently react
with electrophilic heteroarenes to furnish the corresponding coupled products. In spite of the
wide diversity of products that can be produced, use of these methods includes several
drawbacks, such as high reaction temperatures, requirement of a stoichiometric amount of
catalysts and poor regioꢀselectivity. Consequently, the development of an effective alternative
method with a wide substrate scope and an ambient reaction temperature is highly desired. It
has also been documented that heteroatom (O, N, P, and S)ꢀbased radicals can behave
electrophilically, and many examples have been reported wherein radicals of this type were
coupled with electronꢀrich nucleophiles, such as alkenes, alkynes, and heteroarenes.14 Two
notable examples are the difunctionalization of olefinic and acetylenic compounds and
related reactions14a and the coupling of the αꢀC(sp3)ꢀH of amides with azoles.14b Considering
our interest in radicalꢀbased reactions,5b,14b,15 we proposed that if readily prepared heteroarene
Nꢀoxides can be converted in situ into corresponding electrophilic Nꢀoxide radicals under
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oxidative reaction conditions, this electrophilic radical can then react with electronꢀrich
species such as acetylenic derivatives and provide a complementary approach for the regioꢀ
selective generation of 2ꢀsubstituted heteroarenes (Figure 1).
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For this synthetic approach, a new chemical reaction method has been successfully developed
for the simple acylation of electronꢀdeficient heteroarenes. The present approach uses the
Minisci reaction with reverse (umpolung) reactivity of coupling partners, deviating from the
classical mechanism. This new synthetic pathway allows for the preparation of heteroarenes
with high regioꢀselectivity and good to excellent yields
Figure 1. Previous and present approaches for the synthesis of 2ꢀsubstituted heteroarenes
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Table 1. Optimization of the Reaction Conditionsa
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Results and discussion:
We selected pyridineꢀNꢀoxide and phenylacetylene as the coupling partners to test the
proposed method (Table 1). The study beganwith treatment of the selected substrates with
silver nitrate (0.2 eq.) as a catalyst and TBHP (3 eq.) as an oxidant in a
dichloromethane:water (DCM:H2O) solvent system at room temperature. Unfortunately, no
coupling was observed under these reaction conditions. In the next experiment, the oxidant
was replacedby potassium persulfate (K2S2O8, 3eq.) and coupling was observed with the
isolated product identified as 2ꢀacylated pyridine 3a (entry 2). The coupled product 3a was
isolated in 84% yield. Under other solvent systems, such as toluene:water and 1,2ꢀ
dichloroethane:water (DCE:H2O), the reaction proceeded but with comparatively lower
yields (entries 3ꢀ4). When the reaction was attempted in water alone, coupling also proceeded
efficiently (entry 5), similarly to that observed in the DCM:water system. However, when the
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reaction was performed in DCM and acetonitrile (ACN), no coupling was observed (entries
6ꢀ7). In an attempt to further refine the process, AgNO3 was changed to Ag2O, AgF(II),
AgF(I), Ag2CO3 and Ag2C2H3O2, but no advantage was observed with the use of these
alternative catalysts (entries 8ꢀ12). When the amount of K2S2O8 added was changed, the
formation of the coupled product was however affected (entries 13ꢀ14). No coupling was
observed when K2S2O8 was removed from the reaction mixture entirely (entry 15). When the
reaction was conducted in the presence of the oxidant alone, coupling was observed, but with
a lower yield of 18% (entry 16), which suggested that K2S2O8 is crucial. Additional
experiments were performed using varied amounts of K2S2O8 and different solvent systems,
but all of these experimental reaction conditions afforded the final product in low yields
(entries 17ꢀ18). From the screening studies, the best coupling conditions were identified as
0.2 eq. of AgNO3 and 3 eq. of K2S2O8 in a water or DCM:water system at room temperature
(entries 2 and 5).
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Equipped with a set of standard conditions, we then explored its diversity by conducting
reaction using various pyridineꢀNꢀoxides and acetylenes. Interestingly, the scope of this
approach was found to be very broad. Various aliphatic and aromatic acetylenes, including
those with both electronꢀdonating and electronꢀwithdrawing substituents, can be successfully
used (Scheme 1). According to Scheme 1, pyridineꢀNꢀoxides underwent a smooth coupling
reaction with electronꢀdonating phenylacetylenes such as 4ꢀethynyltoluene, 4ꢀethynylanisole
and 4ꢀethynyl biphenyl to afford the corresponding coupled products 3b, 3c and 3d in yields
of 74, 76 and 46%, respectively. Similarly, electronꢀwithdrawing phenyl acetylenes such as
1ꢀethynylꢀ4ꢀfluorobenzene, 1ꢀchloroꢀ4ꢀethynylbenzene, 1ꢀethynylꢀ4ꢀ(trifluoromethyl)benzene
and 1ꢀethynylꢀ4ꢀ(nitro)benzene also underwent reaction with pyridineꢀNꢀoxide 1 and
furnished the corresponding acylated products 3e, 3f, 3g and 3h in good to moderate yields
(45ꢀ77%). When pyridineꢀNꢀoxide 1 was treated with 1ꢀethynylꢀ4ꢀphenoxybenzene, the
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corresponding 2ꢀacylated product 3i was obtained in a 59% yield. PyridineꢀNꢀoxide 1 also
reacted well with orthoꢀsubstituted and bisubstituted phenylacetylenes such as 1ꢀethynylꢀ2ꢀ
nitrobenzene and 1ꢀethynylꢀ4ꢀfluoroꢀ3ꢀmethylbenzene, and the respective products 3j and 3k
were obtained in yields of 50 and 56%, respectively. The observed smooth reaction of
acetylenes containing electronꢀwithdrawing substituents are considered to be one of the major
advantages of the proposed method.
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Scheme 1. Substrate scope
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R
R
X
X
N
AgNO3, K2S2O8
H2O, rt
R1
R1
N
O
O
R1 = Aryl or Alkyl
X = CH or N
3
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2
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F
R2
N
R
N
CH3
N
N
O
O
O
NO2
3k, 56%
3j, 50%
3a: R2 = 4-H; 85%
3b: R2 = 4-OMe; 74%
3c: R2 = 4-Me; 76%
3d: R2 = 4-Phenyl; 46%
R2
R1
N
3e: R2 = 4-F; 77%
3f : R2 = 4-Cl; 62%
O
O
3g: R2 = 4-CF3; 48%
3h: R2 = 4-NO2; 45%
3i: R2 = 4-Phenoxy; 59%
# 3l: R1 = butyl; 38%
# 3m: R1 = hexyl; 37%
3n: R = 4-Me, R2 = 4-H; 78%
3o: R = 4-Me, R2 = 4-F; 73%
R
R3
R2
R2
R2
N
N
O
N
R
O
O
3x, R2 = 4-H; 28%, 3x' = <10%
( 3x = C2, 3x' = C6), R3 = CH3
3y, R2 = 4-F; 31%, 3y' = <10%
(3y = C2, 3y' = C6),R3 = CH3
3z, R2 = 4-H; 37%, 3z' = <10%
(3z = C2, 3z' = C6), R3 = Br
3u: R = 2-Me, R2 = 4-H; 74%
3v: R = 2-Me, R2 = 4-F; 72%
3w: R = 2-OMe, R2 = 4-H; 71%
3p: R = 4-NO2, R2 = 4-H; 55%
3q: R = 4- NO2, R2 = 4-F; 44%
#3r: R = 4-CF3, R2 = 4-H; 42%
#3s: R = 4-CF3, R2 = 4-F; 42%
#3t: R = 4-CN, R2 = 4-H; 25%
O
N
N
N
N
O
O
N
3ab, 30%
3aa, 35%
3ac, 0%
Reaction conditions: 1 (0.5 mmol), 2 (0.6 mmol), AgNO3 (0.1mmol) and K2S2O8 (1.5 mmol) in H2O
(3 ml) at room temperature for 3-4 hrs. 5eq of acetylene,# 1ml of DCM,#Time of reaction 12 hrs.#
Similarly, the reaction of pyridineꢀNꢀoxide 1 with aliphatic acetylenes such as 1ꢀHexyne and
1ꢀoctyne was tested under the optimized conditions, resulting in production of the
corresponding coupled products 3l and 3m but at comparatively lower yields (~38%).
Substituted pyridineꢀNꢀoxides were also used to examine the further potential diversification
of the method applications. Reaction of 4ꢀmethyl, 2ꢀmethyl and 2ꢀmethoxy pyridineꢀNꢀoxides
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with substituted and unsubstituted phenylacetylenes afforded the corresponding products (3n,
3o, 3u, 3v and 3w) in good to excellent yields (71ꢀ78%). PyridineꢀNꢀoxides with electronꢀ
withdrawing substituents, such as 4ꢀnitro, 4ꢀ(trifluoromethyl) and 4ꢀcyno groups, were also
analyzed and afforded the corresponding 2ꢀacylated products 3p-3t in low to moderate yields
(23ꢀ55%). When 3ꢀmethyl pyridineꢀNꢀoxide was treated with phenylacetylene and 1ꢀethynylꢀ
4ꢀfluorobenzene, however, it afforded a separable mixture of the 2ꢀsubstituted products 3x,
3y and 3z in a moderate yield of 38, 41 and 47% respectively along with traces of the 6ꢀ
substituted products 3x, 3y’and 3z’. Reaction of 2,2’ꢀbipyridylꢀNꢀoxide was also found to
furnish the coupled product 3aa in 35% yield. Treatments of pyrazine, diazine, with
phenylacetylene produced are the action that generated the acylated product 3ab in a yield of
30%. In the case of lutidineꢀNꢀoxide, where both the 2nd and 6th positions were blocked,
coupling was not detected, suggesting that a free CꢀH bond on the heteroatom adjacent to the
nitrogen is necessary for the successful coupling reaction.
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Scheme 2. Substrate scope
After investigating the scope of pyridineꢀNꢀoxides and acetylenes suitable for application in
the oxidative acylation, we focused our attention on the determination of the scope of fused
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heteroarenes (Scheme 2) that could be successfully used. Pleasingly, a variety of fused
heteroarenes were found to react smoothly with the acetylenes. Reaction of quinoline Nꢀoxide
with substituted and unsubstituted phenylacetylenes provided 2ꢀacylated products 5aꢀ5e in
good yields (61ꢀ70%). Under the same optimized reaction conditions, quinoxaline Nꢀoxide
was also found to react with acetylene to produce the acylated product 5f in a 25% yield.
Isoquinoline Nꢀoxide also reacted smoothly with substituted and unsubstituted acetylenes
under the optimized conditions (Scheme 2). These reactions occurred in the presence of both
electronꢀwithdrawing and electronꢀdonating containing substituents on the phenylacetylenes
to gave the Cꢀ1 arylated coupled products 7aꢀ7f but at comparatively lower yields (35ꢀ63%)
than those obtained with quinoline Nꢀoxide.
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Scheme 3. Substrate scope
A notable potential application for the present method is the acylation of the wellꢀknown
natural product quinine, an antiꢀmalarial drug. Under the optimized reaction conditions, when
quinine analogue 8a was reacted with phenylacetylene (Scheme 3), the reaction proceeded
and the corresponding coupled product 9a was obtained in a moderate yield of 34%. The
successful acylation of quinineꢀbased functional molecules further widen its utility towards
functionalization and diversification of this type of heterocycle, opening new avenues for the
functionalization of compounds like quinine to decrease side effects.16
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Scheme 4. Control experiments:
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Figure 2. Isotope experiment
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To gain insight into the reaction mechanism, a series of control experiments were performed
(eq. 1ꢀ10, Scheme 4) When the reactions were performed in the presence of free radical
scavengers such as TEMPO, the formation of the product 3a, was significantly suppressed
(eq. 1), confirming the involvement of a radical pathway. The pathway for the conversion of
phenylacetylenes into glycoxal/glyoxylic acid 10a/b and subsequent coupling with
heteroarenes via decarboxylation was ruled out by performing the reaction with
phenylacetylene underoxidative conditions and looking for the formation of
glycoxal/glyoxylic acid 10a/b (eq. 2ꢀ3). Under these conditions, no glycoxal/glycoxylic acid
10a/b formation was observed, suggesting that the present reaction proceeded through an
alternative pathway. When the reaction was performed with pyridine and its salt, no coupled
product was observed, again ruling out the possibility of the formation of glycoxal/glycoxylic
acid 10a/b and its involvement (eq. 4ꢀ5). The reaction under a nitrogen atmosphere preceded
smoothly, suggested that atmosphere oxygen does not play any role in the reaction (eq. 6).
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Next, we conducted the reaction in the presence of 18Oꢀlabelled water, wherein LC−MS
analysis showed a 70% presence of 18O in the product17 (Figure 2) suggested that water is the
source of oxygen atom in acylated product. The phenyl acetylene is known to form silver
acetylide on reaction with silver salt and its existence in the present conditions was also
confirmed. When the heteroarene Nꢀoxide 1 was treated with preformed silver acetylide 10
(prepared by known procedure),18 the corresponding coupled product was obtained (eq. 7)
suggested its role in the present reaction. The reaction of pyridine salt when tried with silver
acetylide, no product formation was seen, again suggested that Nꢀoxide is important for the
reaction (eq. 8). In another attempt, the intermolecular competition experiment was also
carried out (eq. 9), indicating that electron density on the phenyl rings plays an important role
in reaction rate, also explaining the reason for lower yield in case of electronꢀwithdrawing
group containing substrates. A kinetic isotope effect (KIE) experiment was conducted with
pyridine Nꢀoxide 1 and its deuterated analogue (eq. 10 and Figure S1 of Supporting
Information(SI)) and KH/KD ratio was found to be 2.1 suggested that the C–H bond cleavage
may also be involved in the rateꢀlimiting step although it is not conclusive at the present stage
(need further investigation).The reaction involves the CꢀC bond cleavage and release of CO2
was understood by carrying out the reaction in a specialized head space sealed bottle and
analyzed the volatiles in GCꢀMS instrument. Samples were collected after regular interval of
times has shown two peaks in the chromatogram at the retention time of 2.3 and 6.8 with m/z
of 44 and 102 Da which correspond to CO2 and phenyl acetylene 2 (Figure 3 and S2 of SI).
Figure 3 shows the percentage of CO2 and phenyl acetylene at different interval of time,
where CO2 concentration constantly increased with time, suggested the CꢀC cleavage
involved the release of CO2 under present oxidative conditions. On the basis of literature
precedents14b,19ꢀ21 and our experiments, the following cascade is proposed for the present
method (Figure 4). First, a persulfate radical anion (SO4ꢀꢁ) generated through the reaction of
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silver nitrate and persulfate abstracts an electron from the Nꢀoxide 1 to generate the radical
intermediate I1,21c which acts as an electrophile and react with in situgenerated silver
acetylide (Figure S3b of SI) to furnish the intermediate I2 (path a),which is confirmed by LCꢀ
MS (Fig S4aꢀb of SI). The possibility of path b, similar to Cuꢀcatalyzed Miura method20
couldn’t be ruled out but reaction between two electron rich species is energetically less
favourable, however, the formation of radical I1 will converts 1 into electrophilic species
which easily facilitate the reaction. No reaction in the absence of persulfate (entry 15, Table
1) as well as in the presence of TEMPO also suggested the involvement of radical pathway.
The intermediate I2 may proceed further by either ketene based intermediate I3 or
metalloketene based intermediate I4.19 During intermediate capturing experiment, ketene
based intermediate I3 was observed (Figure S5b of SI) suggested the involvement of ketene
based intermediate I3 in the present method. The intermediate I3 will further undergo reaction
with water and generate intermediate I4, similar to Wolfꢀrearrangement,21 which will
isomerize into more stable acidꢀbased intermediate I6. The intermediate I6 will form silver
carboxylate I7 (captured in LCꢀMS study (Figure S5a of SI), which undergoes
decarboxylation in the presence of Ag2+. Then I7 undergoes decarboxylation (release of CO2
is confirmed by GCꢀMS, Figure S2 of SI) followed by electronꢀloss and water attack
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(confirmed by H2 O experiment) to give final 2ꢀacylated product 3.
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Figure 3: Headspace GCꢀMS analysis for the release of CO2
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Figure 4. Plausible reaction mechanism
In summary, we have developed an original regioꢀselective acylation method for electronꢀ
deficient heteroarenes using various types of alkynes. The optimized method presents a
unique and powerful approach for the functionalization of the CꢀH bond of heteroarenes. The
room temperature, openꢀatmosphere operation and regioꢀselectivity of the present method are
its main advantages over previously reported methods. The optimized method has worked
with wide range of substrates. Additionally, direct acylation of functional molecules such as
2,2'ꢀbipyridine and quinine was also achieved using the proposed method.
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Experimental section:
General Information
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All the reactions were performed at room temperature in air and monitored by using
preꢀcoated silica gel TLC (60 F254, 20 × 20 cm). TLC plates were visualized by exposing
UV spectrometry at 254 nm or by iodine vapors or by charring in Dragendorff reagent. Buchi
rotavapor was used for concentration of organic solvents. Compounds were purified by flash
column chromatography on flash silica gel 230−400 mesh size. All the 1H NMR spectra were
recorded with 400 and 500 MHz NMR instruments. Chemical data for protons are given in
parts per million (ppm, scale) relative to TMS and referenced to the residual proton in the
NMR solvent (CDCl3: δ 7.26, or other solvents as mentioned). MestReNova software was
used to process NMR spectra. The coupling constant (J) are in Hz. Mass spectra were
obtained by using QꢀTOFꢀLC/MS spectrometer, using electron spray ionization. All the
heteroarene Nꢀoxides were synthesized in the lab by following reported procedures.22ꢀ25
General Procedure for oxidative acylated reaction:
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In a 10 ml Round bottom flask, to a solution of 1or 4 or 6 or 8a (0.5mmol, 1eq) in H2O (3 ml)
were added 2 (0.6 mmol), AgNO3 (0.1 mmol), K2S2O8 (1.5 mmol). The resulting solution was
stirred at room for several hours (Schemes 2ꢀ5). After completion, the reaction mixture was
transferred to separation funnel, 20 ml of bicarbonate solution were added, and reaction
mixture was extracted with dichloromethane (3x20ml). The combined organic layers were
dried over NaSO4, filtered and concentrated. The crude material was purified by column
chromatography using ethylacetate/ hexane as eluent to afford 3 or 5 or 7 or 9.
Phenyl(pyridin-2-yl)methanone26 (3a, Scheme 1)
TLC Rf = 0.5 (10% EtOAc/Hexane); Yield 85% (77.8 mg); Light yellow solid, m.p. 42ꢀ44 ºC;
1H NMR (400 MHz, CDCl3) δ 8.73 (d, J = 4.7 Hz, 1H), 8.12 – 8.02 (m, 3H), 7.91 (td, J = 7.7,
1.7 Hz, 1H), 7.59 (dd, J = 10.6, 4.2 Hz, 1H), 7.49 (dd, J = 10.5, 4.4 Hz, 3H);13C NMR (101
MHz, CDCl3) δ 193.8, 193.5, 155.1, 148.5, 137.0, 136.3, 132.9, 130.9, 128.1, 126.1, 124.61;
HRMS (ESI+) calcd. for: C12H10NO 184.0757 (M+ H), found 184.0751.
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(4-Methoxyphenyl)(pyridin-2-yl)methanone26 (3b, Scheme 1)
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º
1
TLC Rf = 0.5 (10 % EtOAc/Hexane); Yield 74% (78.8 mg); White solid, mp. 95ꢀ97 C; H
NMR (400 MHz, CDCl3) δ 8.70 (d, J = 4.7 Hz, 1H), 8.12 (d, J = 8.9 Hz, 2H), 7.98 (d, J = 7.8
Hz, 1H), 7.86 (td, J = 7.7, 1.6 Hz, 1H), 7.46 – 7.43 (m, 1H), 6.96 (t, J = 5.8 Hz, 2H), 3.87 (s,
3H);13C NMR (101 MHz, CDCl3) δ 192.2, 163.6, 155.8, 148.3, 136.9, 133.5, 129.0, 125.7,
124.5, 113.5, 55.4; MS (ESI+) found for: C13H12NO2 214.10 (M+H).
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Pyridin-2-yl(p-tolyl)methanone26 (3c, Scheme 1) TLC Rf = 0.5 (10 % EtOAc/Hexane);
1
Yield 76% (74.8 mg); Light yellow oil; H NMR (400 MHz, CDCl3) δ 8.72 (d, J = 4.7 Hz,
1H), 7.99 (dd, J = 13.2, 8.0 Hz, 3H), 7.89 (td, J = 7.7, 1.7 Hz, 1H), 7.47 (ddd, J = 7.6, 4.8, 1.2
Hz, 1H), 7.28 (d, J = 8.1 Hz, 2H), 2.43 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.5, 155.5,
148.5, 143.7, 136.9, 133.7, 131.1, 128.8, 125.9, 124.4, 21.6; HRMS (ESI+) calcd. for:
C13H12NO 198.0913 (M+ H), found 198.0909.
[1,1'-Biphenyl]-4-yl(pyridin-2-yl)methanone (3d, Scheme 1)
TLC Rf = 0.5 (10% EtOAc/Hexane); Yield 46% (59.5 mg); yellow crystalline solid; m.p. 87.5
°C; 1H NMR (400 MHz, CDCl3) δ 8.75 (d, J = 4.7 Hz, 1H), 8.20 – 8.13 (m, 2H), 8.07 (d, J =
7.8 Hz, 1H), 7.92 (td, J = 7.7, 1.7 Hz, 1H), 7.74 – 7.68 (m, 2H), 7.65 (dd, J = 5.2, 3.3 Hz,
2H), 7.53 – 7.44 (m, 3H), 7.44 – 7.36 (m, J = 8.4, 6.3 Hz, 1H);13C NMR (101 MHz, CDCl3) δ
193.3, 155.3, 148.5, 145.6, 140.2, 137.0, 135.0, 131.6, 128.9, 128.1, 127.3, 126.9, 126.1,
124.6; HRMS (ESI+) calcd. for: C18H14NO 260.1070. (M+H), found 260.1067.
(4-Fluorophenyl)(pyridin-2-yl)methanone26(3e, Scheme 1)
º
1
TLC Rf = 0.4 (10% EtOAc/Hexane); Yield 77% (77 mg); White solid; m.p. 80 C; H NMR
(400 MHz, CDCl3) δ 8.71 (d, J = 4.7 Hz, 1H), 8.23 – 8.13 (m, 2H), 8.05 (d, J = 7.9 Hz, 1H),
7.90 (td, J = 7.7, 1.7 Hz, 1H), 7.48 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.19 – 7.09 (m, 2H); 13C
NMR (126 MHz, CDCl3) δ 192.0 165.7 (d, J = 255.53 Hz), 155.0, 146.4, 137.1,133.8 (d, J =
10.1 Hz), 132.5 (d, J = 3.03 Hz), 126.2, 124.6, 115.2 (d, J = 22.22 Hz); HRMS (ESI+) calcd.
for: C12H9FNO 202.0663.(M+H), found 202.0674.
(4-Chlorophenyl)(pyridin-2-yl)methanone26 (3f, Scheme 1)
TLC Rf = 0.4 (10% EtOAc/Hexane); Yield 62% (67.2 mg); Light yellow oil; 1H NMR (400
MHz, CDCl3) δ 8.71 (d, J = 4.6 Hz, 1H), 8.11 – 8.03 (m, 3H), 7.90 (td, J = 7.7, 1.6 Hz, 1H),
7.54 – 7.40 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 192.3, 154.7, 148.5, 139.4, 137.1, 134.6,
132.5, 128.4, 126.4, 124.6; HRMS (ESI+) cald. for C12H9ClNO 218.0373 found 218.0367
(M+H).
Pyridin-2-yl(4-(trifluoromethyl)phenyl)methanone26 (3g, Scheme 1)
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TLC Rf = 0.4 (10% EtOAc/Hexane); Yield 48% (60.2 mg); yellowish oil; H NMR (400
MHz, CDCl3) δ 8.72 (d, J = 4.7 Hz, 1H), 8.19 (d, J = 8.2 Hz, 2H), 8.13 (d, J = 7.9 Hz, 1H),
7.93 (td, J = 7.7, 1.7 Hz, 1H), 7.75 (d, J = 8.3 Hz, 2H), 7.52 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H);
13C NMR (101MHz, CDCl3) δ 192.6, 154.2, 148.6, 139.4, 137.2, 133.9 (d, J = 33.33Hz)
131.2, 126.7, 125.0 (q, J = 4.04Hz), 124.7, 122.4; HRMS (ESI+) calcd. for: C13H9F3NO
252.0631. (M+ H), found 252.0634.
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(4-Nitrophenyl)(pyridin-2-yl)methanone27 (3h, Scheme 1)
TLC Rf = 0.3 (10% EtOAc/Hexane); Yield 45% (51.3 mg); pale yellow solid; m.p. 98 OC; H
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NMR (400 MHz, CDCl3) δ 8.66 (d, J = 4.7 Hz, 1H), 8.26 (d, J = 8.9 Hz, 2H), 8.22 – 8.16 (m,
2H), 8.10 (d, J = 7.9 Hz, 1H), 7.89 (td, J = 7.7, 1.7 Hz, 1H), 7.52 – 7.45 (m, 1H); 13C NMR
(101 MHz, CDCl3) δ 192.0, 153.7, 149.9, 148.8, 141.6, 137.4, 132.4, 126.9, 125.2; HRMS
(ESI+) calcd. for: C12H9N2O3 229.0608. (M+ H), found 229.0611.
(4-Phenoxyphenyl)(pyridin-2-yl)methanone (3i, Scheme 1)
1
TLC Rf = 0.6 (10% EtOAc/Hexane); Yield 59% (81.1 mg); pale brown oil; H NMR (400
MHz, CDCl3) δ 8.73 – 8.69 (m, 1H), 8.14 – 8.09 (m, 2H), 8.03 (d, J = 7.8 Hz, 1H), 7.90 (td, J
= 7.7, 1.7 Hz, 1H), 7.48 (ddd, J = 7.6, 4.8, 1.2 Hz, 1H), 7.43 – 7.37 (m, 2H), 7.20 (t, J = 7.4
13
Hz, 1H), 7.09 (dt, J = 9.0, 1.8 Hz, 2H), 7.05 – 7.01 (m, 2H); C NMR (101 MHz, CDCl3) δ
192.2, 162.0, 155.5, 155.4, 154.1, 148.4, 137.1, 133.5, 130.6, 130.0, 126.0, 124.6, 124.6,
120.3, 117.0; HRMS (ESI+) calcd. For: C18H14NO2 276.1019. (M+ H), found 276.1029.
(2-Nitrophenyl)(pyridin-2-yl)methanone28 (3j, Scheme 1)
º
1
TLC Rf = 0.3 (10% EtOAc/Hexane); Yield 50% (57 mg); light red solid; m.p. 115 C; H
NMR (400 MHz, CDCl3) δ 8.52 (d, J = 4.7 Hz, 1H), 8.29 (d, J = 7.9 Hz, 1H), 8.20 (dd, J =
8.2, 0.8 Hz, 1H), 7.92 (td, J = 7.7, 1.7 Hz, 1H), 7.80 (td, J = 7.5, 1.1 Hz, 1H), 7.69 (td, J =
8.1, 1.4 Hz, 1H), 7.61 (dd, J= 7.5, 1.4 Hz, 1H), 7.44 (ddd, J = 7.6, 4.8, 1.1 Hz, 1H); 13C
NMR (101 MHz, CDCl3) δ 193.4, 152.6, 149.2, 137.1, 135.6, 134.1, 130.7, 129.4, 127.1,
123.5, 122.6; HRMS (ESI+) calcd. for: C12H9N2O3 229.0608. (M+ H), found 229.0598
(4-Fluoro-3-methylphenyl)(pyridin-2-yl)methanone (3k, Scheme 1)
O
1
TLC Rf = 0.3 (10% EtOAc/Hexane); Yield 56% (60.2 mg); cream solid; m.p. 56.7 C; H
NMR (400 MHz, CDCl3) δ 8.76 – 8.66 (m, 1H), 8.02 (d, J = 7.8 Hz, 1H), 8.00 – 7.92 (m,
2H), 7.89 (td, J = 7.7, 1.7 Hz, 1H), 7.48 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 7.09 (t, J = 8.9 Hz,
1H), 2.33 (d, J = 1.8 Hz, 3H);13C NMR (101 MHz, CDCl3) δ 192.4, 164.4 (d, J = 254.52Hz),
155.2, 148.4, 137.0, 134.7 (d, J = 7.07Hz), 132.3 (d, J = 3.03Hz), 132.2 (d, J = 10.1 Hz),
126.1, 124.5, 124.9 (d, J = 18.18 Hz), 114.8 (d, J = 23.23 Hz), 14.5 (d, J = 4.04 Hz); HRMS
(ESI+) calcd. for: C13H11FNO 216.0819. (M+ H), found 216.0795.
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1-(Pyridin-2-yl)pentan-1-one29 (3l, Scheme 1)
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TLC Rf = 0.5 (10% EtOAc/Hexane); Yield 21% (17.1 mg); Colorless liquid; 1H NMR (400
MHz, CDCl3) δ 8.67 (d, J = 4.4 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.82 (td, J = 7.7, 1.6 Hz,
1H), 7.54 – 7.37 (m, 1H), 3.22 (dd, J = 14.8, 7.4 Hz, 2H), 1.72 (dt, J = 15.1, 7.5 Hz, 2H),
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202.2, 153.4, 148.9, 136.8, 126.9, 121.8, 37.4, 26.1, 22.4, 13.9; HRMS (ESI+) calcd. for:
C10H14NO 164.1070. (M+ H), found 164.1052.
1-(pyridin-2-yl)heptan-1-one (3m, Scheme 1)
1
TLC Rf = 0.2 (10% EtOAc/Hexane); Yield 20% (20.5 mg); Colorless liquid; H NMR (400
MHz, CDCl3) δ 8.71 – 8.63 (m, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.82 (td, J = 7.7, 1.7 Hz, 1H),
7.46 (ddd, J = 7.5, 4.8, 1.1 Hz, 1H), 3.21 (t, J = 7.5 Hz, 2H), 1.75 – 1.69 (m, 2H), 1.45 – 1.29
(m, 6H), 0.89 – 0.86 (m, 3H); 13C NMR (101 MHz, CDCl3) δ 202.2, 153.6, 148.9, 136.8,
126.9, 121.7, 37.7, 31.7, 29.0, 23.9, 22.5, 14.0; HRMS (ESI+) calcd. for: C12H18NO 192.1383
(M+ H), found 192.1384.
(4-Methylpyridin-2-yl)(phenyl)methanone30 (3n, Scheme 1)
TLC Rf = 0.5(10% EtOAc/Hexane); Yield 78% (77.1 mg); Yellow oil; 1H NMR (400 MHz,
CDCl3) δ 8.55 (d, J = 5.0 Hz, 1H), 8.03 (d, J = 7.2 Hz, 2H), 7.84 (s, 1H), 7.56 (t, J = 7.4 Hz,
1H), 7.46 (t, J = 7.6 Hz, 2H), 7.31 – 7.25 (m, 1H), 2.45 (s, 3H); 13C NMR (126 MHz, CDCl3)
δ 194.2, 155.0, 148.3, 136.5, 132.8, 130.9, 128.1, 126.9, 125.3, 21.1; HRMS (ESI+) calcd.
for: C13H12NO 198.0913. (M+ H), found 198.0936.
(4-Fluorophenyl)(4-methylpyridin-2-yl)methanone31 (3o, Scheme 1)
O
1
TLC Rf = 0.4 (10% EtOAc/Hexane); Yield 73% (78.4 mg); White solid; m.p. 95.1 C; H
NMR (400 MHz, CDCl3) 1H NMR (400 MHz, CDCl3) δ 8.56 (d, J = 4.9 Hz, 1H), 8.19 – 8.12
(m, 2H), 7.87 (d, J = 0.6 Hz, 1H), 7.31 (d, J = 4.9 Hz, 1H), 7.19 – 7.10 (m, 2H), 2.47 (s, 3H);
13C NMR (101 MHz, CDCl3) δ 192.3, 165.7 (d, J = 255.53 Hz), 154.8, 148.5, 148.3,133.7 (d,
J = 9.09Hz), 132.7 (d,J = 4.04 Hz), 127.1, 125.4, 115.2 (d, J = 22.22 Hz), 21.1; MS (ESI+)
found for: C13H11FNO 216.15.
(4-Nitropyridin-2-yl)(phenyl)methanone (3p, Scheme 1)
1
TLC Rf = 0.3 (10% EtOAc/Hexane); Yield 55% (62.7 mg); light orange oil; H NMR (400
MHz, CDCl3) δ 9.05 (d, J = 5.3 Hz, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.29 – 8.20 (m, 3H), 7.26 –
7.18 (m, 2H); 13C NMR (101MHz, CDCl3) δ 191.2, 157.9, 154.9, 150.8, 135.2, 133.6, 131.0,
128.4, 118.2; HRMS (ESI+) calcd. for: C12H9N2O3 229.0608 (M+ H), found 229.0608.
(4-Fluorophenyl)(4-nitropyridin-2-yl)methanone (3q, Scheme 1)
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TLC Rf = 0.2 (10% EtOAc/Hexane); Yield 44% (54.1 mg); brown oil; H NMR (400 MHz,
CDCl3) δ 9.05 (d, J = 5.3 Hz, 1H), 8.79 (d, J = 2.1 Hz, 1H), 8.29 – 8.20 (m, 3H), 7.26 – 7.18
(m, 2H); 13C NMR (101 MHz, CDCl3) δ 189.3, 166.1 (d, J = 257.55 Hz), 157.7, 155.0, 150.7,
133.9 (d,J = 9.09 Hz), 131.5 (d, J = 3.03 Hz), 118.3, 117.5, 115.6 (d, J = 22.22 Hz); HRMS
(ESI+) calcd. for: C12H8FN2O3 247.0513. (M+ H), found 247.0506.
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Phenyl(4-(trifluoromethyl)pyridin-2-yl)methanone32 (3r, Scheme 1)
1
TLC Rf = 0.4 (10% EtOAc/Hexane); Yield 30% (37.6 mg); brown oil; H NMR (400 MHz,
CDCl3) δ 8.91 (d, J = 5.0 Hz, 1H), 8.29 (s, 1H), 8.14 – 8.05 (m, 2H), 7.72 (dd, J = 5.0, 1.0
Hz, 1H), 7.63 (ddd, J = 8.7, 2.5, 1.2 Hz, 1H), 7.51 (dd, J = 10.7, 4.7 Hz, 2H); 13C NMR (101
MHz, CDCl3) δ 192.2, 156.3, 149.5, 139.7 (d, J = 35.35 Hz), 135.5, 133.4, 131.0, 128.3,
123.8, 121.6 (q, J = 3.03 Hz), 120.5 (q, J = 3.03 Hz); MS (ESI+) found for: C13H9F3NO
252.0631 (M+H).
(4-Fluorophenyl)(4-(trifluoromethyl)pyridin-2-yl)methanone(3s, Scheme 1)
TLC Rf = 0.4 (10% EtOAc/Hexane); Yield 24% (32.2 mg); brown oil; 1H NMR (400 MHz,
CDCl3) δ 8.91 (d, J = 5.0 Hz, 1H), 8.30 (s, 1H), 8.26 – 8.13 (m, 1H), 7.73 (d, J = 4.9 Hz, 1H),
7.24 – 7.12 (m, 2H); 13C NMR (101 MHz, CDCl3) δ 190.3, 166.0 (d, J = 256.54 Hz), 156.18,
149.4, 133.9 (d, J = 9.09 Hz), 131.8 (d, J = 3.03 Hz), 123.7, 121.6 (d, J = 3.03 Hz), 120.5 (d,
J = 4.04 Hz) 115.5 (d, J = 22.22 Hz); HRMS (ESI+) calcd. for: C13H8F4NO 270.0537. (M+
H), found 270.0526.
2-Benzoylisonicotinonitrile33 (3t, Scheme 1)
TLC Rf = 0.5 (10% EtOAc/Hexane); Yield 23% (23.9mg); brown solid; m.p. 93 ºC; 1H NMR
(400 MHz, CDCl3) δ 8.91 (d, J = 4.9 Hz, 1H), 8.28 (s, 1H), 8.11 – 8.05 (m, 2H), 7.71 (dd, J =
13
4.9, 1.5 Hz, 1H), 7.64 (t, J = 7.4 Hz, 1H), 7.51 (t, J = 7.7 Hz, 2H); C NMR (101 MHz,
CDCl3) δ 191.6, 156.1, 149.4, 135.1, 133.6, 131.0, 128.4, 127.3, 126.4, 121.9, 115.9; HRMS
(ESI+) calcd. for: C13H9N2O 209.0709, (M+ H), found 209.0699.
(6-Methylpyridin-2-yl)(phenyl)methanone26 (3u, Scheme 1)
1
TLC Rf = 0.5 (10% EtOAc/Hexane); Yield 74% (72.8 mg); Colorless oil; H NMR (400
MHz, CDCl3) δ 8.13 – 8.05 (m, 1H), 7.80 – 7.70 (m, 1H), 7.62 – 7.54 (m, 1H), 7.47 (t, J =
7.6 Hz, 1H), 7.33 (dd, J = 6.8, 1.8 Hz, 1H), 2.63 (s, 2H); 13C NMR (101 MHz, CDCl3) δ
193.8, 157.7, 154.7, 137.0, 136.3, 132.8, 131.2, 128.0, 125.7, 121.6, 24.5; HRMS (ESI+)
calcd. for: C13H12NO 198.0913, (M+ H), found 198.0935.
(4-Fluorophenyl)(6-methylpyridin-2-yl)methanone (3v, Scheme 1)
1
TLC Rf = 0.5 (10% EtOAc/Hexane); Yield 72% (77.4 mg); White crystals; m.p. 55 C; H
NMR (400 MHz, CDCl3) δ 8.27 – 8.15 (m, 2H), 7.80 (dt, J = 15.1, 7.4 Hz, 2H), 7.36 (d, J =
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7.4 Hz, 1H), 7.21 – 7.11 (m, 2H), 2.64 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 192.0, 165.7
(d, J = 255.53 Hz), 157.6, 154.6, 137.1, 133.9 (d, J = 9.09 Hz), 132.6 (d, J = 3.03 Hz), 125.8,
121.6, 115.1 (d, J = 22.22 Hz), 24.4; HRMS (ESI+) calcd. for: C13H11FNO 216.0819. (M+
H), found 216.0818.
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(6-Methoxypyridin-2-yl)(phenyl)methanone (3w, Scheme 1)
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TLC Rf = 0.5 (10% EtOAc/Hexane); Yield 71% (75.6 mg); light brown oil; H NMR (400
MHz, CDCl3) δ 8.70 (d, J = 4.7 Hz, 1H), 8.12 (d, J = 8.9 Hz, 2H), 7.98 (d, J = 7.8 Hz, 1H),
7.86 (td, J = 7.7, 1.6 Hz, 1H), 7.51 – 7.39 (m, 1H), 6.96 (t, J = 5.8 Hz, 2H), 3.87 (s, 3H); 13C
NMR (101 MHz, CDCl3) δ 192.2, 163.6, 155.8, 148.3, 136.9, 133.5, 129.0, 125.7, 124.5,
113.5, 55.4; HRMS (ESI+) calcd. for: C13H12NO2 214.0863. (M+H), found 214.0861.
(3-Methylpyridin-2-yl)(phenyl)methanone (3x, Scheme 1)
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TLC Rf = 0.3(10% EtOAc/Hexane); Yield 28% (27 mg); brown liquid. H NMR (400 MHz,
CDCl3) δ 8.50 (d, J = 4.6 Hz, 1H), 7.96 – 7.75 (m, 2H), 7.65 (d, J = 7.8 Hz, 1H), 7.58 (t, J =
13
7.4 Hz, 1H), 7.45 (t, J = 7.7 Hz, 2H), 7.33 (dd, J = 7.8, 4.7 Hz, 1H), 2.41 (s, 3H); C NMR
(101 MHz, CDCl3) δ 195.2, 155.1, 145.9, 138.9, 136.5, 133.3, 132.8, 130.4, 128.4, 124.5,
18.35; HRMS (ESI+) calcd. for: C13H12NO 198.0913. (M+H), found 198.0925.
(4-Fluorophenyl)(3-methylpyridin-2-yl)methanone (3y, Scheme 1)
TLC Rf = 0.3(10% EtOAc/Hexane); Yield 41% (44 mg); brown liquid; 1H NMR (400 MHz,
CDCl3) δ 8.48 (d, J = 3.9 Hz, 1H), 7.95 – 7.84 (m, 2H), 7.64 (d, J = 7.8 Hz, 1H), 7.32 (dd, J =
7.8, 4.7 Hz, 1H), 7.16 – 7.06 (m, 2H), 2.40 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 193.5,
165.9 (d, J = 296.94 Hz), 154.7, 145.9, 139.1, 133.2 (d, J = 10.1 Hz), 133.0, 132.9 (d, J =
3.03 Hz) 124.7, 115.5 (d, J = 22.22 Hz), 18.4; HRMS (ESI+) calcd. for: C13H11FNO
216.0819. (M+H), found 216.0847.
(3-Bromopyridin-2-yl)(phenyl)methanone34 (3z, Scheme 1)
TLC Rf = 0.2 (10% EtOAc/Hexane); Yield 37% (48.5 mg); yellow gum; 1H NMR (400 MHz,
CDCl3) δ 8.62 (dd, J = 4.7, 1.3 Hz, 1H), 8.02 (dd, J = 8.2, 1.3 Hz, 1H), 7.87 – 7.81 (m, 2H),
7.61 (dd, J = 10.5, 4.3 Hz, 1H), 7.48 (t, J = 7.7 Hz, 2H), 7.32 (dd, J = 8.2, 4.7 Hz, 1H);
MS (ESI+) calcd. for: C17H13N2O 262.10 (M+H).
[2,2'-Bipyridin]-6-yl(phenyl)methanone35 (3aa, Scheme 1)
TLC Rf = 0.3 (20% EtOAc/Hexane); Yield 35% (45.5 mg); light yellow gum; 1H NMR (400
MHz, CDCl3) δ 8.71 – 8.67 (m, 1H), 8.65 (dd, J = 7.7, 1.2 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H),
8.22 – 8.16 (m, 2H), 8.08 (dd, J = 7.7, 1.3 Hz, 1H), 8.03 (t, J = 7.7 Hz, 1H), 7.78 (td, J = 7.8,
1.8 Hz, 1H), 7.62 (d, J = 7.4 Hz, 1H), 7.51 (dd, J = 10.5, 4.7 Hz, 2H), 7.35 – 7.30 (m, 1H);
13C NMR (101 MHz, CDCl3) δ 193.5, 155.4, 154.9, 154.2, 149.2, 137.9, 137.0, 136.4, 132.8,
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131.2, 128.0, 124.4, 124.1, 123.3, 121.3; HRMS (ESI+) calcd. for: C17H13N2O 261.1022.
(M+H), found 261.1025.
Phenyl(pyrazin-2-yl)methanone36 (3ab, Scheme 1)
TLC Rf = 0.2 (10% EtOAc/Hexane); Yield 30% (13.6 mg); brown gum; 1H NMR (400 MHz,
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CDCl3) δ 9.25 (d, J = 1.4 Hz, 1H), 8.78 (d, J = 2.5 Hz, 1H), 8.69 (dd, J = 2.4, 1.5 Hz, 1H),
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8.10 – 8.06 (m, 2H), 7.67 – 7.61 (m, 1H), 7.51 (dd, J = 10.7, 4.7 Hz, 2H); C NMR (101
MHz, CDCl3) δ 192.2, 150.0, 146.8, 146.1, 142.9, 135.5, 133.5, 130.1, 128.4; MS (ESI+)
found for: C11H9N2O 185.30 (M+H).
Phenyl(quinolin-2-yl)methanone37 (5a, Scheme 2)
TLC Rf = 0.4 (10% EtOAc/Hexane); Yield 70% (81.5 mg); red solid; m.p. 96ꢀ98 ºC; 1H NMR
(400 MHz, CDCl3) δ 8.33 (d, J = 8.5 Hz, 1H), 8.26 – 8.16 (m, 3H), 8.09 (d, J = 8.5 Hz, 1H),
7.89 (d, J = 8.1 Hz, 1H), 7.77 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.68 – 7.58 (m, 2H), 7.49 (dd, J
= 10.6, 4.7 Hz, 2H); 13C NMR (101 MHz, CDCl3) δ 193.7, 154.8, 146.8, 137.0, 136.2, 133.0,
131.4, 130.6, 130.0, 128.9, 128.4, 128.1, 127.6, 120.7; HRMS (ESI+) calcd. for: C16H12NO
234.0913. (M+ H), found 234.0916.
Quinolin-2-yl(p-tolyl)methanone38 (5b, Scheme 2)
º
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TLC Rf = 0.5 (10% EtOAc/Hexane); Yield 68% (83.9 mg); brown solid; m.p. 62ꢀ64 C; H
NMR (400 MHz, CDCl3) δ 8.33 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.15 (d, J = 8.2
Hz, 1H), 8.08 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.1 Hz, 1H), 7.78 (t, J = 4.2 Hz, 1H), 7.71 –
13
7.58 (m, 1H), 7.32 (d, J = 8.1 Hz, 1H), 2.46 (s, 1H); C NMR (101 MHz, CDCl3) δ 193.4,
193.2, 155.1, 146.7, 143.9, 136.9, 133.6, 131.5, 130.5, 129.9, 128.8, 128.8, 128.2, 127.6,
120.7, 21.7; HRMS (ESI+) calcd. for: C17H14NO 248.1070. (M+ H), found 248.1060.
(4-Methoxyphenyl)(quinolin-2-yl)methanone38 (5c, Scheme 2)
º
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TLC Rf = 0.4 (10% EtOAc/Hexane); Yield 61% (80.2 mg); White solid; m.p. 65ꢀ68 C; H
NMR (400 MHz, CDCl3) δ 8.42 – 8.24 (m, 1H), 8.21 (d, J = 8.5 Hz, 1H), 8.06 (d, J = 8.5 Hz,
1H), 7.91 (d, J = 8.2 Hz, 1H), 7.85 – 7.72 (m, 1H), 7.66 (dd, J = 11.0, 4.0 Hz, 1H), 7.07 –
6.91 (m, 1H), 3.91 (s, 1H); 13C NMR (126 MHz, CDCl3) δ 192.1, 163.7, 155.4, 146.7, 136.9,
133.9, 130.4, 130.0, 129.0, 128.8, 128.1, 127.6, 120.9, 113.5, 55.5; HRMS (ESI+) calcd. for:
C17H14NO2 264.1019 (M+ H), found 264.1013.
(4-Fluorophenyl)(quinolin-2-yl)methanone39 (5d, Scheme 2)
TLC Rf = 0.5 (10% EtOAc/Hexane); Yield 67% (84 mg); white solid; m.p. 131 C; 1H NMR
º
(400 MHz, CDCl3) δ 8.34 (dq, J = 5.0, 2.7 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.5
Hz, 1H), 7.91 (d, J = 8.1 Hz, 1H), 7.80 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 7.70 – 7.63 (m, 1H),
7.23 – 7.15 (m, 1H); 13C NMR (101 MHz, CDCl3) δ 191.9, 165.8 (d, J = 255.5), 154.5, 146.6,
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137.2, 134.2 (d, J = 10.1Hz), 132.5 (d, J = 3.03 Hz) 130.5, 130.1, 128.9, 128.53, 127.6,
120.7, 115.2 (d, J = 22.22 Hz); HRMS (ESI+) calcd. for: C16H11FNO 252.0819. (M+ H),
found 252.0812.
(4-Fluoro-3-methylphenyl)(quinolin-2-yl)methanone (5e, Scheme 2)
TLC Rf = 0.5 (10% EtOAc/Hexane); Yield 65% (85.8mg); creamish solid; m.p. 103.5 ºC; 1H
NMR (400 MHz, CDCl3) δ 8.35 (d, J = 8.5 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 8.18 – 8.06 (m,
3H), 7.91 (d, J = 8.0 Hz, 1H), 7.84 – 7.76 (m, 1H), 7.67 (t, J = 7.5 Hz, 1H), 7.12 (t, J = 8.8
Hz, 1H), 2.36 (d, J = 1.5 Hz, 3H); 13C NMR (101 MHz, CDCl3) δ 192.4, 164.5 (d, J = 254
Hz), 154.7, 146.7, 137.1, 135.1 (d, J = 6.6 Hz), 132.2 (d, J = 4.04 Hz), 131.7 (d, J = 9.3 Hz),
130.5, 130.1, 128.9, 128.4, 127.6, 125.0 (d, J = 17.7 Hz), 120.8, 114.8 (d, J = 23.23 Hz),
14.6(d, J = 3.5 Hz); HRMS (ESI+) calcd. for: C17H13FNO 266.0976. (M+ H), found
266.0980.
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(3-Methylquinoxalin-2-yl)(phenyl)methanone (5f, Scheme 2)
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TLC Rf = 0.2 (10% EtOAc/Hexane); Yield 25% (31mg); light brown solid; m.p. 75.1 C; H
NMR (400 MHz, CDCl3) δ 8.09 (d, J = 8.5 Hz, 2H), 7.96 (dd, J = 8.3, 1.2 Hz, 2H), 7.87 –
7.80 (m, 1H), 7.79 – 7.73 (m, 1H), 7.65 (dd, J = 10.6, 4.3 Hz, 1H), 7.51 (t, J = 7.8 Hz, 2H),
2.80 (s, 3H); 13C NMR (101 MHz, CDCl3) δ 194.0, 152.3, 150.8, 142.1, 139.4, 135.6, 134.1,
131.2, 130.7, 129.7, 129.5, 128.7, 128.6, 22.7; HRMS (ESI+) calcd. for: C16H13N2O
249.1022. (M+ H), found 249.1026.
Isoquinolin-1-yl(phenyl)methanone39(7a, Scheme 2)
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TLC Rf = 0.3 (10% EtOAc/Hexane); Yield 63% (73.3 mg); Brown oil; H NMR (400 MHz,
CDCl3) δ 8.62 (d, J = 5.6 Hz, 1H), 8.27 – 8.19 (m, 1H), 7.96 (dt, J = 10.4, 5.1 Hz, 3H), 7.82
(d, J = 5.6 Hz, 1H), 7.80 – 7.72 (m, 1H), 7.63 (ddd, J = 12.0, 7.1, 1.2 Hz, 2H), 7.48 (dd, J =
10.6, 4.8 Hz, 2H); HRMS (ESI+) calcd. for: C16H12NO 234.0913 (M+ H), found 234.0911.
Isoquinolin-1-yl(p-tolyl)methanone39(7b, Scheme 2)
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TLC Rf = 0.3 (10% EtOAc/Hexane); Yield 48% (58.8 mg); Brown oil; H NMR (400 MHz,
CDCl3) δ 8.59 (d, J = 5.6 Hz, 1H), 8.19 (d, J = 8.5 Hz, 1H), 7.90 (d, J = 8.3 Hz, 1H), 7.85 (d,
J = 8.2 Hz, 2H), 7.78 (d, J = 5.6 Hz, 1H), 7.72 (t, J = 7.3 Hz, 1H), 7.59 (t, J = 7.3 Hz, 1H),
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7.26 (d, J = 8.0 Hz, 2H), 2.42 (s, 3H); C NMR (101 MHz, CDCl3) δ 194.4, 156.9, 144.6,
141.2, 136.7, 134.2, 130.8, 130.6, 129.2, 128.1, 127.0, 126.4, 126.2, 122.3, 21.7; HRMS
(ESI+) calcd. for: C17H14NO 248.1070 (M+ H), found 248.1066.
Isoquinolin-1-yl(4-methoxyphenyl)methanone39(7c, Scheme 2)
º
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TLC Rf = 0.3 (10% EtOAc/Hexane); Yield 45% (59.1 mg); Brown solid; m.p. 73ꢀ75 C; H
NMR (400 MHz, CDCl3) δ 8.60 (d, J = 5.7 Hz, 1H), 8.17 (d, J = 8.5 Hz, 1H), 7.97 – 7.88 (m,
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3H), 7.79 (d, J = 5.6 Hz, 1H), 7.76 – 7.71 (m, 1H), 7.63 – 7.58 (m, 1H), 6.99 – 6.91 (m, 2H),
3.88 (s, 3H); HRMS (ESI+) calcd. for: C17H14NO2 264.1019 (M+ H), found 264.0987.
(4-Fluorophenyl)(isoquinolin-1-yl)methanone39(7d, Scheme 2)
º
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TLC Rf = 0.3 (10% EtOAc/Hexane); Yield 59% (74 mg); Brown solid; m.p. 94ꢀ95 C; H
NMR (400 MHz, CDCl3) δ 8.60 (d, J= 5.6 Hz, 1H), 8.23 (d, J = 8.5 Hz, 1H), 8.06 – 7.97 (m,
2H), 7.93 (d, J = 8.3 Hz, 1H), 7.82 (d, J = 5.6 Hz, 1H), 7.75 (t, J = 7.6 Hz, 1H), 7.63 (t, J =
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7.7 Hz, 1H), 7.19 – 7.10 (m, 2H); C NMR (101 MHz, CDCl3) δ 193.0, 166.1 (d, J = 257.5
Hz), 156.0, 141.1, 136.8, 133.5 (d, J = 9.09 Hz), 133.1 (d, J= 2.02 Hz), 130.8, 128.4, 127.15,
126.4, 126.1, 122.7, 115.6 (d, J = 22.22 Hz); HRMS (ESI+) calcd. for: C16H11FNO 252.0819.
(M+ H), found 252.0817.
Isoquinolin-1-yl(4-(trifluoromethyl)phenyl)methanone38(7e, Scheme 2)
TLC Rf = 0.4 (10% EtOAc/Hexane); Yield 35% (52.7mg); White solid; m.p. 96 C; 1H NMR
º
(400 MHz, CDCl3) δ 8.61 (d, J = 5.6 Hz, 1H), 8.35 (d, J = 8.5 Hz, 1H), 8.08 (d, J = 8.1 Hz,
2H), 7.96 (d, J = 8.3 Hz, 1H), 7.86 (d, J = 5.6 Hz, 1H), 7.82 – 7.72 (m, 3H), 7.71 – 7.65 (m,
1H); HRMS (ESI+) calcd. for: C17H11F3NO 302.0787. (M+ H), found 302.0788.
(4-Fluoro-3-methylphenyl)(isoquinolin-1-yl)methanone (7f, Scheme 2)
º
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TLC Rf = 0.4 (10% EtOAc/Hexane); Yield 44% (58.3 mg); White solid; m.p. 81.2 C; H
NMR (400 MHz, CDCl3) δ 8.60 (d, J = 5.6 Hz, 1H), 8.20 (d, J = 8.5 Hz, 1H), 7.93 (d, J = 8.3
Hz, 1H), 7.88 – 7.71 (m, 4H), 7.63 (t, J = 7.7 Hz, 1H), 7.08 (t, J = 8.9 Hz, 1H), 2.30 (d, J =
1.5 Hz, 3H); 13C NMR (126 MHz, CDCl3) δ 193.4, 164.8 (d, J = 255.53 Hz), 156.3, 141.1,
136.7, 134.4 (d, J = 7.07Hz), 132.8 (d, J = 4.04 Hz), 130.9 (d, J = 5.05 Hz), 130.7, 128.3,
127.1, 126.4, 126.1, 125.4 (d, J = 18.18 Hz), 122.6, 115.2 (d, J = 24.24 Hz) 14.5 ( d, J = 3.03
Hz); HRMS (ESI+) calcd. for: C17H13FNO 266.0976. (M+ H), found 266.0982.
(4-((1S)-(Benzyloxy)((1S,4S,5R)-5-vinylquinuclidin-2-yl)methyl)-6-methoxyquinolin-2-
yl)(phenyl)methanone (9a, Scheme3)
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TLC Rf = 0.3 (5% MeOH/DCM); Yield 34% (108.5 mg); brown oil; H NMR (400 MHz,
CDCl3) δ 8.34 (s, 1H), 8.29 – 8.22 (m, 2H), 8.14 (d, J = 9.2 Hz, 1H), 7.82 (s, 1H), 7.62 (d, J =
7.4 Hz, 1H), 7.54 – 7.47 (m, 3H), 7.41 – 7.33 (m, 5H), 5.61 (ddd, J = 17.2, 10.3, 6.7 Hz, 1H),
5.09 – 5.03 (m, 2H), 4.63 (dd, J = 38.3, 10.7 Hz, 2H), 4.19 (s, 3H), 3.49 – 3.36 (m, 2H), 3.20
– 3.08 (m, 2H), 2.69 (s, 2H), 2.09 (s, 1H), 1.66 – 1.48 (m, 3H), 0.87 (t, J = 6.7 Hz, 1H); 13C
NMR (101 MHz, CDCl3) δ 193.3, 161.0, 151.5, 143.3, 136.6, 136.3, 133.0, 132.9, 131.4,
129.7, 128.7, 128.3, 128.2, 128.1, 124.1, 118.3, 117.3, 101.0, 77.3, 77.2, 77.0, 76.7, 72.0,
59.6, 54.6, 43.7, 37.1, 31.9, 27.0, 24.5, 18.9; HRMS (ESI+) calcd. for: C34H35N2O3 519.2642.
(M+ H), found 519.2649.
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ASSOCIATED CONTENT:
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Supporting Information Copies of NMR, HRMS, LCMS and GCMS spectra are provided.
This material is available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION:
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Corresponding Author
* Eꢀmail: ppsingh@iiim.ac.in.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS:
Authors thank CSIR for the financial support through research grants BSC 0108 and HCPꢀ
0008. S.S.and M. K. thank CSIR and UGC respectively for the award of the fellowship.
REFERENCES:
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