Regiospecific benzoylation of electron-deficient n -heterocycles with methylbenzenes via a minisci-type reaction

Article abstract of DOI:10.1021/acs.joc.5b00501

A regioselective cross-dehydrogenative coupling between electron-deficient N-heterocycles (isoquinoline, quinolines, and quinoxalines) and methylbenzenes leading to regiospecific C-aroylation has been accomplished using AlCl₃ as the catalyst in

Full text of DOI:10.1021/acs.joc.5b00501

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Article
Regiospecific Benzoylation of Electron-Deficient N-
Heterocycles with Methylbenzenes via a Minisci Type Reaction
Wajid Ali, Ahalya Behera, Srimanta Guin, and Bhisma K. Patel
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b00501 • Publication Date (Web): 04 May 2015
Downloaded from http://pubs.acs.org on May 6, 2015
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Regiospecific Benzoylation of Electron-Deficient N-Heterocycles
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with Methylbenzenes via a Minisci Type Reaction
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Wajid Ali, Ahalya Behera, Srimanta Guin, Bhisma K. Patel*
Department of Chemistry
Indian Institute of Technology Guwahati, Guwahatiꢀ781039, India
Fax: (+91)361ꢀ26909762.
Eꢀmail: patel@iitg.ernet.in
RECEIVED DATE (will be automatically inserted after manuscript is accepted).
ABSTRACT: A regioslective crossꢀdehydrogenative coupling between electronꢀdeficient
N−heterocycles (isoquinoline, quinolines and quinoxalines) and methylbenzenes leading to
regiospecific C−aroylation has been accomplished using AlCl3 as the catalyst in the presence of
oxidant TBHP. This protocol is a practical alternative to classical Minisci reaction.
INTRODUCTION
In organic chemistry one of the most important and fundamental challenge is to build
C−C bonds in a rapid and efficient manner.1 Of significant interests are methods that provide
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access to molecule in step and atom economic fashion from readily available precursors. In past
few decades, the construction of C−C bonds through C−H bonds activation is a rapidly
expanding field of research as it provides atom economical and shorter route for the synthesis of
organic compounds and offers substantial benefits.2 In this context, crossꢀdehydrogenative
coupling between two different C−H bonds represent an useful alternative approach towards
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C−C bond formations between organic components through the functionalization of all types (sp,
sp2, sp3) of C−H bonds.1a,d,e,3 Mild reactivity and poor site selective are the two important
challenges that need to be addressed in CDC protocols. Hence, the developments of new and
efficient CDC reactions in which such challenges can be overcome are of great significance in
synthetic organic chemistry
.
Nitrogenous heterocycles are widely distributed in nature and present in large proportion
in commercial drugs.4 These heterocycles have also enormous applications in both chemistry and
biology.5 Heterocyclic moieties bearing acyl group have been found in drugs which are
important in pharmacological studies.4 Till date a number of methods have been developed for
the synthesis of electronꢀdeficient heterocycles, but their functionalization using crossꢀ
dehydrogenative coupling is far less visited. In contrast to electronꢀrich heterocycles,6aꢀg
acylation of electronꢀdeficient heterocycles are much more challenging and only few reports are
available.6hꢀj Among these, Minisci reaction is the most commonly used approach,4a,6i,7ꢀ10 which
involves the addition of an in situ generated nucleophilic acyl radical from aldehyde to an
electronꢀdeficient heterocycle. Although it represents a straightforward stratergy but suffers from
certain drawbacks such as harsh reaction conditions, poor site selectivity, limited substrate scope
and the use of transition metal salts up to stoichiometric amounts.7a To overcome these aspects,
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Antonchick6h and Prabhu11 groups independently reported metal free analogues of Minisci
reaction under ambient conditions (Scheme 1, known methods).
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Scheme 1. Reported and designed route for the direct acylation
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Recently our group has developed a number of CDC protocols for the construction of C−C
and C−O bonds using alkylbenzenes as the surrogates of ArCH2O−,12a ArCO−,12b,c,d ArCH2−12e
and ArCOO−12e,f under oxidative conditions. In continuation to our interest in utilizing
alkylbenzenes as different surrogates via metal and metal free C−H functionalization strategies,
we envisaged that can an acyl radical (generated in situ from methylarenes under oxidative
conditions) be utilized for the direct acylation of Nꢀheterocycles. Antonchick et al6h in their
report demonstrated that the in situ generated CF3COOH from PhI(OCOCF3)2 protonates the Nꢀ
atom of heterocycle thereby making α−C to nitrogen more electrophilic in nature. This facilitates
the attack of the nucleophilic acyl radical on to the α−C. Intrigued by the key mechanistic
features; we anticipated that the direct use of CF3COOH could generate a similar protonated
intermediate. On the other hand employing TBHP as the oxidant is expected to afford the other
coupling counterpart the acyl radical from methylarenes.12b,c,d
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RESULTS AND DISCUSSION
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To give a practical shape to this coupling concept, a reaction between isoquinoline (1) and pꢀ
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xylene (d) were initiated in the presence of CF3COOH and TBHP at 110 C. As hypothesized,
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the reaction provided C1ꢀaroylated product (1d) but in a mere yield of 26% (Table 1, entry 1). In
a quest to improve the yield, both weak (CH3COOH) and strong (CF3SO3H) organic acids were
used in lieu of CF3COOH; however poorer yields were obtained in both these cases (Table 1,
entries 2 and 3). Even a threefold excess of CF3COOH had no substantial effect on the product
yield (Table 1, entry 4). These observations suggest that neither the strength of acid nor their
concentrations are the determining factors for better conversion. Thus we attempted the reaction
in the presence of Lewis acids instead of protic acids.
Gratifyingly, the use of Lewis acid AlCl3 afforded the acylated product in an improved yield
of 58% (Table 1, entry 5). Encouraged by this result, other Lewis acids such as FeCl3 (42%),
ZnCl2 (< 8%), TiCl4 (40%), SnCl2 (48%) and Cu(OTf)2 (38%) were tested but all were found to
be inferior to AlCl3 (58%) (Table 1, entries 5−10). Interestingly, when the quantity of AlCl3 was
reduced to half (50 mol %) and quarter (25 mol %) the yield virtually remained unaltered (Table
1, entries 11 and 12). However, the yield dropped marginally when AlCl3 loading was decreased
to 20 mol % (Table 1, entry 13). A 9% increase in the yield was observed (Table 1, entry 14)
upon performing the reaction at a lower temperature of 95 oC. The better yield (65%) obtained at
o
o
lower temperature (95 C) compared to the lower yield (56%) at higher temperature (110 C)
may be related to some of the thermodynamic parameters in the reaction as the acylated product
o
formed is stable at high temperature. Maintaining the temperature at 95 C and performing the
reaction under N2 atmosphere resulted in 6% further enhancement in the yield (Table 1, entry
15). No major improvements in the product yield was noticed with an increased amount of
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oxidant (3.5 equiv), while the use of 2 equiv was not sufficient for this transformation (Table 1,
entries 16 and 17). Aq TBHP was found to be less effective compared to that of a decane
solution of TBHP (Table 1, entry 18). Control experiment in the absence of Lewis acid AlCl3
afforded acylated product in < 15% suggesting the essential requirement of AlCl3 to bring about
the desired transformation (Table 1, entry 19). To check whether AlCl3 has definite role or the
acid (HCl) generated in the reaction medium is activating the Nꢀatom a reaction was carried out
in the presence of 1 equiv. of HCl. The formation of product in a modest yield of 33% ascertains
the distinct role of AlCl3 in this transformation. From these screening studies, the optimal
condition established was the use of AlCl3 (25 mol %) and TBHP (5−6 M in decane) (3 equiv) at
95 oC under N2 atmosphere (Table 1, entry 15).
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Table 1. Screening of Reaction Conditionsa
entry
catalyst
(mol %)
oxidant
(equiv)
temp
(oC)
110
110
110
110
110
110
110
110
yield b
(%)
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CF3COOH (100) TBHP (3)
CH3COOH (100) TBHP (3)
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<8
40
CF3SO3H (100)
CF3COOH (300) TBHP (3)
TBHP (3)
AlCl3 (100)
FeCl3 (100)
ZnCl2 (100)
TiCl4 (100)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
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SnCl2 (100)
Cu(OTf)2 (100)
AlCl3 (50)
AlCl3 (25)
AlCl3 (20)
AlCl3 (25)
AlCl3 (25)
AlCl3 (25)
AlCl3 (25)
AlCl3 (25)
ꢀ
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
TBHP (3)
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110
110
110
110
95
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65
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<15
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95
TBHP (3.5) 95
TBHP (2) 95
aq.TBHP(3) 95
TBHP (3) 95
aReaction condition: 1 (0.25 mmol), d (1.25 mmol),
time 18 h. bIsolated pure product. cUnder N2 atmoshphere.
With this optimized conditions in hand we examined the scope of this crossꢀ
dehydrogenative couplings by reacting isoquinoline (1) with a set of alkylbenzenes (a−i)
possessing both electronꢀdonating as well as electronꢀwithdrawing substituents (Scheme 2).
Under the present conditions, isoquinoline was smoothly acylated with various alkylbenzenes to
afford the corresponding coupled products (1a−1i) in moderate to good yields as shown in
Scheme 2. Substituents present in the phenyl ring of alkylbenzenes play a role in controlling the
product yields as evident from their yields and the reaction times (Scheme 2). Methylbenzenes
bearing additional ꢀMe group(s) irrespective of their position like o−Me (b), m−Me (c) and p−Me
(d) provided good yields of their corresponding coupled products (1b−1d) with the retention of
other ꢀMe group(s); an observation consistent with our previous reports.12aꢀf However, a slightly
lower yield was obtained for ortho substituted alkylbenzene, o−xylene (b) compared to m− and
p− analogues (1c and 1d) could be due to steric reason imparted by the orthoꢀsubstituent. Where
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a strongly electronꢀdonating −OMe (e) group is expected to give higher yield of the acylated
product (1e, Scheme 2) but the actual result was contrary to the expected. This may be due to the
coordination of the methoxy group of alkylbenzene (e) with the Lewis acid (AlCl3) thereby
making it less available for its catalytic activity. In order to expand the scope of this coupling
reaction isoquinoline substituted with various groups like 3−Me (2), 4−Br (3) and 5−NO2 (4)
were reacted with alkylbenzenes (a and d) (Scheme 2). As can be seen from Scheme 2, all these
isoquinolines underwent efficient coupling with alkylbenzenes (a and d) under the present
reaction conditions to afford products (2a), (3a), (4a), and (4d) in good to moderate yields
(Scheme 2).
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Scheme 2. Substrate Scope for C1 Acylation of Isoquinolinesa,b
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Me
AlCl3 (25 mol%)
R2
R1
(1a-4d)
+
N
N
TBHP (3 equiv.)
95 oC
R1
(a-i)
(1-4)
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O
R2
N
N
N
N
Me
Me
O
O
O
O
1d, 70%
1a, 62%
1b, 58%
1c, 68%
Me
Me
N
N
N
N
O
O
O
O
1f, 57%
1h, 70%
1e, 55%
1g, 59%
OMe
Br
Cl
Me
NO2
Br
Me
N
N
N
N
I
O
O
O
O
1i, 59%
4a, 66%
3a, 65%
2a, 52%
NO2
Me
N
O
4d, 67%
Me
aReaction conditions: isoquinoline (0.5 mmol), alkylbenzenes (2.5 mmol), AlCl3 (0.125 mmol),
TBHP in decane (5−6 M) (3 equiv), 95 oC, time 18−24 h. bYields of the pure product reported.
The next focus of this strategy was to acylate other electronꢀdeficient heterocyclic
compounds such as quinolines and quinoxalines (Scheme 3). Quinoline underwent crossꢀ
dehydrogenative coupling with different alkylbenzenes (a−i) to give exclusive C2 monoacylated
products (5a−5i, Scheme 3). It is to be noted that in case of quinolines the acylation took place
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regioselectively at its C2 position only with no traces of other regioisomers. However, in earlier
reports by Antonchick6h and Prabhu11 a mixture of both monoꢀ (at C2 position) and diꢀ (at C2
and C4 positions) acylated products were formed in various proportions. No C4 aroylation
product was observed even when the C2 position was blocked with a methyl or a tertꢀbutyl
groups suggesting the strong regioselective nature of the present transformation (Scheme 4). It is
well known that under an acidic condition (protic acid) because of the Nꢀprotonation in quinoline
both Cꢀ2 and Cꢀ4 positions are susceptible towards nucleophilic radical addition. Due to
pronounced –I effect of adjacent protonated Nꢀatom there is higher preference at the Cꢀ2
position. However, coordination of weak Lewis acid (AlCl3) with nitrogen of quinoline is just
sufficient to activate the Cꢀ2 position and not the Cꢀ4 thereby giving only one regioisomer. The
reactivity of different alkylbenzenes with quinoline is similar to that observed for their reaction
with isoquinoline, but the overall yields of coupled products were marginally lower (Scheme 3).
Other substituted quinolines like 8−methylquinoline (6) and 8ꢀmethoxyquinoline (7) reacted with
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alkylbenzenes (a, c, d and f) to provide their respective acylated products (6a, 6c, 6d, 6f and 7d)
in moderate yields as shown in Scheme 3. Heterocycles bearimg two Nꢀatoms like quinoxaline
(8) were also mono functionalized in good yields (8a−8h, Scheme 3). Similarly, electronꢀ
deficient heterocycle, 7−methylquinoxaline (9) when coupled with pꢀxylene (d) under the
optimized reaction conditions resulted in an inseparable mixture of two regioisomeric acylated
products (9d, Scheme 3).
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Scheme 3. Scope of N-Heterocylesa,b
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8
X
Me
X
N
AlCl3 (25 mol %)
TBHP (3 equiv.)
95 oC
R2
R2
R1
+
R1
N
(a-i)
(5 9)
(5a 9a)
O
9
X = CH, N
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Me
Me
R
N
O
I
Me
N
N
O
O
O
5h, 64%
5i, 57%
R = H (5a, 58%)
R = o-Me (5b, 54%)
R = m-Me (5c, 62%)
R = p-Me (5d, 63%)
Me
Me
N
N
R = p-OMe (5e, 49%)
R = p-Cl (5f, 51%)
R = p-Br (5g, 54%)
O
Me
Me
6a, 57%
6c, 59%
Me
Cl
N
N
N
O
O
O
O
O
Me
Me
OMe
6f, 48%
6d, 62%
7d, 46%
Me
N
N
N
R
Me
N
N
N
O
8a, 74%
8h, 78%
R = m-Me (8c, 74%)
R = p-Me (8d, 79%)
R = p-Cl (8f, 67%)
O
Me
N
N
N
Me
Me
N
Me
O
1:1
9d, 72%
aReaction conditions: 5-9 (0.5 mmol), alkylbenzenes (2.5 mmol), AlCl3 (0.125
mmol), TBHP in decane (5−6 M) (3 equiv), 95 oC, time 18−24 h. bYields of the pure
product reported.
Next the mechanism of the direct acylation was investigated. Substantial quenching of
product formation in the presence of radical inhibitor (TEMPO) was observed (Scheme 5).
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Along with the formation of a trace (~ 4%) of coupled product, a TEMPO ester (58%) was also
isolated under the reaction conditions. This provides an evidence for the formation of an acyl
radical in the medium, thus supporting a radical pathway. The observed kinetic isotope effect
(kH/kD∼1) (see SI for calculation) during an intermolecular competing reaction of toluene and d8ꢀ
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toluene with isoquinoline implies sp3 C−H bond cleavage not to be the rate determining step in
this process (Scheme 6). Based on these observations and literature precedences, a plausible
mechanism is proposed in Scheme 7.
Scheme 4. Demonstration of Regioselectivity in Quinoline
Scheme 5. Trapping of Acyl Intermediate with TEMPO
Scheme 6. Kinetic Isotope Study
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In the presence of TBHP, alkylbenzene (a) is oxidized sequentially to benzyl alcohol (I),
benzaldehyde (II) which subsequently generates acyl radical (III) via the cleavage of aldehydic
C−H bond. On the other hand AlCl3 coꢀordinates with the Nꢀatom of heterocycle (1) to form
intermediate (A), making the heterocyclic ring further electronꢀdeficient. An acyl radical (III)
formed in the medium is nucleophilic in nature which attacks at the more electrophilic C1
position of heterocycle to form corresponding radical intermediate (B). Reꢀaromatization of
intermediate (B) provides the desired acylated product (1a) (Scheme 7). When the reaction was
performed either with benzyl alcohol or with benzaldehyde instead of toluene under otherwise
identical conditions the yields of product (1a) obtained was 84% and 90% respectively, thereby
supporting the intermediacy of benzylalcohol and aldehyde in this reaction. The selective
acylation could be explained in term of nucleophilic character of acyl radical (III) generated,
which attacks at the more electrophilic position of coꢀordinated heterocycle (A). A similar
mechanism is expected for other Nꢀheterocycles.
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Scheme 7. Proposed Reaction Mechanism
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CONCLUSION
In conclusion, we have developed an efficient, mild and cost effective method for the
regiospecific acylation of electronꢀdeficient N−heterocycles using methylbenzenes. In this
transformation Lewis acid AlCl3 is used as catalyst and TBHP as oxidant. This reaction tolerates
wide range of functional groups and proceeds efficiently for the acylation of N−heterocycles.
The reaction serves as complement to classical Minisci reaction.
EXPERIMENTAL SECTION
General information:
All the compounds were commercial grade and were used without further purification.
Organic extract were dried over anhydrous sodium sulphate. Solvents were removed in a rotary
evaporator under reduce pressure. Silica gel (60−120 mesh size) was used for the column
chromatography. Reactions were monitored by TLC on silica gel 60 F254 (0.25 mm). NMR
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spectra were recorded in CDCl3 with tetramethylsilane as the internal standard for proton NMR
(400 and 600 MHz) CDCl3 solvent as internal standard for 13C NMR (100 and 150 MHz).
HRMS spectra were recorded using ESI mode (QꢀTOF type Mass Analyzer). IR spectra were
recorded in KBr or neat.
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General Procedure for the Synthesis of Isoquinolin-1-yl(p-tolyl)methanone (1d).
Isoquinoline (0.5 mmol, 64.5 mg), AlCl3 (0.125 mmol, 16.6 mg), pꢀxylene (2.5 mmol, 265 mg)
and 5−6 M decane TBHP (1.5 mmol, 300 µL) were added sequentially into an oven dried 25 mL
round bottom flask. Then the resultant mixture was heated at 95 oC for 18 h under an atmosphere
of N2 sealed with a rubber septum. After completion of the reaction, as indicated by TLC, the
reaction mixture was cooled to room temperature and admixed with ethyl acetate (30 mL). The
organic layer was washed sequentially with a saturated solution of sodium bicarbonate (2 x 5
mL) and water (2 x 5 mL). The organic layer was dried over anhydrous Na2SO4 and evaporated
under vacuum. The crude product so obtained was then purified by column chromatography
using EtOAc and hexane (0.4:9.6) to give aroylated product 1d (88 mg, 71%).
Trapping of Radical Intermediates with Radical Scavenger TEMPO. Isoquinoline (0.5
mmol, 64.5 mg), AlCl3 (0.125 mmol, 16.6 mg), toluene (2.5 mmol, 230 mg) and 5−6 M decane
TBHP (1.5 mmol, 300 µL) and TEMPO (1.5 mmol, 234 mg) were added sequentially into an
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oven dried 25 mL round bottom flask. Then the resultant mixture was heated at 95 C for 18 h.
After completion of the reaction, as indicated by TLC, the reaction mixture was cooled to room
temperature and admixed with ethyl acetate (30 mL). The organic layer was washed sequentially
with a saturated solution of sodium bicarbonate (2 x 5 mL) and water (2 x 5 mL). The organic
layer was dried over anhydrous Na2SO4 and evaporated under vacuum. The crude products so
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obtained were then purified by column chromatography using EtOAc and hexane as the eluents.
TEMPO ester adduct 2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl benzoate (10a) was isolated in 58% yield
along with a trace of (1a).
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Kinetic Isotope Effect Studies. To a mixture of isoquinoline (1) (0.5 mmol, 64.5 mg) and AlCl3
(0.125 mmol, 16.6 mg) was added an equimolar quantity of toluene (a) (1.25 mmol, 115 mg),
and d8ꢀtoluene (a’) (1.25 mmol, 125 mg). To this resultant heterogeneous mixture was then
added 5−6 M decane TBHP (300 ꢁL, 1.5 mmol) and the resultant mixture was heated in a pre
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heated oil bath at 95 C for 18 h. The reaction mixture was admixed with water (10 mL) and the
product was extracted with ethyl acetate (50 mL). The organic phase was dried over anhydrous
sodium sulphate and concentrated in vacuo. The crude product so obtained was purified over a
column of silica gel and eluted with hexane/ethyl acetate 9.4:0.4 to give the expected product in
42% yield (1a and 1a’). The ratio of the deuterated (1a’) and non deuterated (1a) aroylated
product was calculated on the basis of the integration ratio of the aromatic proton peak at 7.48
(originating from toluene) and –aromatic proton at 8.60 (originated from Nꢀheterocycle) by
adopting the procedure of (Xie, P.; Xie, Y.; Qian, B.; Zhou, H.; Xia, C.; Huang, H. J. Am. Chem.
Soc. 2012, 134, 9902).
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Isoquinoline-1-yl(phenyl)methanone (1a).6h Orange gummy; yield 72 mg, 62%; H NMR (400
MHz, CDCl3): δ (ppm) 7.47 (t, 2H, J = 7.6 Hz), 7.59−7.64 (m, 2H), 7.74 (t, 1H, J = 7.6 Hz), 7.81
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(d, 1H, J = 6.0Hz), 7.91−7.96 (m, 3H), 8.22 (d, 1H, J = 8.8 Hz), 8.60 (d, 1H, J = 5.6 Hz); C
NMR (150 MHz, CDCl3): δ (ppm) 122.8, 126.4, 126.6, 127.3, 128.5, 128.7, 130.9, 133.8, 136.8,
136.9, 141.4, 156.6, 194.9; IR (KBr): 3056, 2926, 2851, 1671, 1581, 1248, 1154, 1020 cmꢀ1;
HRMS (ESI): calcd. for C16H11NO (MH+) 234.0913; found 234.0919.
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Isoquinolin-1-yl(o-tolyl)methanone (1b).6h Brown gummy; yield 72 mg, 58%; H NMR (600
MHz, CDCl3): δ (ppm) 2.53 (s, 3H), 7.21 (t, 1H, J = 7.8 Hz), 7.32 (d, 1H, J = 7.8 Hz), 7.40 (d,
1H, J = 7.8 Hz), 7.43 (t, 1H, J = 8.4 Hz), 7.67 (t, 1H, J = 6.6 Hz), 7.76 (t, 1H, J = 7.8 Hz), 7.79
(d, 1H, J = 6.0 Hz), 7.92 (d, 1H, J = 7.8 Hz), 8.62 (d, 1H, J = 8.4 Hz), 8.86 (d, 1H, J = 5.4 Hz);
13C NMR (150 MHz, CDCl3): δ (ppm) 21.5, 123.1, 125.7, 126.5, 126.6, 127.3, 128.8, 130.9,
131.99, 132.0, 132.3, 137.0, 137.6, 139.9, 141.6, 157.2, 198.0; IR (KBr): 3057, 2926, 2855,
1669, 1576, 1243, 1156, 1041 cmꢀ1; HRMS (ESI): calcd. for C17H13NO (MH+) 248.1070; found
248.1074.
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Isoquinolin-1-yl(m-tolyl)methanone (1c).6h Orange gummy; yield 84 mg, 68%; H NMR (400
MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 7.33 (t, 1H, J = 7.6 Hz), 7.40 (d, 1H, J = 7.6 Hz), 7.59 (t,
1H, J = 6.8 Hz), 7.71 (d, 2H, J = 9.6 Hz), 7.74 (d, 1H, J = 7.6 Hz), 7.78 (d, 1H, J = 5.6 Hz), 7.90
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(d, 1H, J = 8.0 Hz), 8.49 (d, 1H, J = 8.4 Hz), 8.58 (d, 1H, J = 6.0 Hz); C NMR (100 MHz,
CDCl3): δ (ppm) 21.5, 122.7, 126.4, 126.5, 127.3, 128.3, 128.4, 128.6, 130.9, 131.2, 134.7,
136.8, 138.5, 141.4, 156.9, 195.2; IR (KBr): 3055, 2924, 2854, 1668, 1584, 1279, 1175, 1049
cmꢀ1; HRMS (ESI): calcd. for C17H13NO (MH+) 248.1070; found 248.1076.
Isoquinolin-1-yl(p-tolyl)methanone (1d).6h,11 Orange gummy; yield 86 mg, 70%; 1H NMR (400
MHz, CDCl3): δ (ppm) 2.42 (s, 3H), 7.27 (d, 2H, J = 8.0 Hz), 7.60 (t, 1H, J = 7.6 Hz), 7.73 (t,
1H, J = 6.8 Hz), 7.79 (d, 1H, J = 5.2 Hz), 7.85 (d, 2H, J = 8.4 Hz), 7.91 (d, 1H, J = 8.0 Hz), 8.91
(d, 1H, J = 8.4 Hz), 8.59 (d, 1H, J = 5.6 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 22.0, 122.6,
126.4, 126.6, 127.3, 128.4, 129.4, 130.9, 131.1, 134.3, 136.9, 141.4, 144.9, 157.0, 194.7; IR
(KBr): 3054, 2923, 1665, 1604, 1249, 1152, 1018 cmꢀ1; HRMS (ESI): calcd. for C17H13NO
(MH+) 248.1070; found 248.1073.
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Isoquinolin-1-yl(4-methoxyphenyl)methanone (1e).6h,11 Brown gummy; yield 72 mg, 55%; H
NMR (600 MHz, CDCl3) δ (ppm) 3.84 (s, 3H), 6.92 (d, 2H, J = 9.0 Hz), 7.57 (t, 1H, J = 7.8 Hz),
7.70 (t, 1H, J = 7.8 Hz), 7.76 (d, 1H, J = 5.4 Hz), 7.88 (d, 1H, J = 8.4 Hz), 7.91 (d, 2H, J = 8.4
Hz), 8.14 (d, 1H, J = 9.0 Hz), 8.56 (d, 1H, J = 6.0 Hz); 13C NMR (150 MHz, CDCl3): δ (ppm)
55.7, 114.0, 122.4, 126.5, 127.2, 128.3, 129.8, 130.0, 130.9, 133.3, 136.9, 141.4, 157.3, 164.3,
193.6; IR (KBr): 3055, 2932, 2840, 1661, 1596, 1422, 1254, 1171, 1074 cmꢀ1; HRMS (ESI):
calcd. for C17H13NO2 (MH+) 264.1019; found 264.1017.
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(4-Chlorophenyl)(isoquinolin-1-yl)methanone (1f).13b Brown solid; yield 76 mg, 57%; M. P.
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73−75 C; H NMR (400 MHz, CDCl3): δ (ppm) 7.43 (d, 2H, J = 8.4 Hz), 7.62 (t, 1H, J = 8.0
Hz), 7.74 (t, 1H, J = 8.0 Hz), 7.80 (d, 1H, J = 5.2 Hz), 7.89−7.92 (m, 3H), 8.23 (d, 1H, J = 8.4
Hz), 8.58 (d, 1H, J = 5.6 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 123.2, 126.3, 126.7, 127.4,
128.7, 129.0, 131.0, 132.4, 135.3, 137.0, 140.4, 141.3, 155.9, 193.6; IR (KBr): 3054, 2926, 2854,
1664, 1584, 1249, 1090 cmꢀ1; HRMS (ESI): calcd. for C16H10ClNO (MH+) 268.0524; found
268.0528.
(4-Bromophenyl)(isoquinolin-1-yl)methanone (1g).11 Brown solid; yield 91 mg, 59%; M. P. 70−72
oC; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.60−7.66 (m, 3H), 7.75 (t, 1H, J = 8.0 Hz), 7.82−7.85 (m,
3H), 7.93 (d, 1H, J = 8.4 Hz), 8.26 (d, 1H, J = 8.8 Hz), 8.59 (d, 1H, J = 8.4 Hz); 13C NMR (150 MHz,
CDCl3): δ (ppm) 123.2, 126.3, 126.7, 127.4, 128.7, 129.2, 131.0, 132.0, 132.4, 135.7, 137.0, 141.3,
155.8, 193.8; IR (KBr): 3053, 2925, 2854, 1662, 1580, 1393, 1247, 1070 cmꢀ1; HRMS (ESI): calcd.
for C16H10BrNO (MH+) 312.0019; found 312.0024.
(3,5-Dimethylphenyl)(isoquinolin-1-yl)methanone (1h).6h Yellow gummy; yield 92 mg, 70%;
1H NMR (400 MHz, CDCl3) δ (ppm) 2.33 (s, 6H), 7.24 (s, 1H), 7.54 (s, 2H), 7.60 (t, 1H, J = 8.4
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Hz), 7.73 (t, 1H, J = 6.8 Hz), 7.79 (d, 1H, J = 5.6 Hz), 7.91 (d, 1H, J = 8.4 Hz), 8.17 (d, 1H, J =
8.4 Hz), 8.59 (d, 1H, J = 5.6 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 21.3, 122.6, 126.4,
126.5, 127.2, 128.4, 128.6, 130.8, 135.7, 136.8, 136.9, 138.3, 141.3, 157.1, 195.5; IR (KBr):
3054, 2919, 2859, 1668, 1601, 1453, 1299, 1144, 1085 cmꢀ1; HRMS (ESI): calcd. for C18H15NO
(MH+) 262.1226; found 262.1233.
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(3-Iodo-5-methylphenyl)(isoquinolin-1-yl)methanone (1i). Brown gummy; yield 111 mg,
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59%; H NMR (400 MHz, CDCl3): δ (ppm) 2.36 (s, 3H), 7.65 (t, 1H, J = 8.0 Hz), 7.70 (s, 1H),
7.74−7.78 (m, 2H), 7.84 (d, 1H, J = 5.6 Hz), 7.94 (d, 1H, J = 8.0 Hz), 8.06 (s, 1H), 8.23 (d, 1H, J
= 8.4), 8.60 (d, 1H, J = 6.0 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 21.1, 94.3, 123.2, 126.3,
126.7, 128.8, 130.8, 131.0, 135.3, 136.8, 138.7, 140.6, 14.6, 141.4, 143.1, 155.8, 193.6; IR
(KBr): 2923, 2853, 1667, 1562, 1429, 1277, 1146, 1018 cmꢀ1; HRMS (ESI): calcd. for
C17H12INO (MH+) 374.0036; found 374.0036.
(3-Methylisoquinolin-1-yl)(phenyl)methanone (2a). Brown solid; yield 64 mg, 52%; M. P.
95−97 oC; 1H NMR (600 MHz, CDCl3): δ (ppm) 2.71 (s, 3H), 7.38−7.49 (m, 3H), 7.57−7.60 (m,
2H), 7.65 (t, 1H, J = 9.6 Hz), 7.79 (d, 1H, J = 7.8 Hz), 7.95 (d, 2H, J = 6.6 Hz), 8.05 (d, 1H, J =
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7.8 Hz); C NMR (100 MHz, CDCl3): δ (ppm) 24.3, 120.6, 124.6, 126.1, 126.4, 126.7, 127.3,
128.6, 130.7, 131.0, 133.9, 136.6, 137.5, 150.4, 195.1; IR (KBr): 3059, 2924, 2855, 1670, 1589,
1447, 1239, 1027 cmꢀ1; HRMS (ESI): calcd. for C17H13NO (MH+) 248.1070; found 248.1072.
(4-Bromoisoquinolin-1-yl)(phenyl)methanone (3a). Red solid; yield 101 mg, 65%; M. P.
129−130 oC; 1H NMR (600 MHz, CDCl3): δ (ppm) 7.48 (t, 2H, J = 7.8 Hz), 7.62 (t, 1H, J = 7.2
Hz), 7.69 (t, 1H, J = 7.8 Hz), 7.87 (t, 1H, J = 8.4 Hz), 7.94 (d, 2H, J = 7.8 Hz), 8.23 (d, 1H, J =
13
9.0 Hz), 8.29 (d, 1H, J = 9.0 Hz), 8.80 (s, 1H); C NMR (100 MHz, CDCl3): δ (ppm) 122.0,
126.7, 126.9, 127.8, 128.7, 129.4, 130.9, 132.2, 134.1, 135.7, 136.6, 143.1, 155.9, 194.2; IR
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(KBr): 3056, 2961, 2855, 1659, 1523, 1268, 1158, 1018 cmꢀ1; HRMS (ESI): calcd. for
C16H10BrNO (MH+) 312.0019; found 312.0025.
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(5-Nitroisoquinolin-1-yl)(phenyl)methanone (4a). White solid; yield 92 mg, 66%; M. P.
106−108 oC; 1H NMR (600 MHz, CDCl3): δ (ppm) 7.49 (t, 2H, J = 7.8 Hz), 7.64 (t, 1H, J = 7.2
Hz), 7.72 (t, 1H, J = 7.8 Hz), 7.93 (d, 2H, J = 7.8 Hz) 8.55 (t, 2H, J = 7.2 Hz), 8.62 (d, 1H, J =
6.0 Hz), 8.82 (d, 1H, J = 6.6 Hz); 13C NMR (150 MHz, CDCl3): δ (ppm) 117.8, 126.89, 126.92,
128.7, 128.8, 129.3, 131.0, 133.4, 134.4, 136.2, 144.6, 145.5, 157.3, 193.9; IR (KBr): 3066,
2922, 2844, 1661, 1526, 1353, 1276, 1161, 1069 cmꢀ1; HRMS (ESI): calcd. for C16H10N2O3
(MH+) 279.0764; found 279.0770.
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(5-Nitroisoquinolin-1-yl)(p-tolyl)methanone (4d). Brown solid; yield 98 mg, 67%; M. P. 107–
109 oC; 1H NMR (400 MHz, CDCl3): δ (ppm) 2.44 (s, 3H), 7.30 (d, 2H, J = 8.4 Hz), 7.72 (t, 1H,
J = 8.4 Hz), 7.83 (d, 2H, J = 8.0 Hz), 7.50−8.57 (m, 2H), 8.62 (d, 1H, J = 6.4 Hz), 8.81 (t, 1H, J
= 6.4 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 22.0, 117.6, 119.5, 126.8, 126.9, 128.7, 129.3,
129.6, 131.1, 133.5, 133.8, 134.0, 144.7, 157.7, 193.6; IR (KBr): 3063, 2924, 2853, 1669, 1448,
1246, 1215, 1180, 1024 cmꢀ1; HRMS (ESI): calcd. for C17H12N2O3 (MH+) 293.0921; found
293.0922.
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Phenyl(quinolin-2-yl)methanone (5a).13a Red solid; yield 68 mg, 58%; M. P. 96–98 C; H
NMR (400 MHz, CDCl3): δ (ppm) 7.50 (t, 2H, J = 7.6 Hz), 7.59−7.66 (m, 2H), 7.77 (t, 1H, J =
7.2 Hz), 7.89 (d, 1H, J = 8.4 Hz), 8.09 (d, 1H, J = 8.4 Hz), 8.17−8.22 (m, 3H), 8.33 (d, 1H, J =
13
8.4 Hz); C NMR (150 MHz, CDCl3): δ (ppm) 121.0, 127.8, 128.4, 128.6, 129.1, 130.3, 130.8,
131.6, 133.3, 136.4, 137.3, 147.0, 154.9, 194.0; IR (KBr): 3054, 2925, 2853, 1661, 1450, 1317,
1168, 1019 cmꢀ1; HRMS (ESI): calcd. for C16H11NO (MH+) 234.0913; found 234.0915.
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Quinolin-2-yl(o-tolyl)methanone (5b). Yellow solid; yield 67 mg, 54%; M. P. 79–80 C; H
NMR (400 MHz, CDCl3): δ (ppm) 2.44 (s, 3H), 7.28 (t, 1H, J = 7.6 Hz), 7.33 (d, 1H, J = 7.6
Hz), 7.45 (t, 1H, J = 7.2 Hz), 7.60 (d, 1H, J = 8.0 Hz,), 7.65 (t, 1H, J = 7.2 Hz), 7.75 (t, 1H, J =
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8.0 Hz), 7.90 (d, 1H, J = 8.0 Hz), 8.14 (t, 2H, J = 8.4 Hz), 8.34 (d, 1H, J = 8.0 Hz); C NMR
(100 MHz, CDCl3): δ (ppm) 21.0, 120.5, 125.2, 127.8, 128.8, 129.2, 130.2, 131.0, 131.3, 131.4,
137.3, 137.4, 138.8, 147.3, 155.0, 197.7; IR (KBr): 3055, 2923, 2853, 1660, 1561, 1454, 1313,
1260, 1092 cmꢀ1; HRMS (ESI): calcd.for C17H13NO (MH+) 248.1070; found 248.1079.
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Quinolin-2-yl(m-tolyl)methanone (5c). White solid; yield 77 mg, 62%; M. P. 80–82 C; H
NMR (400 MHz, CDCl3): δ (ppm) 2.43 (s, 3H), 7.38 (d, 1H, J = 8.0 Hz), 7.43 (t, 1H, J = 7.2
Hz), 7.66 (t, 1H, J = 7.2 Hz), 7.79 (t, 1H, J = 7.2 Hz), 7.91 (d, 1H, J = 8.0 Hz), 8.00 (d, 2H, J =
13
6.8 Hz), 8.08 (d, 1H, J = 8.4 Hz), 8.21 (d, 1H, J = 8.4 Hz), 8.34 (d, 1H, J = 8.8 Hz); C NMR
(150 MHz, CDCl3): δ (ppm) 21.6, 121.0, 127.8, 128.2, 128.5, 129.0, 129.1, 130.3, 130.8,
131.9,134.1, 136.3, 137.2, 138.1, 146.9, 155.1, 194.4; IR (KBr): 3052, 2924, 2856, 1660, 1596,
1458, 1313, 1139, 1139, 1013 cmꢀ1; HRMS (ESI): calcd.for C17H13NO (MH+) 248.1070; found
248.1067.
Quinolin-2-yl(p-tolyl)methanone (5d).11 Brown solid; yield 78 mg, 63%; M. P. 62–64 C; H
NMR (400 MHz, CDCl3): δ (ppm) 2.44 (s, 3H), 7.30 (d, 2H, J = 8.0 Hz), 7.64 (t, 1H, J = 6.8Hz),
7.76 (t, 1H, J = 7.6 Hz), 7.88 (d, 1H, J = 8.0 Hz), 8.06 (d, 1H, J = 8.4 Hz), 8.13 (d, 2H, J = 8.0
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Hz), 8.18 (d,1H, J = 8.4 Hz), 8.32 (d, 1H, J = 8.8 Hz); C NMR (150 MHz, CDCl3): δ (ppm)
22.0, 121.0, 127.9, 128.5, 129.07, 129.13, 130.3, 130.7, 131.8, 133.8, 137.2, 144.2, 147.0, 155.3,
193.7; IR (KBr): 3066, 2922, 2852, 1659, 1456, 1317, 1161, 1112 cmꢀ1; HRMS (ESI): calcd.for
C17H13NO (MH+) 248.1070; found 248.1077.
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(4-Methoxyphenyl)(quinolin-2-yl)methanone (5e).13b White solid; yield 65 mg, 49%; M. P.
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65–68 C; H NMR (400 MHz, CDCl3): δ (ppm) 3.87 (s, 3H), 6.99 (d, 2H, J = 7.2 Hz), 7.65 (t,
1H, J = 7.6 Hz), 7.78 (t, 1H, J = 7.2 Hz), 7.90 (d, 1H, J = 7.6 Hz), 8.06 (d, 1H, J = 8.4 Hz), 8.20
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(d, 1H, J = 8.0 Hz), 8.28 (d, 2H, J = 6.8 Hz), 8.33 (d, 1H, J = 8.4 Hz); C NMR (150 MHz,
CDCl3): δ (ppm) 55.7, 113.8, 121.1, 127.9, 128.4, 129.0, 129.2, 130.2, 130.7, 134.1, 137.2,
146.9, 155.6, 163.9, 192.4; IR (KBr): 3059, 2927, 2848, 1652, 1507, 1319, 1256, 1157, 1025 cmꢀ
1; HRMS (ESI): calcd. for C17H13NO2 (MH+) 264.1019; found 264.1025.
(4-Chlorophenyl)(quinolin-2-yl)methanone (5f).13b Brown solid; yield 68 mg, 51%; M. P.
105–107 oC; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.47 (d, 2H, J = 8.4 Hz), 7.65 (t, 1H, J = 8.4
Hz), 7.78 (t, 1H, J = 6.8 Hz), 7.89 (d, 1H, J = 7.6 Hz), 8.11 (d, 1H, J = 8.8 Hz), 8.17 (d, 1H, J =
8.4 Hz), 8.22 (d, 2H, J = 8.8 Hz), 8.34 (d, 1H, J = 8.8 Hz); 13C NMR (150 MHz, CDCl3): δ
(ppm) 120.9, 127.9, 128.7, 128.8, 129.2, 130.4, 130.7, 133.1, 134.8, 137.5, 139.8, 146.9, 154.5,
192.6; IR (KBr): 2926, 2854, 1663, 1590, 1459, 1316, 1209, 1170, 1089 HRMS (ESI): calcd. for
C16H10ClNO (MH+) 268.0524; found 268.0521.
(4-Bromophenyl)(quinolin-2-yl)methanone (5g). Brown solid; yield 84 mg, 54%; M. P. 111–
113 oC; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.65 (t, 3H, J = 9.6 Hz), 7.78 (t, 1H, J = 9.2 Hz),
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7.89 (d, 1H, J = 7.6 Hz), 8.10−8.17 (m, 4H), 8.33 (d, 1H, J = 8.4 Hz); C NMR (150 MHz,
CDCl3): δ (ppm) 120.9, 127.9, 128.5, 128.8, 129.2, 130.4, 130.7, 131.6, 133.2, 135.2, 137.4,
146.9, 154.4, 192.7; IR (KBr): 3048, 2956, 2926, 1664, 1586, 1458, 1316, 1167, 1068 cmꢀ1;
HRMS (ESI): calcd. for C16H10BrNO (MH+) 312.0019; found 312.0026.
(3,5-Dimethylphenyl)(quinolin-2-yl)methanone (5h). Red solid; yield 84 mg, 64%; M. P. 87–
89 oC; 1H NMR (400 MHz, CDCl3): δ (ppm) 2.37 (s, 6H), 7.24 (s, 1H), 7.64 (t, 1H, J = 8.0 Hz),
7.75−7.79 (m, 3H), 7.89 (d, 1H, J = 8.0 Hz), 8.03 (d, 1H, J = 8.8 Hz), 8.19 (d, 1H, J = 8.4 Hz),
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8.32 (d, 1H, J = 8.8 Hz); 13C NMR (150 MHz, CDCl3): δ (ppm) 21.5, 121.0, 127.8, 128.5, 129.1,
129.3, 130.2, 130.8, 135.1, 136.4, 137.2, 138.0, 147.0, 155.4, 194.7; IR (KBr): 3060, 2923, 2855,
1662, 1598, 1461, 1325, 1143, 1035 cmꢀ1; HRMS (ESI): calcd. for C18H15NO (MH+) 262.1226;
found 262.1229.
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(3-Iodo-5-methylphenyl)(quinolin-2-yl)methanone (5i). Brown solid; yield 106 mg, 57%; M.
o
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P. 121–123 C; H NMR (400 MHz, CDCl3): δ (ppm) 2.37 (s, 3H), 7.66 (t, 1H, J = 7.2 Hz),
7.76−7.80 (m, 2H), 7.89 (d, 1H, J = 8.0 Hz), 7.95 (s, 1H), 8.08 (d, 1H, J = 8.8 Hz), 8.19 (d, 1H, J
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= 8.0 Hz), 8.33 (d, 2H, J = 8.8 Hz); C NMR (150 MHz, CDCl3): δ (ppm) 21.2, 93.9, 120.9,
127.9, 128.8, 129.2, 130.4, 130.8, 131.4, 137.4, 137.6, 138.1, 140.2, 142.5, 147.0, 154.3, 192.6;
IR (KBr): 2924, 2853, 1664, 1563, 1311, 1143, 1016 cmꢀ1; HRMS (ESI): calcd. for C17H12INO
(MH+) 374.0036; found 374.0041.
(8-Methylquinolin-2-yl)(phenyl)methanone (6a).13c White solid; yield 70 mg, 57%; M. P. 63–
o
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64 C; H NMR (400 MHz, CDCl3): δ (ppm) 2.78 (s, 3H), 7.50−7.57 (m, 3H), 7.63 (t, 2H, J =
7.2 Hz), 7.74 (d, 1H, J = 8.0 Hz), 8.19 (d, 1H, J = 8.8 Hz), 8.31 (d, 1H, J = 8.4 Hz), 8.36 (d, 2H,
J = 8.8 Hz); 13C NMR (150 MHz, CDCl3): δ (ppm) 18.1, 120.6, 125.7, 128.1, 128.6, 129.2,
130.3, 131.9, 132.9, 136.8, 137.4, 139.1, 146.1, 153.3, 193.7; IR (KBr): 3056, 2953, 2922, 1660,
1594, 1445, 1322, 1286, 1159, 1070 cmꢀ1; HRMS (ESI): calcd. for C17H13NO (MH+) 248.1070;
found 248.1078.
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(8-Methylquinolin-2-yl)(m-tolyl)methanone (6c). Yellow liquid; yield 77 mg, 59%; H NMR
(600 MHz, CDCl3): δ (ppm) 2.44 (s, 3H), 2.77 (s, 3H), 7.38 (t, 1H, J = 7.8 Hz), 7.42 (d, 1H, J =
7.8 Hz), 7.52 (t, 1H, J = 7.8 Hz), 7.62 (d, 1H, J = 6.6 Hz), 7.71 (d, 1H, J = 8.4 Hz), 8.15 (t, 2H, J
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= 8.4 Hz), 8.20 (s, 1H), 8.28 (d, 1H, J = 9.0 Hz); C NMR (150 MHz, CDCl3): δ (ppm) 18.1,
21.6, 120.6, 125.7, 127.9, 128.5, 129.15, 129.17, 130.2, 132.4, 133.7, 136.7, 137.3, 137.7, 139.0,
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146.0, 153.4, 193.7; IR (KBr): 3043, 2955, 2923, 1659, 1584, 1465, 1374, 1287, 1141, 1079 cmꢀ
1; HRMS (ESI): calcd. for C18H15NO (MH+) 262.1226; found 262.1228.
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(8-Methylquinolin-2-yl)(p-tolyl)methanone (6d). Yellow liquid; yield 81 mg, 62%; H NMR
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(400 MHz, CDCl3): δ (ppm) 2.47 (s, 3H), 2.80 (s, 3H), 7.32 (d, 2H, J = 8.0 Hz), 7.54 (t, 1H, J =
8.0 Hz), 7.63 (d, 1H, J = 7.2 Hz), 7.73 (d, 1H, J = 8.0 Hz), 8.16 (d, 1H, J = 8.4 Hz), 8.28−8.31
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(m, 3H); C NMR (150 MHz, CDCl3): δ (ppm) 18.2, 22.0, 120.7, 125.7, 128.4, 128.9, 129.2,
130.2, 132.1, 134.2, 137.4, 139.0, 143.8, 146.1, 153.7, 193.2; IR (KBr): 3093, 2922, 1653, 1463,
1319, 1250, 1156, 1020 cmꢀ1; HRMS (ESI): calcd. for C18H15NO (MH+) 262.1226; found
262.1219.
(4-Chlorophenyl)(8-methylquinolin-2-yl)methanone (6f). Yellow solid; yield 67 mg, 48%; M.
P. 79–81 oC; 1H NMR (400 MHz, CDCl3): δ (ppm) 2.78 (s, 3H), 7.50 (d, 2H, J = 8.8 Hz), 7.56 (t,
1H, J = 7.6 Hz), 7.65 (t, 1H, J = 7.6 Hz), 7.74 (d, 1H, J = 8.4 Hz), 8.19 (d, 1H, J = 8.4 Hz), 8.32
(d, 1H, J = 8.0 Hz), 8.35 (d, 2H, J = 8.4 Hz); 13C NMR (150 MHz, CDCl3): δ (ppm) 18.2, 120.6,
125.8, 128.4, 128.8, 129.3, 130.4, 133.4, 135.2, 137.6, 139.0, 139.4, 146.0, 152.9, 192.3; IR
(KBr): 2962, 2923, 2855, 1638, 1459, 1311, 1089 cmꢀ1; HRMS (ESI): calcd. for C17H12ClNO
(MH+) 282.0680; found 282.0685.
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(8-Methoxyquinolin-2-yl)(p-tolyl)methanone (7d). Red liquid; yield 64 mg, 46%; H NMR
(400 MHz, CDCl3): δ (ppm) 2.43 (s, 3H), 4.05 (s, 3H), 7.10 (d, 1H, J = 7.2 Hz), 7.30 (d, 2H, J =
8.4 Hz), 7.44 (d, 1H, J = 7.2 Hz), 7.56 (t, 1H, J = 8.4 Hz), 8.09 (d, 1H, J = 8.8 Hz), 8.24−8.29
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(m, 3H); C NMR (150 MHz, CDCl3): δ (ppm) 21.9, 56.4, 108.6, 119.5, 121.6, 127.2, 128.9,
130.2, 132.1, 133.8, 137.0, 138.9, 144.0, 153.9, 156.5, 193.0; IR (KBr): 3066, 2928, 2838, 1655,
1606, 1465, 1325, 1260, 1131, 1040 cmꢀ1; HRMS (ESI): calcd. for C18H15NO2 (MH+) 278.1176;
found 278.1172.
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Phenyl(quinoxalin-2-yl)methanone (8a).13a Black solid; yield 86 mg, 74%; M. P. 100–102 C;
1H NMR (600 MHz, CDCl3): δ (ppm) 7.52 (t, 2H, J = 7.8 Hz), 7.64 (t, 1H, J = 7.8 Hz), 7.84 (t,
1H, J = 6.6 Hz), 7.88 (t, 1H, J = 8.4 Hz), 8.19 (m, 2H), 8.22 (d, 2H, J = 7.8 Hz), 9.47 (s, 1H); 13C
NMR (150 MHz, CDCl3): δ (ppm) 128.6, 129.6, 130.6, 130.9, 131.0, 131.5, 132.2, 132.4, 133.8,
143.3, 143.4, 145.5, 192.5; IR (KBr): 3062, 2925, 2853, 1659, 1597, 1322, 1234, 1127, 1014 cmꢀ
1; HRMS (ESI): calcd. for C15H10N2O (MH+) 235.0866; found 235.0869.
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Quinoxalin-2-yl(m-tolyl)methanone (8c). Brown gummy; yield 92 mg, 74%; H NMR (400
MHz, CDCl3): δ (ppm) 2.44 (s, 3H), 7.43 (t, 1H, J = 8.0 Hz), 7.48 (d, 1H, J = 7.2 Hz), 7.85−7.93
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(m, 2H), 8.00 (s, 2H), 8.22 (d, 2H, J = 8.8 Hz), 9.47 (s, 1H); C NMR (150 MHz, CDCl3): δ
(ppm) 21.6, 128.5, 128.9, 129.6, 130.7, 130.9, 131.7, 132.2, 134.7, 135.8, 138.5, 140.7, 143.3,
145.5, 149.1, 192.9; IR (KBr): 2924, 2854, 1658, 1489, 1317, 1151, 1017 cmꢀ1; HRMS (ESI):
calcd. for C16H12N2O (MH+) 249.1022; found 249.1028.
o
Quinoxalin-2-yl(p-tolyl)methanone (8d).6h,11,13a Red solid; yield 98 mg, 79%; M. P. 97–99 C;
1H NMR (400 MHz, CDCl3): δ (ppm) 2.42 (s, 3H), 7.30 (d, 2H, J = 7.6 Hz), 7.78−7.87 (m, 2H),
13
8.11 (d, 2H, J = 8.4 Hz), 8.16 (d, 2H, J = 8.4 Hz), 9.42 (s, 1H); C NMR (150 MHz, CDCl3): δ
(ppm) 22.0, 129.3, 129.5, 130.5, 130.9, 131.5, 132.0, 133.1, 140.6, 143.2, 144.8, 145.5, 149.1,
192.0; IR (KBr): 3053, 2922, 2851, 1657, 1601, 1324, 1229, 1157, 1121 cmꢀ1; HRMS (ESI):
calcd. for C16H12N2O (MH+) 249.1022; found 249.1019.
(4-Chlorophenyl)(quinoxalin-2-yl)methanone (8f).13d Brown solid; yield 90 mg, 67%; M. P.
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85–87 C; H NMR (600 MHz, CDCl3): δ (ppm) 7.50 (d, 2H, J = 8.4 Hz), 7.83−7.88 (m, 1H),
7.90 (t, 1H, J = 8.4 Hz), 8.17−8.23 (m, 4H), 9.49 (s, 1H); 13C NMR (150 MHz, CDCl3): δ (ppm)
129.0, 129.7, 130.7, 130.9, 131.2, 132.5, 132.9, 134.1, 140.5, 143.3, 145.5, 148.4, 191.2; IR
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(KBr): 2926, 2855, 1663, 1460, 1313, 1164, 1087 cmꢀ1; HRMS (ESI): calcd. for C15H9ClN2O
(MH+) 269.0476; found 269.0480.
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(3,5-Dimethylphenyl)(quinoxalin-2-yl)methanone (8h). Red solid; yield 102 mg, 78%; M. P.
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151–152 C; H NMR (600 MHz, CDCl3): δ (ppm) 2,40 (s, 6H), 7.30 (s, 1H), 7.78 (s, 2H),
7.86−7.91 (m, 2H), 8.20−8.22 (m, 2H), 9.43 (s, 1H); 13C NMR (150 MHz, CDCl3): δ (ppm) 21.5,
129.1, 129.6, 130.7, 131.0, 132.1, 135.7, 135.8, 138.3, 140.8, 143.3, 145.4, 149.4, 193.2; IR
(KBr): 3063, 2920, 2859, 1659, 1601, 1327, 1214, 1149, 1031 cmꢀ1 HRMS (ESI): calcd. for
C17H14N2O (MH+) 263.1179; found 263.1184.
(6-Methylquinoxalin-2-yl)(p-tolyl)methanone
and
(7-Methylquinoxalin-2-yl)(p-
1
tolyl)methanone (9d). Red semisolid; yield 95 mg, 72%; H NMR (400 MHz, CDCl3): δ (ppm)
2.44 (s, 3H), 2.62 (s, 3H), 7.31 (d, 2H, J = 8.0 Hz), 7.65−7.71 (m, 1H), 7.94 (s, 1H), 8.06 (d, 1H,
J = 8.4 Hz), 8.11 (d, 2H, J = 8.0 Hz), 9.39 (d, 1H, J = 15.6 Hz); 13C NMR (150 MHz, CDCl3): δ
(ppm) 22.0, 22.3, 22.9, 128.4, 129.1, 129.3, 129.4, 130.2, 131.6, 133.31, 133.34, 134.5, 139.2,
140.8, 141.7, 141.9, 143.2, 143.4, 144.7, 144.75, 144.8, 145.6, 148.4, 149.2, 192.25, 192.31; IR
(KBr): 2953, 2924, 2854, 1656, 1497, 1322, 1276, 1167, 1017 cmꢀ1; HRMS (ESI): calcd. for
C17H14N2O (MH+) 263.1179; found 263.1174.
2,2,6,6-Tetramethylpiperidin-1-yl benzoate (10a).12f Yellow gummy; yield 76 mg, 58%; H
1
NMR (400 MHz, CDCl3): δ (ppm) 1.16 (s, 6H), 1.31 (s, 6H), 1.48−1.52 (broad singlet, 1H),
1.61−1.64 (broad singlet, 2H), 1.71 (m, 3H), 7.50 (t, 2H, J = 7.6 Hz), 7.61 (t, 1H, J = 6.8 Hz),
8.11 (d, 2H, J = 7.2 Hz); 13C NMR (100 MHz, CDCl3): δ (ppm) 17.1, 21.0, 32.1, 39.2, 60.5,
128.6, 129.7, 133.0, 166.5; IR (KBr): 2974, 2934, 1749, 1540, 1378, 1255, 1176, 1081, cmꢀ1;
HRMS (ESI): calcd. for C16H23NO2 (MH+) 262.1802; found 262.1806.
AUTHOR INFORMATION
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Corresponding Author
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*E mail: patel@iitg.ernet.in.
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ACKNOWLEDGMENT
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B. K. P acknowledges the support of this research by the Department of Science and
Technology (DST) (SB/S1/OCꢀ53/2013), New Delhi, and the Council of Scientific and Industrial
Research (CSIR) (02(0096)/12/EMRꢀII). WA and SG thank CSIR for fellowship.
Supporting Information Available
Kinetic isotope effect experiment and spectral data for all compounds. This material is available
free of charge via the Internet at http://pubs.acs.org.
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