Iron-catalyzed cross-coupling of electron-deficient heterocycles and quinone with organoboron species via innate C-H functionalization: Application in total synthesis of pyrazine alkaloid botryllazine A

Article abstract of DOI:10.1021/jo302797r

Here, we report an iron-catalyzed cross-coupling reaction of electron-deficient heterocycles and quinone with organoboron species via innate C-H functionalization. Iron(II) acetylacetonate along with oxidant (K ₂S₂O₈) and phase-transfer catalyst (TBAB) under open flask conditions efficiently catalyzed the cross-coupling of pyrazine with arylboronic acids and gave monoarylated products in good to excellent yields. Optimized conditions also worked for other heterocylces such as quinoxalines, pyridines, quinoline, and isoquinoline as well as quinones. In addition, we demonstrated as a first example its application for the synthesis of anticancer marine pyrazine alkaloid botryllazine A.

Full text of DOI:10.1021/jo302797r

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Article
Iron catalyzed cross coupling of electron-deficient heterocycles and
quinone with organoboron species via innate C-H functionalization:
Application in total synthesis of pyrazine alkaloid Botryllazine A
Parvinder Pal Singh, Sravan Kumar Aithagani, Mahipal Yadav, Varun Pratap Singh, and Ram A. Vishwakarma
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo302797r • Publication Date (Web): 19 Feb 2013
Downloaded from http://pubs.acs.org on February 25, 2013
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Iron catalyzed crossꢀcoupling of electron-deficient heterocycles and quinone with
organoboron species via innate C-H functionalization: Application in total synthesis of
pyrazine alkaloid Botryllazine A
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Parvinder Pal Singh,* Sravan Kumar Aithagani, Mahipal Yadav, Varun Pratap Singh and
Ram A. Vishwakarma*
Medicinal Chemistry Division, Indian Institute of Integrative Medicine (Council of Scientific &
Industrial Research), Jammu 180 001, India
Tel.: +91-191-2569111, Fax: +91-191-2569333, e-mail: ppsingh@iiim.res.in and
ram@iiim.res.in
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OH
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N
N
N
N
N
N
N
4 Steps
MeO
(Hetero)aryl
boron species
H
N
N
O
(Hetero)Ar
Fe(acac)2
K2S2O8
N
O
9
Other heterocycles:
Pyridine, Quinoline,
Isoquinoline and
Quinones
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HO
OH
Overall 41 Examples
Marine natural product
Botryllazine A
Abstract:
Here, we report an ironꢀcatalyzed cross-coupling reaction of electronꢀdeficient heterocycles and
quinone with organoboron species via innate CꢀH functionalization. Iron (II) acetylacetonate
along with oxidant (K2S2O8) and phase transfer catalyst (TBAB) under open flask condition
efficiently catalyzed the cross-coupling of pyrazine with arylboronic acids and gave
monoarylated products in good to excellent yields. Optimized conditions also worked for other
heterocylces such as quinoxalines, pyridines, quinoline, isoquinoline as well as quinones. In
addition, we demonstrated as a first example its application for the synthesis of anticancer
marine pyrazine alkaloid Botryllazine A.
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Introduction:
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Traditionally, a cross-coupling reaction for CꢀC bond formation requires two starting
materials; organometallic species and organic halides. However, replacing one of the coupling
partner with an appropriate CꢀH species offers a far more efficient and versatile alternative, and
many such methods have been reported.1ꢀ3 Most of these CꢀH activation mediated cross-coupling
methods reported during last two decades are restricted only to the electronꢀrich (hetero)arenes4
and are not suitable for electronꢀdeficient (hetero)arenes. To address this issue, transition metal
catalysis have been employed5ꢀ9 for crossꢀcoupling with electronꢀdeficient (hetero)arenes. In the
last decade, many transition metal catalysts have been employed for such cross-coupling
reactions with electronꢀdeficient heterocycles; the examples of metals include palladium5
(coupling of electronꢀdeficient heterocycles with aryl halides), rhodium6 (coupling of pyridine
and quinoline with arylbromide), copper7 (coupling of heterocycles with aryl halides), nickel8
(coupling of electronꢀdeficient heterocycles with arylzinc reagents) and gold9 (coupling of
pyrazine and pyridine with aryl bromide). However, these transition metal catalyzed methods
also have some limitations such as need of large excess of heterocyclic partners, expensive
ligands and harsh reaction condition. In a major improvement, Baran et al, recently reported a
method10 for the cross-coupling of electronꢀdeficient (hetero)arenes and quinones with
arylboronic acids under classical Minisci condition (Ag catalyst).11 In last two decades, iron
based catalysts have drawn the attention as cheap, nontoxic and environmentally friendly
materials for the cross-coupling reactions.12 In the case of electronꢀdeficient (hetero)arenes, J.
Wen et al13a reported a ironꢀoxalate mediated coupling which required large excess of
heterocycle partner and stoichiometric amount of iron species, ligand and high temperature. Very
recently, J. Wang et al13b reported a heterogeneous FeS mediated cross-coupling using
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stoichiometric amounts of iron species. Keeping in view the radical chemistry literature of iron
and our recent interest in iron catalyzed methods for CꢀC bond formation,14 we envisioned
that environmentally friendly iron catalysts could be explored for cross-coupling of electronꢀ
deficient (hetero)arenes with organometallic species. In this direction, we now report a new and
efficient cross-coupling reaction of electronꢀdeficient (hetero)arenes via functionalization of
C(sp2)ꢀH bond with organoboron species using catalytic amount of iron catalyst under openꢀflask
condition. This method was successfully utilized for direct arylation of variety of (hetero)arenes
such as pyrazine, quinoxaline, pyridine, quinoline, isoquinoline and quinones. In addition, we
demonstrated as a first example its application for the synthesis of anticancer marine pyrazine
alkaloid Botryllazine A.15aꢀb
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Since many biologically active natural products are comprised of substituted electronꢀ
deficient heterocycles such as pyrazine, quinoxaline, pyridine, quinoline, isoquinoline,
pyrimidine etc., our method offers tremendous potential for introducing functionalities into
aforementioned moieties containing natural/bioꢀactive compounds as well as their total
synthesis.15
Results and Discussion:
We selected various iron salts to test the idea and started this study by the reaction of pyrazine
with phenylboronic acid in the presence of trifluoroacetic acid using water/dichloromethane
solvent system (results summarized in Table 1). During our study, potassium persulfate (K2S2O8)
was used as a oxidant. When we examined the reaction of pyrazine 1 with phenylboronic acid 2
in the presence of 20 mol% of FeSO4 at room temperature, the 2ꢀphenylpyrazine 3a was obtained
with 55% yield along with biphenyl 4a as byproduct (Table 1, entry 1). The composition of
crude product was determined by HPLC. Among the various iron salts tried (Table 1, entries 2ꢀ7)
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iron(III) acetylacetonate {Fe(acac)3 gave desired product 3a with 65% yield. Further, the use of
iron(II) acetylacetonate {(Fe(acac)2} increased the formation of 2ꢀphenylpyrazine 3a to 72%
yield (Table 1, entry 8). To know the effective amount of iron salt required for catalysis,
experiments with lower amount (20 to 10 mol%) as well as higher amounts (20 to 30 to 100%) of
Fe(acac)2 did not show any improvement in the formation of desired product 3a (Table 1, entries
9ꢀ11). Evaluation with other metals such as Mn, Ag and Cu didn’t show any improvement (Table
1, entries 12ꢀ14). In the absence of iron salt, no product formation was observed (Table 1, entry
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15).
Table 1: Optimization studies for the crossꢀcoupling reaction
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Investigation towards optimization of coupling conditions such as different oxidants, solvent
systems, phase transfer catalyst, temperature and surrounding atmosphere were tried and all the
results summarized in Table 2. Among the various oxidants tried {terꢀbutyl hydrogen peroxide
(TBHP), Diꢀterꢀbutyl hydrogen peroxide (DTBP) and oxone}, only TBHP gave 20% of desired
product 3a (Table 2, entries 1ꢀ3). Change in the sovlent system also affected the formation of 2ꢀ
phenylpyrazine (Table 2, entries 4ꢀ8). As the reaction conditions involved two immiscible
substances, the addition of phase transfer catalyst was tested (Table 2, entries 9ꢀ11) and with 5
mol% of tetrabutylammonium bromide (TBAB), formation of 2ꢀphenylpyrazine increased to
84% (Table 2, entry 9, HPLC data provided in supporting information). As observed during
experiment the addition of TBAB supressed the emulsion formation and made the reaction
mixture a very clear solution which allowed effective coupling and yield improvement as
compared to J. wang method13b where because of heterogenous nature of FeS, its stoichiometric
quantity was required. Moreover, decrease in the amount of K2S2O8 also decreased the yield of
3a (Table 2, entries 12ꢀ13). In the absence of oxidant K2S2O8, no product formation was
observed (Table 2, entry 14). The presence of O2 instead of air and increase in the temperature
did not affect the formation of desired product (Table 2, entries 15ꢀ16).
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Table 2: Optimization studies for the crossꢀcoupling reaction of pyrazine with phenylboronic acid
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Under optimized conditions, the reactivity of various organoboronic acids towards
pyrazine was investigated, and all the reults are given in Table 3. Various ortho-, meta- and
para- substituted organoboronic acids on reaction with pyrazine provided the desired monoꢀ
arylated coupled products 3a-s with varying yields. Arylboronic acids possessing electronꢀ
donating groups at para, meta and ortho position smoothly underwent cross-coupling reaction
and gave good to excellent yields of desired products 3b-g while diꢀsubstituted such as 2,5ꢀ
dimethylphenylboronic acid gave moderate yield of coupled product 3h. Similarly, electronꢀ
withdrawing groups possessing arylboronic acids underwent cross-coupling reaction to afford
corresponding 2ꢀarylpyrazine derivatives 3i-n in moderate to good yields. Moreover, hindered
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Table 3: Crossꢀcoupling reaction of pyrazines with organoboronic acids
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1ꢀnapthylboronic acid underwent cross-coupling and gave 2ꢀnapthylpyrazine 3o in 45% yield.
Vinylic boronic acid such as transꢀ2ꢀphenylvinylboronic acid also coupled with pyrazine and
afforded corresponding coupled product 3p in 48% yield. 2,3ꢀdimethylpyrazine on reaction with
pꢀtolylboronic acid also underwent cross-coupling and gave 2ꢀ(pꢀtolyl)ꢀ5,6ꢀdimethylpyrazine 3q
in 64% yield. Under optimized conditions, heteroaryl boronic acid were also tried where 2ꢀ
chloropyridineꢀ4ꢀboronic acid underwent reaction with pyrazine and gave very less yield 15% of
coupled product 3r while thiophenylꢀ2ꢀboronic acid gave only trace quantity of desired product
as detected by MS analysis.
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The present method under optimized conditions when tried with benzannnulated pyrazine such
as quinoxalines 5 also gave monoꢀarylated product in moderate to good yields (results
summmarized in Table 4). Quinoxaline on reaction with phenylboronic acid furnished 62% of 2ꢀ
Table 4: Crossꢀcoupling reaction of quinoxalines with arylboronic acids
phenyl quinoxoline 6a. Electronꢀdonating groups (EDGs) such as 4ꢀmethyl and 4ꢀmethoxy
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containing phenylꢀboronic acids gave 65 and 52% of correseponding coupled products 6b and 6c
respectively. Electronꢀwithdrawing groups (EWGs) containing phenylboronic acid gave
comparatively lower yield. 4ꢀfluoro and 3ꢀchloro phenyl boronic acids gave 48 and 45% of 6d
and 6e respectively. Similarly, the reaction of 2ꢀmethylquinoxaline with pꢀtolylphenyl boronic
acid gave monoꢀarylated coupled product 6f of 45% yield.
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Other electronꢀdeficient heterocycles such as un/substitued pyridines 7a, quinoline 7b and
isoquinoline 7c were also explored for cross-coupling reaction. Unlikely literature reports,10a,13b
our optimized condition gave surprisingly regioꢀselective monoꢀarylated coupled product (need
further investigation) but with comparatively lower yields (all the results given in Table 5).
Pyridine with phenylboronic acid gave 45% yield of 8a. 4ꢀChloropyridine as hydrochloride salt
on reaction with phenylboronic acid gave monoarylated coupled product, 2ꢀphenylꢀ4ꢀchloroꢀ
pyridine 8b with 35% yield. 4ꢀChloropyridine hydrochloride with EDGs such as 4ꢀmethyl and 4ꢀ
methoxy containing phenylboronic acids gave corresponding 40 and 38% of monoꢀarylated
coupled product 8c and 8d respectively. In case of reaction of 4ꢀchloropyridine hydrochloride
with 2,5ꢀdimethylphenyl boronic acid also underwent and gave 32% of desired monoꢀarylated
8e. On the other hand, 4ꢀchloropyridine hydrochloride on coupling with 4ꢀfluorophenylboronic
acid gave 32% of desired monoꢀarylated product 8f. Quinoline on reaction with phenyl, pꢀtolyl
and 4ꢀchlorphenyl boronic acids gave 34, 38 and 30% of corresponding monoꢀ2ꢀarylated
products 8g, 8h and 8i respectively. Similarly, isoquinoline under optimized conditions coulpled
with phenylboronic acid and gave moderate 40% of monoꢀarylated 1ꢀphenylisoquinoline 8j.
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Table 5: Crossꢀcoupling reaction of pyridines, quinoline and isoquinoline with arylboronic acids
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R
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HO
OH
Fe(acac)2
TFA, K2S2O8
B
Y
9
X
Y
DCM:H2O
TBAB
X
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X= N or CH
Y= N or CH
FG
FG
8a-j
7a-c
2
Cl
Cl
N
N
N
(8b, 14h, 35%)a
(8c, 40%)a
(8a, 45%)
Cl
Cl
Cl
N
N
N
O
F
(8e, 14h, 32%)a (8f, 16h, 32%)a
(8d, 38%)a
N
N
CH3
(8g, 34%)
(8h, 38%)
N
N
Ph
Cl
(8i, 30%)
(8j, 40%)
Reaction conditions (unless otherwise stated): 7 (1 mmol),
2 (1.1 mmol), TFA (1 mmol), Fe(acac)2 (20 mol%), K2S2O8 (3
mmol), TBAB (5mol%), CH2Cl2:H2O, 12h, under air at rt.
a4-Chloropyridine hydrochloride was used and without TFA
Present optimized method also worked very well with quinone 9. Quinone underwent
coupling with various un/substituted organoboronic acids gave monoꢀarylated cross-coupled
products 10a-f and all the results were summarized in Table 6. Phenyl as well as EDGsꢀ (4ꢀMe,
4ꢀOMe) containing arylboronic acids gave coupled product 10a-c in excellent yields. Bulky
substituted arylboronic acid such as 2ꢀPhenoxyphenylboronic acid also reacted and gave good
yield (65%) of coupled product 10d. EWG (3ꢀCF3) containing phenyl boronic acid smoothly
underwent cross-coupling and gave 35% of coupled product 10e. Likewise, heteroarylboronic
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acid such as 2ꢀfluoropyridineꢀ3ꢀboronic acid also coupled with quinone but gave comparatively
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lower yield of 10f (25%).
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Table 6: Crossꢀcoupling reaction of quinone with organoboronic acids
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In order to see the compatibility of other organoboron species, potassium
organotrifluoroborate salts and arylboronic acid pinacol ester was tried (shown in Fig 1).
Potassium organotrifluoroborate salt i.e. phenyltrifluoroborate 11 underwent cross-coupling
smoothly with pyrazine and gave 2ꢀphenyl pyrazine in 78% yield and on the other hand
arylboronic acid pinacol ester 12 gave comparatively lower yield of 2ꢀphenylpyrazine (30%).
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Fig 1: Crossꢀcoupling reaction of pyrazine with potassium organotrifluoroborate salts and arylboronic acid pinacol
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ester
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BF3K
Fe(acac)2 (0.2 eq)
TFA (1 eq)
K2S2O8 (3 eq)
N
N
N
N
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1:1: CH2Cl2:H2O
TBAB
11
3a, 12h, 78%
1
O
O
Fe(acac)2 (0.2 eq)
TFA (1 eq)
K2S2O8 (3 eq)
B
N
N
N
N
1:1: CH2Cl2:H2O
TBAB
1
3a, 15h, 30%
12
Efforts to understand the mechanism were made (Fig. 2). Addition of free radical
scavenger such as (2,2,6,6ꢀtetramethylpiperidinꢀ1ꢀyl)oxyl (TEMPO) in the reaction mixture
drastically suppressed the formation of 2ꢀphenylpyrazine 3a, suggested the involvement of free
radical intermediates (Fig 2). Furthermore when the optimized reaction was performed with
ArB(OH)2 in the absence of heterocycle, GCꢀMS studies shown the formation of phenol and
biphenyl also suggested that Fe2+/SO4 system activate the aryl boronic acid. Based on a
2ꢀ
literature precedent10, 11 and present experimental findings, the plausible mechanism seemed to
be similar as reported by Baran et al.10
Fig 2: Exploration of present method towards freeꢀradical mechanism
HO
OH
B
Fe(acac)2
K2S2O8 (3 eq)
OH
CH2Cl2:H2O
2
4
13
After exploring the versatility and diversity of present iron catalyzed cross-coupling reaction
of Nꢀheterocycles with hetero(aryl)boron reagent, its application towards the synthesis of bioꢀ
active natural product was explored. In this direction, we successfully developed a new and more
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concise (5 steps as compared to 7 steps literature reported method15b) and effective route for the
synthesis of a pyrazine alkaloid Botryllazine A, isolated from marine red ascidian Botryllus
leachi.15aꢀb As per strategy 1, we first tried the synthesis of pyrazine 2,3ꢀdicarboxylate 14 from
2,3ꢀdimethylpyrazine or quinoxaline 1 on oxidation with aqueous KMNO4 or HNO3 but in our
case we did not get the expected pyrazineꢀ2,3ꢀdicarboxylate in all the tried conditions (Scheme
1). However, the synthesis of 14 was successfully achieved from commercially available
pyrazine anhydride 15, which was further converted into 2,3ꢀdibenzoyl pyrazine 16
but the subsequent arylation with 4ꢀanisyl boronic acid under optimized condition did not give
the expected methylated Botryllazine A 17 (Scheme 1). Then as per strategy 2, quinoxaline 1
under optimized condition was converted into 2ꢀ(pꢀmethoxyphenyl)quinoxaline 6c which on
oxidation with aq. KMNO4 or HNO3 condition underwent decomposition of pyrazine ring and
gave pꢀmethoxybenzoic acid 18 as a sole product (Scheme 2). Next, 2,3ꢀdimethyl pyrazine under
optimized condition was converted into 2ꢀ(pꢀmethoxyphenyl)ꢀ5,6ꢀdimethylpyrazine 19 (scheme
3). 2ꢀ(pꢀMethoxyphenyl)ꢀ5,6ꢀdimethylpyrazine 19 was converted into dialdehyde 20 on
treatment with SeO2. Further, dialdehyde 20 when treated with 4ꢀanisylmagnesium bromide at ꢀ
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o
70 C gave Botryllazine skelton 21 which on oxidation with PCC gave methylated Botryllazine
A 17. The methylated Botryllazine A 17 on demethylated with pyridinehydrochloride15b gave
final Botryllazine A 22 (Scheme 3). This reaction has opened new opportunities to iron catalysed
functionalization of electronꢀdeficient heterocycles as well as towards the synthesis of these
heterocycles containing natural products.
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Fig 4: Retroꢀsynthetic strategies for the synthesis of pyrazine alkaloidꢀBotryllazine A
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Scheme 1: Studies towards the synthesis of pyrazine alkaloidꢀBotryllazine A
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8
O
O
N
N
N
N
N
N
OMe
OMe
a, b
b
O
9
1 (2,3-Dimetylpyrazine
or Quinoxaline)
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O
15
O
14
c
OMe
OMe
N
N
N
d
O
O
O
O
N
MeO
OMe
OMe
16
17
Reagents and conditions: a) Aq.KMnO4 or 60%HNO3 reflux, 18h; b)
PTSA, MeOH rt, 12h; c) 4-anisyl-MgBr, Dry THF, -700C; d) 4-anisyl-B(OH)2,
TFA, Fe(acac)2, K2S2O8, TBAB, CH2Cl2:H2O, 12h.
Scheme 2: Studies towards the synthesis of pyrazine alkaloidꢀBotryllazine A
OH
O
N
N
N
a
b
N
Quinoxaline
MeO
OMe
18
6c
1
Reagents and conditions: a) 4-anisyl-B(OH)2, TFA, Fe(acac)2, K2S2O8,
TBAB, CH2Cl2:H2O, 12h; b) Aq.KMnO4 or 60%HNO3 reflux, 18h.
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Scheme 3: Studies towards the synthesis of pyrazine alkaloidꢀBotryllazine A
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8
O
N
N
N
N
b
H
H
a
N
N
9
MeO
OH
O
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1
MeO
20 (50%)
19 (60%)
OMe
OMe
c
N
N
N
N
N
N
e
O
O
d
O
O
OH
OH
HO
MeO
MeO
OH
OMe
OMe
22 (80%)
Botryllazine A
17 (89%)
21 (70%)
Reagents and conditions: a) 4-anisyl-B(OH)2, TFA, Fe(acac)2, K2S2O8, TBAB,
CH2Cl2:H2O, 12h; b) SeO2, dioxane, reflux, 24h; c) 4-anisyl-MgBr, Dry THF, -700C;
d) PCC, DCM, rt; e) pyridinehydrochloride, 220 o C, 1h.
Conclusions:
In summary, an iron catalyzed cross-coupling reaction for the electronꢀdeficient
heterocycles and quinone with organoboron species via innate CꢀH functionalization has been
developed. Iron (II) acetylacetonate along with oxidant (K2S2O8) and phase transfer catalyst
(TBAB) in dichloromethane:water under open flask condition efficiently catalyzed the cross-
coupling reaction of pyrazine with aryl boronic acids and gave monoarylated products in good to
excellent yields. This optimized conditions worked with other Nꢀheterocylces such as
quinoxaline, pyridine, quinoline, isoquinoline as well as quinones. The present methodology was
successfully utilized for the synthesis of Botryllazine Aꢀ a marine derived natural product.
Moreover, heteroarylboronic acids also worked under optimized condition but gave less yield of
coupled product. Further extension of present method to other (hetero)arenes and studies towards
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yield improvement/regioꢀselectivity wherever noted are underway and will be reported in due
course.
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Experimental Section:
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General:
All reactions were performed under air atmosphere. Analytical thin layer chromatography
was performed using TLC preꢀcoated silica gel 60 F254 (20 x 20 cm). TLC plates were visualized
by exposing UV light or by iodine vapours or immersion in an acidic staining solution of pꢀ
anisaldehyde followed by heating on hot plate. Organic solvent were concentrated by rotary
evaporation. Flash column chromatography was performed on flash silica gel 230ꢀ400 mesh size.
1H NMR spectra were recorded with 400 and 500 MHz NMR instruments. Chemical data for
protons are reported in parts per million (ppm, scale) downfield from tetramethylsilane and are
referenced to the residual proton in the NMR solvent (CDCl3: δ 7.26, or other solvents as
mentioned). Mass spectra were recorded with LCMSꢀQTOF instrument. HPLC were performed
on instrument equipped with DAD VL detector using 5ꢁm, 4.6 x 250 mm column.
General procedure for crossꢀcoupling (hetero)arene with organoboron species: To a
solution of (hetero)arene (1 mmol) in dichloromethane (8 mL) was added trifluoroacetic acid (80
µL, 1 mmol) followed by arylboronic acid (1.1 mmol). Water (8 mL) was then added, followed
by iron (II) acetylacetonate (0.2 mmol), and potassium persulfate (3 mmol). TBAB was then
added {5 mol% w.r.t. (hetero)arenes} and the solution was stirred vigorously at room
temperature till completion as monitored by TLC. Then reaction mixture was diluted with
dichloromethane and washed with saturated sodium bicarbonate solution. The layers were
separated and the aqueous layer was extracted with dichloromethane. Organic layers were
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compiled, dried over sodium sulfate and evaporated in vacuo. Purification was performed by
silica gel chromatography to get pure product and characterized by NMR and HRMS.
Note: Trifluoroacetic acid was not added in case of 4-chloropyridine hydrochloride and
quinone.
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2-Phenylpyrazine (Table 3, 3a)16: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.50 (hexane/EtOAc, 8:2); yield 80% (125 mg); light yellow solid; H
NMR (400MHz, CDCl3) δ = 9.02 (d, J = 1.4 Hz, 1H), 8.62 (dd, J = 2.4, 1.6 Hz, 1H), 8.49 (d, J =
2.5 Hz, 1H), 8.02ꢀ7.99 (m, 2H), 7.52ꢀ7.46 (m, 3H); 13C NMR (125 MHz, CDCl3) δ = 152.8,
144.1, 142.8, 142.2, 136.3, 129.9, 129.0, 126.9; HRMS (ESIꢀTOF) cald. for C10H8N2 [M +
H]+157.0766; found 157.0750.
2-(p-Tolyl)pyrazine (Table 3, 3b)9: Column chromatography (flash silica gel,
hexane/EtOAc); Rf = 0.55 (hexane/EtOAc, 8:2); yield 86% (147 mg); pale yellow solid; 1H NMR
(400MHz, CDCl3) δ = 8.99 (s, 1H), 8.59 (dd, J = 3.1, 1.6 Hz, 1H), 8.45 (t, J = 2.3 Hz, 1H), 7.90
(dd, J = 8.1, 1.7 Hz, 2H), 7.30 (d, J = 7.8 Hz, 2H), 2.41 (s, 3H).13C NMR (125 MHz, CDCl3) δ =
152.8, 144.1, 142.5, 142.0, 140.1, 133.5, 129.8, 126.8, 21.3; HRMS (ESIꢀTOF) cald. for
C11H10N2 [M + H]+ 171.0917; found 171.0912.
2-(m-Tolyl)pyrazine (Table 3, 3c)9: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.53 (hexane/EtOAc, 8:2); yield 80% (136 mg); light yellow oil; H NMR
(400 MHz, CDCl3) δ = 9.02 (d, J = 1.5 Hz, 1H), 8.63 (dd, J = 2.5, 1.6 Hz, 1H), 8.50 (d, J = 2.5
Hz, 1H), 7.85 (s, 1H), 7.79 (d, J = 7.8 Hz, 1H), 7.41 (t, J = 7.6 Hz, 1H), 7.30 (d, J = 7.6 Hz, 1H),
13
2.46 (s, 3H); C NMR (100 MHz, CDCl3) δ = 153.0, 144.1, 142.8, 142.3, 138.8, 136.3, 130.7,
128.9, 127.6, 124.0, 21.5; HRMS (ESIꢀTOF) cald. for C11H10N2 [M + H]+ 171.0917; found
171.0912.
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2-(2-Ethylphenyl)pyrazine (Table 3, 3d): Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.55 (hexane/EtOAc, 8:2); yield 78% (144 mg); light yellow oil; H NMR
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9
(400 MHz, CDCl3) δ = 8.71 (d, J = 1.5 Hz, 1H), 8.66 (dd, J = 2.5, 1.6 Hz, 1H), 8.54 (d, J = 2.5
Hz, 1H), 7.44 – 7.29 (m, 4H), 2.73 (q, J = 7.5 Hz, 2H), 1.13 (t, J = 7.6 Hz, 3H); 13C NMR (100
MHz, CDCl3) δ = 155.9, 145.1, 143.8, 142.6, 142.5, 136.4, 129.9, 129.4, 129.3, 126.0, 26.0,
15.6; HRMS (ESIꢀTOF) cald. for C12H12N2 [M + H]+ 185.1079; found 185.1065.
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2-(4-Isopropylphenyl)pyrazine (Table 3, 3e): Column chromatography (flash silica gel,
hexane/EtOAc); Rf = 0.56 (hexane/EtOAc, 8:2); yield 82% (163 mg); light yellow solid; mp 52ꢀ
54 oC; 1H NMR (400 MHz, CDCl3) δ = 9.01 (d, J = 1.5 Hz, 1H), 8.61 (dd, J = 2.5, 1.6 Hz, 1H),
8.47 (d, J = 2.5 Hz, 1H), 7.97 – 7.94 (m, 2H), 7.39 – 7.37 (m, 2H), 2.98 (septet, J = 6.9 Hz, 1H),
13
1.30 (d, J = 6.9 Hz, 6H); C NMR (125 MHz, CDCl3) δ = 152.9, 151.0, 144.1, 142.5, 142.0,
133.9, 127.2, 126.9, 34.0, 23.8; HRMS (ESIꢀTOF) cald. for C13H14N2 [M + H]+ 199.1230; found
199.1226.
2-(4-Methoxyphenyl)pyrazine (Table 3, 3f)16: Column chromatography (flash silica
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gel, hexane/EtOAc); Rf = 0.40 (hexane/EtOAc, 8:2); yield 65% (121 mg); colorless solid; H
NMR (400 MHz, CDCl3) δ = 8.98 (d, J = 1.5 Hz, 1H), 8.58 (dd, J = 2.5, 1.6 Hz, 1H), 8.44 (d, J =
2.5 Hz, 1H), 8.00 – 7.97 (m, 2H), 7.05 – 7.02 (m, 2H), 3.88 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ = 161.2, 152.5, 144.0, 142.1, 141.6, 128.8, 128.3, 114.5, 55.4; HRMS (ESIꢀTOF) cald.
for C11H10N2O [M + H]+ 187.0866; found 187.0862.
2-(3-Methoxyphenyl)pyrazine (Table 3, 3g)16: Column chromatography (flash silica
1
gel, hexane/EtOAc); Rf = 0.40 (hexane/EtOAc, 8:2); yield 65% (121 mg); pale yellow solid; H
NMR (400 MHz, CDCl3) δ = 9.02 (d, J = 1.4 Hz, 1H), 8.63 (dd, J = 2.4, 1.6 Hz, 1H), 8.51 (d, J =
2.5 Hz, 1H), 7.60 – 7.56 (m, 2H), 7.42 (t, J = 7.9 Hz, 1H), 7.03 (ddd, J = 8.2, 2.6, 0.9 Hz, 1H),
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3.90 (s, 3H); 13C NMR (100 MHz, CDCl3) δ = 160.3, 152.6, 144.1, 142.9, 142.3, 137.7, 130.0,
119.2, 116.0, 112.1, 55.4; HRMS (ESIꢀTOF) cald. for C11H10N2O [M + H]+ 187.0866; found
187.0861.
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2-(2,5-Dimethylphenyl)pyrazine (Table 3, 3h): Column chromatography (flash silica
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gel, hexane/EtOAc); Rf = 0.55 (hexane/EtOAc, 8:2); yield 55% (102 mg); light yellow oil; H
NMR (400 MHz, CDCl3) δ = 8.72 (d, J = 1.5 Hz, 1H), 8.66 (dd, J = 2.4, 1.6 Hz, 1H), 8.52 (d, J =
13
2.5 Hz, 1H), 7.25 (s, 1H), 7.19 (q, J = 7.8 Hz, 2H), 2.38 (s, 3H), 2.36 (s, 3H); C NMR (125
MHz, CDCl3) δ = 155.7, 145.2, 143.8, 142.4, 136.5, 135.7, 133.0, 131.0, 130.4, 129.9, 20.9,
19.8; HRMS (ESIꢀTOF) cald. for C12H12N2 [M + H]+ 185.1073; found 185.1067.
2-(4-Bromophenyl)pyrazine (Table 3, 3i)17: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.50 (hexane/EtOAc, 8:2); yield 78% (182 mg); light yellow solid; H
NMR (400 MHz, CDCl3) δ = 9.02 (d, J = 1.4 Hz, 1H), 8.63 (dd, J = 2.3, 1.7 Hz, 1H), 8.53 (d, J =
2.4 Hz, 1H), 7.92 – 7.90 (m, 2H), 7.65 (dd, J = 8.8, 2.0 Hz, 2H); 13C NMR (125 MHz, CDCl3) δ
= 151.7, 144.3, 143.2, 141.9, 135.2, 132.3, 128.4, 124.6; HRMS (ESIꢀTOF) cald. for C10H7BrN2
[M + H]+ 234.9865; found 234.9839.
2-(4-Chlorophenyl)pyrazine (Table 3, 3j)17: Column chromatography (flash silica gel,
hexane/EtOAc); Rf = 0.45 (hexane/EtOAc, 8:2); yield 76% (145 mg); pale yellow solid; 1H NMR
(400 MHz, CDCl3) δ = 9.01 (d, J = 1.5 Hz, 1H), 8.63 (dd, J = 2.2, 1.8 Hz, 1H), 8.53 (d, J = 2.5
Hz, 1H), 7.99 – 7.97 (m, 2H), 7.51 – 7.48 (m, 2H); 13C NMR (125 MHz, CDCl3) δ = 151.7,
144.2, 143.2, 141.9, 136.2, 134.7, 129.3, 128.2; HRMS (ESIꢀTOF) cald. for C10H7ClN2 [M + H]+
191.0371; found 191.0361.
2-(3-Chlorophenyl)pyrazine (Table 3, 3k)18: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.45 (hexane/EtOAc, 8:2); yield 65% (124 mg); light yellow solid, H
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NMR (400 MHz, CDCl3) δ = 9.02 (d, J = 1.5 Hz, 1H), 8.65 (dd, J = 2.4, 1.6 Hz, 1H), 8.55 (d, J =
2.5 Hz, 1H), 8.05 – 8.04 (m, 1H), 7.93 – 7.87 (m, 1H), 7.46 – 7.44 (m, 2H); 13C NMR (125
MHz, CDCl3) δ = 151.4, 144.3, 143.4, 142.0, 138.0, 135.2, 130.3, 129.9, 127.1, 124.9; HRMS
(ESIꢀTOF) cald. for C10H7ClN2 [M + H]+ 191.0371; found 191.0363.
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2-(4-Fluorophenyl)pyrazine (Table 3, 3l)17: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.40 (hexane/EtOAc, 8:2); yield 52% (91 mg); brownish solid; H NMR
(400 MHz, CDCl3) δ = 9.02 (s, 1H), 8.64 (d, J = 1.5 Hz, 1H), 8.52 (d, J = 2.3 Hz, 1H), 8.06 –
19
13
8.02 (m, 2H), 7.22 (t, J = 8.5 Hz, 2H); F NMR (376 MHz, CDCl3) δ = ꢀ111.17 (m, 1F); C
NMR (100 MHz, CDCl3) δ = 164.0 (d, J = 250.3 Hz ), 151.8, 144.1, 142.8, 141.8, 132.5 (d, J =
3.2 Hz ), 128.8 (d, J = 8.5 Hz ), 116.1 (d, J = 21.8 Hz ); HRMS (ESIꢀTOF) cald. for C10H7FN2
[M + H]+ 175.0666; found 175.0659.
2-(4-(Trifluoromethyl)phenyl)pyrazine (Table 3, 3m)19: Column chromatography
(flash silica gel, hexane/EtOAc); Rf = 0.35 (hexane/EtOAc, 8:2); yield 30% (68 mg); pale yellow
1
solid; H NMR (400 MHz, CDCl3) δ = 9.10 (d, J = 1.4 Hz, 1H), 8.71 (dd, J = 2.4, 1.6 Hz, 1H),
8.61 (d, J = 2.4 Hz, 1H), 8.18 (d, J = 8.1 Hz, 2H), 7.81 (d, J = 8.2 Hz, 2H); 19F NMR (376 MHz,
13
CDCl3) δ = ꢀ63.20 (s, 3F); C NMR (100 MHz, CDCl3) δ = 151.3, 144.3, 143.8, 142.3, 139.7,
132.1 (q, J = 32.6 Hz), 127.2, 126.6 (q, J = 272.4 Hz), 126.0 (q, J = 3.8 Hz); HRMS (ESIꢀTOF)
cald. for C11H7F3N2 [M + H]+ 225.0635; found 225.0646.
2-([1,1’Biphenyl]-4-yl)pyrazine (Table 3, 3n)20: Column chromatography (flash silica
1
gel, hexane/EtOAc); Rf = 0.45 (hexane/EtOAc, 8:2); yield 50% (116 mg); light yellow solid; H
NMR (400 MHz, CDCl3) δ = 9.09 (d, J = 1.8 Hz, 1H), 8.66 – 8.65 (m, 1H), 8.52 (dd, J = 6.1, 2.6
Hz, 1H), 8.12 – 8.10 (m, 2H), 7.78 – 7.74 (m, 2H), 7.69 – 7.66 (m, 2H), 7.51 – 7.46 (m, 2H),
13
7.41 – 7.25 (m, 1H); C NMR (125 MHz, CDCl3) δ = 152.5, 144.3, 142.8, 142.7, 142.1, 140.2,
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135.1, 128.9, 128.7, 128.3, 127.8, 127.7 127.3, 127.1, 126.7; HRMS (ESIꢀTOF) cald. for
C16H12N2 [M + H]+ 233.1073; found 233.1064.
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2-(Naphthalene-1-yl)pyrazine (Table 3, 3o)9: Column chromatography (flash silica gel,
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1
hexane/EtOAc); Rf = 0.50 (hexane/EtOAc, 8:2); yield 45% (93 mg); light yellow oil; H NMR
(400 MHz, CDCl3) δ = 8.90 (s, 1H), 8.77 – 8.76 (m, 1H), 8.64 – 8.63 (m, 1H), 8.09 (d, J = 7.0
13
Hz, 1H), 8.10 – 7.92 (m, 2H), 7.63 – 7.53 (m, 4H); C NMR (125 MHz, CDCl3) δ = 155.1,
145.8, 144.1, 142.8, 134.6, 133.9, 134.0, 130.0, 128.6, 128.2, 127.0, 126.3, 125.3,124.9; HRMS
(ESIꢀTOF) cald. for C14H10N2 [M + H]+ 207.0917; found 207.0912.
(E)-2-Styrylpyrazine (Table 3, 3p)16: Column chromatography (flash silica gel,
hexane/EtOAc); Rf = 0.35 (hexane/EtOAc, 8:2); yield 48% (88 mg); light yellow solid; 1H NMR
(400 MHz, CDCl3) δ = 8.65 (d, J = 1.4 Hz, 1H), 8.55 – 8.54 (m, 1H), 8.40 (d, J = 2.5 Hz, 1H),
7.76 (d, J = 16.1 Hz, 1H), 7.61 – 7.59 (m, 2H), 7.42 – 7.33 (m, 3H), 7.16 (d, J = 16.1 Hz, 1H);
13C NMR (125 MHz, CDCl3) δ = 151.3, 144.3, 143.7, 142.7, 136.0, 135.2, 129.0, 128.8, 127.3,
124.0; HRMS (ESIꢀTOF) cald. for C12H10N2 [M + H]+ 183.0917; found 183.0907.
2,3-Dimethyl-5-(p-tolyl)pyrazine (Table 3, 3q): Column chromatography (flash silica
gel, hexane/EtOAc); Rf = 0.60 (hexane/EtOAc, 8:2); yield 64% (127 mg); colorless solid; mp
109ꢀ111 oC; 1H NMR (400 MHz, CDCl3) δ = 8.68 (s, 1H), 7.89 – 7.87 (m, 2H), 7.28 (d, J = 7.9
13
Hz, 2H), 2.60 (s, 3H), 2.56 (s, 3H), 2.41 (s, 3H); C NMR (125 MHz, CDCl3) δ = 151.6, 150.0,
149.4, 139.2, 138.0, 134.0, 129.6, 126.5, 22.2, 21.7, 21.3; HRMS (ESIꢀTOF) cald. for C13H14N2
[M + H]+ 199.1230; found 199.1223.
2-(2-Chloropyridin-4-yl) pyrazine (Table 3, 3r): Column chromatography (flash silica
gel, hexane/EtOAc); Rf = 0.30 (hexane/EtOAc, 8:2); yield 15% (29 mg); light yellow solid; mp
111ꢀ112 oC; 1H NMR (400 MHz, CDCl3) δ = 9.10 (d, J = 1.3 Hz, 1H), 8.72 – 8.67 (m, 1H), 8.67
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(d, J = 2.4 Hz, 1H), 8.56 (d, J = 5.2 Hz, 1H), 8.01 (d, J = 0.7 Hz, 1H), 7.85 (dd, J = 5.2, 1.4 Hz,
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1H); C NMR (125 MHz, CDCl3) δ = 152.8, 150.5, 148.9, 146.6, 145.3, 144.7, 142.3, 121.7,
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119.5; HRMS (ESIꢀTOF) cald. for C9H6ClN3 [M + H]+ 192.0328; found 192.0322.
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2-Phenylquinoxaline (Table 4, 6a)21: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.50 (hexane/EtOAc, 8:2); yield 62% (128 mg); light yellow solid; H
NMR (400 MHz, CDCl3) δ = 9.33 (s, 1H), 8.21 – 8.12 (m, 4H), 7.81 – 7.73 (m, 2H), 7.60 – 7.51
(m, 3H); 13C NMR (100 MHz, CDCl3) δ = 151.8, 143.3, 142.3, 141.6, 136.8, 130.2, 130.1, 129.6,
129.5, 129.1, 127.5; HRMS (ESIꢀTOF) cald. for C14H10N2 [M + H]+ 207.0917; found 207.0912.
2-(p-Tolyl)quinoxaline (Table 4, 6b)21: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.55 (hexane/EtOAc, 8:2); yield 65% (143 mg); light yellow solid; H
NMR (400 MHz, CDCl3) δ = 9.31 (s, 1H), 8.15 – 8.09 (m, 4H), 7.75 (dddd, J = 14.9, 8.4, 6.9, 1.6
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Hz, 2H), 7.37 (d, J = 8.0 Hz, 2H), 2.45 (s, 3H); C NMR (125 MHz, CDCl3) δ = 151.8, 143.3,
142.3, 141.4, 140.5, 133.9, 130.2, 129.9, 129.5, 129.3, 129.1, 127.4, 21.4; HRMS (ESIꢀTOF)
cald. for C15H12N2 [M + H]+ 221.1073; found 221.1068.
2-(4-Methoxyphenyl)quinoxaline (Table 4, 6c) 21: Column chromatography (flash silica
1
gel, hexane/EtOAc); Rf = 0.40 (hexane/EtOAc, 8:2); yield 52% (123 mg); colorless solid; H
NMR (400 MHz, CDCl3) δ = 9.29 (s, 1H), 8.19 – 8.13 (m, 2H), 8.11 (ddd, J = 9.8, 8.4, 1.3 Hz,
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2H), 7.74 (dddd, J = 21.2, 8.4, 6.9, 1.5 Hz, 2H), 7.10 – 7.06 (m, 2H), 3.90 (s, 3H); C NMR
(125 MHz, CDCl3) δ = 161.4, 151.5, 143.1, 142.3, 141.2, 130.2, 129.4, 129.3, 129.0, 128.9,
114.6, 55.4; HRMS (ESIꢀTOF) cald. for C15H12N2O [M + H]+ 237.1022; found 237.1017.
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2-(4-Fluorophenyl)quinoxaline (Table 4, 6d) : Column chromatography (flash silica
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gel, hexane/EtOAc); Rf = 0.40 (hexane/EtOAc, 8:2); yield 48% (108 mg); light yellow solid; H
NMR (400 MHz, CDCl3) δ = 9.30 (s, 1H), 8.23 – 8.19 (m, 2H), 8.15 – 8.12 (m, 2H), 7.83 – 7.73
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(m, 2H), 7.28 – 7.24 (m, 2H); 19F NMR (376 MHz, CDCl3) δ = ꢀ110.56 (m, 1F); 13C NMR (100
MHz, CDCl3) δ = 164.2 (d, J = 250.8 Hz), 150.7, 142.9, 142.2, 141.5, 132.9 (d, J = 3.2 Hz),
130.4, 129.5, 129.5, 129.5 (d, J = 8.3 Hz), 129.1, 116.2 (d, J = 21.8 Hz); HRMS (ESIꢀTOF) cald.
for C14H9FN2 [M + H]+ 225.0823; found 225.0813.
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2-(3-Chlorophenyl)quinoxaline (Table 4, 6e) 22: Column chromatography (flash silica
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gel, hexane/EtOAc); Rf = 0.45 (hexane/EtOAc, 8:2); yield 45% (108 mg); light yellow oil; H
NMR (400 MHz, CDCl3) δ = 9.31 (s, 1H), 8.24 (d, J = 0.9 Hz, 1H), 8.18 – 8.13 (m, 2H), 8.08 –
8.06 (m, 1H), 7.84 – 7.76 (m, 2H), 7.51 – 7.50 (m, 2H); 13C NMR (125 MHz, CDCl3) δ = 150.3,
142.9, 142.2, 141.8, 138.5, 135.3, 130.5, 130.4, 130.2, 130.0, 129.7, 129.1, 127.7, 125.5; HRMS
(ESIꢀTOF) cald. for C14H9ClN2 [M + H]+ 241.0527; found 241.0518.
2-Methyl-3-(p-tolyl)quinoxaline (Table 4, 6f) 10a: Column chromatography (flash silica
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gel, hexane/EtOAc); Rf = 0.60 (hexane/EtOAc, 8:2); yield 45% (106 mg); pale yellow oil; H
NMR (400 MHz, CDCl3) δ = 8.12 – 8.10 (m, 1H), 8.05 – 8.03 (m, 1H), 7.73 – 7.70 (m, 2H), 7.56
13
(d, J = 8.1 Hz, 2H), 7.34 (d, J = 8.3 Hz, 2H), 2.79 (s, 3H), 2.45 (s, 3H); C NMR (125 MHz,
CDCl3) δ = 154.9, 152.6, 141.1, 141.0, 139.0, 136.1, 129.6, 129.2, 129.2, 129.1, 128.9, 128.2,
24.4, 21.3; HRMS (ESIꢀTOF) cald. for C16H14N2 [M + H]+ 235.1235; found 235.1223.
2-Phenylpyridine (Table 5, 8a)23: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.60 (hexane/EtOAc, 8:2); yield 45% (70 mg); colorless solid; H NMR
(400 MHz, CDCl3) δ = 8.70 – 8.69 (m, 1H), 8.00 ꢀ 7.98 (m, 2H), 7.75 – 7.73 (m, 2H), 7.52 –
7.38 (m, 3H), 7.25 – 7.21 (m, 1H); HRMS (ESIꢀTOF) cald. for C11H9N [M + H]+ 156.0813;
found 156.0815.
4-Chloro-2-phenylpyridine (Table 5, 8b)23: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.50 (hexane/EtOAc, 8:2); yield 35% (67 mg); light yellow semiꢀsolid; H
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NMR (400 MHz, CDCl3) δ = 8.57 (d, J = 5.3 Hz, 1H), 7.96 (dt, J = 8.4, 2.1 Hz, 2H), 7.72 (d, J =
1.9 Hz, 1H), 7.48 – 7.43 (m, 3H), 7.23 (dd, J = 5.3, 1.9 Hz, 1H); HRMS (ESIꢀTOF) cald. for
C11H8ClN [M + H]+ 190.0424; found 190.0418.
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4-Chloro-2-(p-tolyl)pyridine (Table 5, 8c) 10a: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.60 (hexane/EtOAc, 8:2); yield 40% (82 mg); colorless semiꢀsolid; H
NMR (400 MHz, CDCl3) δ = 8.55 (d, J = 5.3 Hz, 1H), 7.87 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 1.9
Hz, 1H), 7.29 – 7.25 (m, 2H), 7.20 (dd, J = 5.3 Hz, 1.9, 1H), 2.41 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ = 159.0, 150.4, 144.6, 139.7, 135.3, 129.5, 126.8, 121.9, 120.4, 21.2; HRMS (ESIꢀ
TOF) cald. for C12H10ClN [M + H]+ 204.0580; found 204.0574.
4-Chloro-2-(4-methoxyphenyl)pyridine (Table 5, 8d)24: Column chromatography
(flash silica gel, hexane/EtOAc); Rf = 0.50 (hexane/EtOAc, 8:2); yield 38% (84 mg); light yellow
semiꢀsolid; 1H NMR (400 MHz, CDCl3) δ = 8.51 (d, J = 5.3 Hz, 1H), 7.93 – 7.90 (m, 2H), 7.63
(d, J = 1.8 Hz, 1H), 7.14 (dd, J = 5.3, 1.9 Hz, 1H), 6.99 – 6.95 (m, 2H), 3.83 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ = 160.9, 158.6, 150.3, 144.6, 130.8, 128.3, 121.5, 119.9, 114.2, 55.3;
HRMS (ESIꢀTOF) cald. for C12H10ClNO [M + H]+ 220.0529; found 220.0529.
4-Chloro-2-(2,5-dimethylphenyl)pyridine (Table 5, 8e): Column chromatography
(flash silica gel, hexane/EtOAc); Rf = 0.60 (hexane/EtOAc, 8:2); yield 32% (70 mg); colorless
oil; 1H NMR (500 MHz, CDCl3) δ = 8.58 (d, J = 5.4 Hz, 1H), 7.42 (d, J = 1.9 Hz, 1H), 7.26 (dd,
J = 5.3, 2.0 Hz, 1H), 7.20 – 7.12 (m, 3H), 2.35 (s, 3H), 2.32 (s, 3H); 13C NMR (125 MHz,
CDCl3) δ = 161.7, 150.0, 144.0, 138.9, 135.5, 132.6, 130.8, 130.1, 129.5, 124.4, 121.9, 20.8,
19.7; HRMS (ESIꢀTOF) cald. for C13H12ClN[M + H]+ 218.0737; found 218.0734.
4-Chloro-2-(4-fluorophenyl)pyridine (Table 5, 8f)24: Column chromatography (flash
silica gel, hexane/EtOAc); Rf = 0.50 (hexane/EtOAc, 8:2); yield 32% (67 mg); light yellow solid;
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1H NMR (400 MHz, CDCl3) δ = 8.55 (d, J = 5.3 Hz, 1H), 7.98 – 7.94 (m, 2H), 7.67 (d, J = 1.7
Hz, 1H), 7.26 – 7.13 (m, 3H); 19F NMR (376 MHz, CDCl3) δ = ꢀ111.89 (m, 1F); 13C NMR (100
MHz, CDCl3) δ = 163.8 (d, J = 249.6 Hz ), 157.9, 150.5, 144.7, 134.3 (d, J = 3.1 Hz ), 128.8 (d,
J = 8.5 Hz ), 122.2, 120.5, 115.8 (d, J = 21.7 Hz ); HRMS (ESIꢀTOF) cald. for C11H7ClFN [M +
H]+ 208.0329; found 208.0327.
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2-Phenylquinoline (Table 5, 8g)25: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.60 (hexane/EtOAc, 8:2); yield 34% (70 mg); colorless solid; H NMR
(400 MHz, CDCl3) δ = 8.22 (d, J = 8.6 Hz, 1H), 8.18 – 8.16 (m, 3H), 7.88 (d, J = 8.6 Hz, 1H),
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7.83 (d, J = 8.1, 1H), 7.75 – 7.71 (m, 1H), 7.55 – 7.51 (m, 3H), 7.49 – 7.45 (m, 1H); C NMR
(125 MHz, CDCl3) δ = 156.9, 147.8, 139.2, 136.3, 129.2, 129.1, 128.8, 128.3, 127.1, 127.0,
126.7, 125.8, 118.5; HRMS (ESIꢀTOF) cald. for C15H11N [M + H]+ 206.0970; found 206.0970.
2-(p-Tolyl)quinoline (Table 5, 8h)25: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.60 (hexane/EtOAc, 8:2); yield 38% (84 mg); colorless solid; H NMR
(400 MHz, CDCl3) δ = 8.17 (dd, J = 12.9, 8.6 Hz, 2H), 8.08 – 8.06 (m, 2H), 7.83 (dd, J = 19.5,
8.4 Hz, 2H), 7.73 – 7.67 (m, 1H), 7.52 – 7.48 (m, 1H), 7.33 (d, J = 8.0 Hz, 2H), 2.43 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ = 157.3, 148.3, 139.4, 136.9, 136.6, 129.6, 129.5, 127.4, 127.4,
127.1, 126.0, 118.8, 21.3; HRMS (ESIꢀTOF) cald. for C16H13N [M + H]+ 220.1126; found
220.1126.
2-(4-Chlorophenyl)quinoline (Table 5, 8i)25: Column chromatography (flash silica gel,
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hexane/EtOAc); Rf = 0.55 (hexane/EtOAc, 8:2); yield 30% (72 mg); colorless solid; H NMR
(500 MHz, CDCl3) δ = 8.22 (d, J = 8.6 Hz, 1H), 8.15 (d, J = 8.5 Hz, 1H), 8.12 (d, J = 8.4 Hz,
2H), 7.83 (dd, J = 8.3, 4.6 Hz, 2H), 7.76 – 7.71 (m, 1H), 7.54 (t, J = 7.5 Hz, 1H), 7.50 – 7.48 (m,
13
2H); C NMR (125 MHz, CDCl3) δ = 156.0, 148.2, 138.0, 136.9, 135.5, 129.8, 129.6, 129.0,
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128.8, 127.4, 127.2, 126.5, 118.5; HRMS (ESIꢀTOF) cald. for C15H10ClN [M + H]+ 240.0580;
found 240.0575.
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1-Phenylisoquinoline (Table 5, 8j)25: Column chromatography (flash silica gel,
hexane/EtOAc); Rf = 0.60 (hexane/EtOAc, 8:2); yield 40% (82 mg); light yellow solid; 1H NMR
(400 MHz, CDCl3) δ = 8.64 – 8.60 (m, 1H), 8.10 (d, J = 8.5 Hz, 1H), 7.88 (d, J = 8.1 Hz, 1H),
7.71 – 7.63 (m, 4H), 7.55 – 7.49 (m, 4H);13C NMR (125 MHz, CDCl3) δ = 160.7, 142.1, 139.5,
136.8, 129.9, 129.8, 128.5, 128.3, 127.5, 127.1, 126.9, 126.6, 119.9; HRMS (ESIꢀTOF) cald. for
C15H11N [M + H]+ 206.0970; found 206.0970.
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2-Phenyl-1,4-benzoquinone (Table 6, 10a)10b: Column chromatography (flash silica
gel, hexane/EtOAc); Rf = 0.60 (hexane/EtOAc, 8:2); yield 90% (166 mg); yellow solid; 1H NMR
(400 MHz, CDCl3) δ = 7.49 – 7.44 (m, 5H), 6.89 – 6.82 (m, 3H); 13C NMR (125 MHz, CDCl3) δ
= 187.6, 186.6, 145.9, 137.0, 136.2, 132.7, 130.1, 129.2, 128.5; HRMS (ESIꢀTOF) cald. for
C12H8O2 [M + H]+ 185.0603; found 185.0602.
2-(4-Methylphenyl)-1,4-benzoquinone (Table 6, 10b)10b: Column chromatography
(flash silica gel, hexane/EtOAc); Rf = 0.70 (hexane/EtOAc, 8:2); yield 92% (183 mg); yellow
solid; 1H NMR (400 MHz, CDCl3) δ = 7.39 (d, J = 8.1 Hz, 2H), 7.27 – 7.25 (m, 2H), 6.87 – 6.80
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(m, 3H), 2.40(s, 3H); C NMR (125 MHz, CDCl3) δ = 187.7, 186.8, 145.8 140.6, 137.0, 136.2,
132.0, 129.8, 129.3, 129.2, 21.4; HRMS (ESIꢀTOF) cald. for C13H10O2 [M + H]+ 199.0759;
found 199.0749.
2-(4-Methoxyphenyl)-1,4-benzoquinone (Table 6, 10c)10b: Column chromatography
(flash silica gel, hexane/EtOAc); Rf = 0.60 (hexane/EtOAc, 8:2); yield 80% (172 mg); red solid;
1H NMR (400 MHz, CDCl3) δ = 7.50 – 7.46 (m, 2H), 6.99 – 6.95 (m, 2H), 6.86 – 6.79 (m, 3H),
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3.86 (s, 3H); C NMR (125 MHz, CDCl3) δ = 187.7, 187.1, 161.4, 145.2, 137.0, 136.2, 131.1,
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130.9, 124.9, 114.1, 55.4; HRMS (ESIꢀTOF) cald. for C13H10O3 [M + H]+ 215.0708; found
215.0697.
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2-(2-Phenoxyphenyl)-1,4-benzoquinone (Table 6, 10d): Column chromatography
(flash silica gel, hexane/EtOAc); Rf = 0.50 (hexane/EtOAc, 8:2); yield 65% (180 mg); yellow oil;
1H NMR (400 MHz, CDCl3) δ = 7.38 – 7.26 (m, 4H), 7.18 – 7.05 (m, 2H), 7.02 (t, J = 11.0 Hz,
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2H), 6.95 – 6.75 (m, 4H); C NMR (125 MHz, CDCl3) δ = 187.5, 185.4, 156.5, 155.3, 145.4,
137.0, 136.2, 134.5, 131.2, 130.9, 129.8, 124.7, 123.8, 123.2, 119.3, 118.3; HRMS (ESIꢀTOF)
cald. for C18H12O3 [M ꢀ H]ꢀ 275.0714; found 275.0717.
2-(3-Trifluoromethylphenyl)-1,4-Benzoquinone
(Table
6,
10e)26:
Column
chromatography (flash silica gel, hexane/EtOAc); Rf = 0.50 (hexane/EtOAc, 8:2); yield 35% (89
1
mg); yellow oil; H NMR (400 MHz, CDCl3) δ = 7.73 (d, J = 9.2 Hz, 2H), 7.68 (d, J = 7.8 Hz,
1H), 7.59 (t, J = 7.7 Hz, 1H), 6.93 – 6.86 (m, 3H); 19F NMR (376 MHz, CDCl3) δ = ꢀ62.75 (s,
3F); 13C NMR (125 MHz, CDCl3) δ = 187.2, 186.0, 144.6, 137.0, 136.4, 133.4, 133.3, 132.5,
131.1 (q, J = 32.6 Hz), 129.1, 126.7 (q, J = 3.6 Hz), 126.1 (q, J = 3.8 Hz), 123.7 (q, J = 272.5
Hz); HRMS (ESIꢀTOF) cald. for C13H7F3O2 [M + H]+ 253.0476; found 253.0472.
2-(2-Fluoropyridin-3-yl)-1,4-Benzoquinone (Table 6, 10f): Column chromatography
(flash silica gel, hexane/EtOAc); Rf = 0.40 (hexane/EtOAc, 8:2); yield 25% (51 mg); brown
o
solid; mp 124ꢀ125 C; 1H NMR (400 MHz, CDCl3) δ = 8.32 – 8.30 (m, 1H), 7.80 (ddd, J = 9.4,
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7.5, 1.9 Hz, 1H), 7.31 (ddd, J = 7.3 Hz, 4.9, 1.7, 1H), 6.97 – 6.87 (m, 3H); F NMR (376 MHz,
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CDCl3) δ = ꢀ66.85 (s, 1F); C NMR (125 MHz, CDCl3) δ = 186.6, 184.6, 160.3 (d, J = 241.2
Hz), 148.8 (d, J = 15.0 Hz), 142.0 (d, J = 3.1 Hz), 140.1 (d, J = 5.2 Hz), 136.8, 136.5, 135.5 (d, J
= 3.1 Hz), 121.3 (d, J = 4.4 Hz), 115.5 (d, J = 29.4 Hz); HRMS (ESIꢀTOF) cald. for C11H6FNO2
[M + H]+ 204.0461; found 204.0449.
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