Palladium-Catalyzed Sequential Acylation/Cyanation of Aryl Iodides: A Regiospecific Synthesis of 2-Cyanoaryl Ketones

Article abstract of DOI:10.1021/acs.joc.5b02710

A palladium-catalyzed, norbornene-mediated acylation/cyanation reaction of iodobenzene was developed by the use of acyl chlorides as acylation reagents and cuprous cyanide. The reaction gave the 2-cyanoaryl ketones efficiently by using readily available starting materials. (Chemical Equation Presented).

Full text of DOI:10.1021/acs.joc.5b02710

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Article
Palladium-Catalyzed Sequential Acylation/Cyanation of Aryl
Iodides: A Regiospecific Synthesis of 2-Cyanoaryl Ketones
Shanfei Pan, Feifei Wu, Ruicheng Yu, and Wanzhi Chen
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02710 • Publication Date (Web): 25 Jan 2016
Downloaded from http://pubs.acs.org on January 26, 2016
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Palladium-Catalyzed Sequential Acylation/Cyanation of Aryl Iodides: A
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Regiospecific Synthesis of 2-Cyanoaryl Ketones
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Shanfei Pan, Feifei Wu, Ruicheng Yu, and Wanzhi Chen*
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Department of Chemistry, Zhejiang University, Hangzhou 310027, China
E-mail: chenwzz@zju.edu.cn
ABSTRACT: A palladium-catalyzed, norbornene-mediated acylation/cyanation reaction of iodobenzene was developed by the use
of acyl chlorides as acylation reagents and cuprous cyanide. The reaction gave the 2-cyanoaryl ketones efficiently by using readily
available starting materials.
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INTRODUCTION
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Palladium-catalyzed coupling reactions, including Heck, Suzuki, and
Sonogashira couplings using commercially available organic halides or pseudo
halides as the substrates, have become the classical protocols for C-C bond formations
in pharmaceutical and material science.1,2 The protocol allows one C-C bond
formation through one C-halide bond. Although sequential double couplings of
dihaloarene may result in difunctionalization of arenes, the availability of the starting
materials is limited.3 Transition-metal-catalyzed direct C-H bond functionalization
represents one of the most promising procedures to produce C-C or C-heteroatom
bonds.4 The combination of C-halide and C-H activation would result in simultaneous
double functionalization. Such step-economic transformations are urgently needed.5
The Catellani reaction allows the introduction of two different groups in one pot
from aryl halides leading to poly-substituted aromatic compounds and fused aromatic
rings using palladium/norbornene as a catalyst.6 The method has been employed for
the synthesis of cyclic or acyclic benzonitriles, helical alkenes, annulated indole
derivatives, diaryl derivatives etc.7 The Catellani reaction is usually limited to
ortho-alkylation and arylation. Recently, palladium-catalyzed ortho C-H amination of
aryl iodides was reported, providing amination products exclusively at the
ortho-position instead of ipso.8 Such a synthetic strategy has been extended to tandem
C-H amination and C-I alkenylation,9a,9b arylation,9c borylation,9d alkynylation9e,9f etc.
for the synthesis of poly-substituted aromatic compounds. Most recently,
palladium/norbornene catalyzed ortho acylation of aryl iodides was reported leading
to diaryl ketones and aryl alkyl ketones.10
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Aryl ketones are very important compounds widely used in pharmaceutical,
fragrance, dye, and agrochemical industries.11 Traditional synthetic methods of aryl
ketones rely primarily on Friedel-Crafts acylation in the presence of Lewis acids or
Brǿnsted acid12 or the reaction of activated carboxylic acid derivatives with
organometallic reagents.13 Although transition-metal catalyzed direct C-H bond
activation/acylation of aromatic compounds offers an atom economic and
environmentally friendly alternative strategy to aromatic ketones, the regioselective
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acylation is limited due to the directing groups.14,15
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We have recently reported the synthesis of 2-alkynylanilines through
palladium/norbornene catalyzed tandem C-H amination and C-I alkynylation.9f As a
continuation, herein we report a palladium/norbornene catalyzed sequential
acylation/cyanation reaction of aryl iodide with acyl chlorides and cuprous cyanide,
which selectively leads to a series of aromatic ketones in moderate to good yields.
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RESULTS AND DISCUSSION
The three-component reaction of 2-iodotoluene (1a), 4-methyl-benzoyl chloride
(2a) and potassium ferrocyanide [K4Fe(CN)6·3H2O] was initially chosen as the model
reaction to optimize the reaction conditions. The combination of palladium
chloride/tri(2-furyl)phosphine (TFP)/norbornene was used as the catalyst in the
presence of Cs2CO3 in toluene at 100 ˚С. The selected results are summarized in
Table 1. The desired product 3a was obtained in 26 % yield (Table 1, entry 1). Further
investigation of various solvents revealed that the yield was slightly improved when
toluene was replaced by 1,4-dioxane (entry 2). More polar solvents such as DMF and
CH3CN were found to be ineffective for this reaction (entries 3 and 4). The effect of
other monodentate phosphine ligands was examined. Only a trace amount of product
was detected when PPh3 and (3-ClPh)3P were employed, and (C6F5)3P was totally
inactive (entries 7-9). Different palladium catalysts, including Pd(ІІ) and Pd(0)
catalysts, were surveyed, and it was found that Pd(OAc)2, [Pd(C3H5)Cl]2, and
Pd2(dba)3·CHCl3 cannot catalyze this reaction (entries 10 and 12). In addition, the
variation of the amount of norbornene did not show a significant influence on the
formation of the target product. Finally, we screened a series of cyanation reagents,
including CuCN, TMSCN, and Zn(CN)2. The yield of the target product was
dramatically increased to 72% when CuCN was used (entry 13). Surprisingly,
employment of TMSCN and Zn(CN)2 did not result in any cyanation products (entries
14 and 15). We found that water is essential to the acylation reaction, and no desired
product was observed when the reaction was conducted in strictly anhydrous dioxane
(entry 16). The reaction did not occur below 80 °C, and higher temperature than
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100 °C resulted in decrease of the yield (entries 17 and 18). The screening of bases
showed that K2CO3 and Na2CO3 are not effective (entries 19-20). Further
investigation revealed that none of the product was detected without palladium
catalyst (entry 21).
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Table 1. Optimization of the reaction conditionsa
yield
(%)
entry
[Pd]
ligand
solvent
[CN]
x
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2
3
4
5
6
7
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
TFP
TFP
TFP
TFP
TFP
TFP
PPh3
toluene K4Fe(CN)6·3H2Ob
dioxane K4Fe(CN)6·3H2Ob
2
2
2
2
1
3
2
26
30
DMF
K4Fe(CN)6·3H2Ob
trace
trace
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CH3CN K4Fe(CN)6·3H2Ob
dioxane K4Fe(CN)6·3H2Ob
dioxane K4Fe(CN)6·3H2Ob
dioxane K4Fe(CN)6·3H2Ob
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trace
(3-ClC6H4)3
P
8
PdCl2
dioxane K4Fe(CN)6·3H2Ob
2
trace
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PdCl2
(C6F5)3P
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
TFP
dioxane K4Fe(CN)6·3H2Ob
dioxane K4Fe(CN)6·3H2Ob
dioxane K4Fe(CN)6·3H2Ob
dioxane K4Fe(CN)6·3H2Ob
2
2
2
2
2
2
2
2
2
2
2
2
2
N.D.
trace
trace
trace
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10
11
Pd(OAc)2
[Pd(C3H5)Cl]2
12 Pd2(dba)3·CHCl3
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PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
PdCl2
--
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
CuCNc
TMSCNd
N.D.
N.D.
N.D.
N.D.
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e
Zn(CN)2
CuCNf
CuCNg
CuCNh
CuCNi
CuCNj
CuCN
trace
N.D.
N.D.
a
1a (0.3 mmol, 1.0 equiv), 2a (0.9 mmol, 3.0 equiv), CuCN (0.36 mmol, 1.2 equiv), Pd (10 mol %), ligand (20
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mol %), norbornene (0.6 mmol, 2.0 equiv), Cs2CO3 (0.9 mmol, 3.0 equiv), H2O (0.6 mmol, 2.0 equiv), solvent (3.0
mL), 100 ˚С, 12 h. b 4 equiv; c 1.2 equiv; d TMSCN (2 equiv), CsF (3 equiv); e Zn(CN)2 (2 equiv); f without H2O; g
80 °С; h 120 °С; i K2CO3 (3.0 equiv); j Na2CO3 (3.0 equiv).
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Under the optimized reaction conditions, the scope of aryl iodides was examined
(Table 2). Generally, aryl iodides containing electron-donating and
electron-withdrawing groups were both tolerated under the reaction conditions,
providing the corresponding diaryl ketones 3a-3k in moderate to good yields (Table
2). The inherent electronic nature of aryl iodides plays an important effect on this
reaction. Aryl iodides 1a and 1b, bearing electronic-donating ortho-substitutents,
reacted smoothly, giving 3a and 3b in ca. 70% yields. However, when
2-chloroiodobenzene was reacted with 4-methylbenzoyl chloride 2a and CuCN, low
yield of the desired product 3d was obtained under the standard conditions. Notably,
the substrate 1c containing a ortho-fluoride substitutent could work well in this
transformation, and the corresponding product 3c was isolated in 62% yield.
1-Iodonaphthalene also worked well, providing the diaryl ketone 3e in good yield
(76%). When aryl iodides with strong electron-withdrawing groups were employed in
the reaction, the desired products could not be obtained at all. Instead, the
cross-coupling products of two molecules of aryl iodides were isolated.
Homocoupling products, diethyl 2'-cyano-[1,1'-biphenyl]-2,3'-dicarboxylate 3g and
2',3-dinitro-[1,1'-biphenyl]-2-carbonitrile 3h were isolated in 93% and 75% yields,
respectively. This result might indicate that the reaction is strongly influenced by the
substituents of iodobenzene. Aryl iodides with strong electron-withdrawing groups are
more reactive than acid anhydrous with respect to oxidative addition towards
palladium. For aryl iodides without ortho substituents, diketones 3j and 3k were
obtained in ca. 40% yields under the standard conditions. Unlike 2-iodotoluene, the
reaction of 3-iodotoluene with 4-methylbenzoyl chloride and CuCN gave a
complicated mixture. Under the similar conditions, 2-bromotoluene and
2-chlorotoluene were not reactive probably because C-Br bond and C-Cl bonds are
more inert than C-I bond.
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The scope of this reaction with a number of functionalized benzoyl chlorides 2
was subsequently explored. Ortho-, para-, and meta-substituted benzoyl chlorides
were all good coupling partners in these reactions, and target ketones were afforded in
moderate to good yields (Table 3, 4a-4p). Generally, benzoyl chlorides with
ortho-substituted groups work better in this reaction than the ones with
para-substituted groups.16 The reactions of 2-methylbenzoyl chloride and
3-methylbenzoyl chloride with 2-iodotoluene yielded the corresponding ketons 4b
and 4c almost quantitatively. Similarly, 2-methoxybenzoyl chloride also afforded 4d
in 86% yield. The structure of 4d was confirmed by X-ray single-crystal diffraction,
and the molecular structure was given in supporting information. For benzoyl
chlorides bearing electron-withdrawing ortho-substituents, the yields of the
corresponding products 4f and 4h are much lower. Benzoyl chlorides having either
electron-donating or electron-withdrawing para-substituents showed relatively lower
activities than unsubstituted benzoyl chloride, and their corresponding products 4e, 4g,
and 4i were obtained in moderate yields. When 2,4,6-trimethylbenzoyl chloride was
applied, 4m was obtained in 64% yield, illustrating that the steric hindrance did not
play a critical role in the reaction. 2-Furoyl chloride is not a suitable substrate, and no
desired furoyl derivatives were obtained. The acetylation reaction was not successful
in the cases of acetyl chloride or cyclohexanecarbonyl chloride. However, we were
able to isolate 2-acetyl-6-methylbenzonitrile 4q in 27% yield when acetic anhydride
was applied under anhydrous conditions.
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Table 2. The substrate scope of aryl iodide a
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a Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2a (3.0 equiv), CuCN (1.2 equiv), PdCl2 (10 mol %), TFP (20 mol
%), norbornene (2.0 equiv), Cs2CO3 (3.0 equiv), H2O (2.0 equiv), 1,4-dioxane (3.0 ml), 100 ˚С, 12h.
Table 3. The substrates scope of benzoyl chloride a
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a Reaction conditions: 1a (0.3 mmol, 1.0 equiv), 2a (3.0 equiv), CuCN (1.2 equiv), PdCl2 (10 mol %), TFP (20 mol
%), norbornene (2.0 equiv), Cs2CO3 (3.0 equiv), H2O (2.0 equiv), 1,4-dioxane (3 ml), 100 ˚С, 12 h; [b] acetic
anhydride (5 equiv).
It is noteworthy that this sequential acylation/cyanation can be performed on the
gram scale, and the loading of palladium catalyst can be lowered to 5 mol % (eq 1).
We used 1-iodonaphthalene and 2-methylbenzoyl chloride as the substrates. The
reaction of 1-iodonaphthalene (3 mmol, 0.761 g) and 2-methylbenzoyl chloride (9
mmol, 1.386 g) was performed in the presence of 0.15 mmol of palladium, 0.3 mmol
of ligand, 6 mmol of H2O and 9 mmol of Cs2CO3 at 100 °C. The desired product 4p
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was isolated in 73% yield within 36 h.
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Scheme 1. Possible catalytic cycle
To gain mechanistic insights of this reaction, two control experiments were
performed and the conversion was calculated according to the isolated products
[eqs 2-6]. When benzoic anhydride was employed other than benzoyl chloride
under anhydrous conditions, 4a was isolated in up to 70 % yield (eq 2). When
benzoyl chloride and CuCN were replaced by benzoyl cyanide, the reaction did not
occur under the standard reaction conditions (eq 3). Further addition of CuCN did
not initiate the reaction of 2-iodotoluene (eq 4). We also found that benzoylation of
2-iodotuluene and benzonitrile with benzoyl chloride was not successful under the
present reaction conditions (eqs 5 and 6). In the eaction of 2-iodotoluene with
benzoyl chlorides, only trace amount of expected 3-methylphenylphenone was
observed,
and
a
significant
amount
of
di(o-tolyl)
ether,
2-(o-tolyl)bicyclo[2.2.1]hept-2-ene,
5,9-dimethyl-1,2,3,4,4a,12b-hexahydro-1,4-methanotriphenylene were formed.
These experiments may indicate that the acylation/cyanation product is not formed
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via acylation of benzonitrile.
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Based on the above experimental results and previous reports,6-10 a plausible
mechanism is proposed in Scheme 1. The reaction is initiated by oxidative addition
of substrate 1 to Pd(0) complex to generate aryl-Pd(II) complex I. A
five-membered palladacycle intermediate III would be produced through
norbornene insertion to the C-Pd bond and subsequent intramolecular C-H
activation reaction via intermediate II. This palladacycle undergoes oxidative
addition with acid anhydride, in situ generated from hydrolysis of benzoyl chloride.
The palladium(IV) species IV undergoes a reductive elimination to give species V.
After de-insertion of norbornene from V, a new aryl-Pd(II) species is formed with
norbornene exclusion. At last, intermediate VII, formed by the transmetallation of
species VI with CuCN, yield the desired product 3 or 4 and regenerate Pd(0)
catalyst after reductive elimination.
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CONCLUSION
In conclusion, a palladium-catalyzed site-selective C-H bond acylation/C-I
acyanation of aryl iodides with commercially available benzoyl choloride was
reported. The reaction provides a straightforward and practical way to prepare a
series of ortho-cyano aryl ketones in good to high yields. The development of
further applications of this transformation is in progress in our laboratory.
EXPERIMENTAL SECTION
General procedure for the sequential acylation/cyanation reaction between
aryl iodides 1, acyl chlorides 2, and CuCN. To a 25 mL of Schlenk tube equipped
with a Teflon-coated magnetic stir bar was charged with aryl iodide (0.3 mmol, 1.0
equiv), benzoyl chloride (126 mg, 0.9 mmol, 3.0 equiv), CuCN (32.2 mg, 0.36 mmol,
1.1 equiv), PdCl2 (5.3 mg, 0.03 mmol, 10 mol %), TFP (13.9 mg, 0.06 mmol, 20
mol %), Cs2CO3 (293 mg, 0.9 mmol, 3.0 equiv), norbornene (56 mg, 0.6 mmol, 2.0
equiv), H2O (10.8 mg, 0.6 mmol, 2.0 equiv) and 1,4-dioxane (3.0 mL). The resulting
light yellow suspension was stirred at room temperature for 5 min under N2, and then
heated to 100 °C overnight. Upon completion of the reaction as monitored by TLC,
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the reaction was allowed to cool to room temperature, diluted with ethyl acetate (5 ml)
and water (15 mL), and extracted with ethyl acetate (10 mL x 3). The organic phase
was collected and washed with brine, dried over anhydrous Na2SO4, then filtered and
concentrated. The crude residue was purified by flash column chromatography on
silica gel using petroleum ether/ethyl acetate as eluent to give the corresponding
products.
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2-methyl-6-(4-methylbenzoyl)benzonitrile (3a): Light yellow oil (50 mg, 72%
yield). 1H NMR (400 MHz, CDCl3): δ 2.44 (s, 3H), 2.64 (s, 3H), 7.29 (d, J = 7.6 Hz,
2H), 7.41 (dd, J = 0.8, 7.6 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H),
13
7.72 (d, J = 8.0 Hz, 2H). C{H} NMR (100 MHz, CDCl3): δ 20.8, 21.8, 111.8,
116.1, 127.0, 129.4, 130.6, 131.6, 132.3, 133.5, 142.5, 143.7, 144.9, 193.9. HR MS
(TOF MS, EI+) m/z calcd. for C16H13NO: 235.0997; found: 235.0993.
2-methoxy-6-(4-methylbenzoyl)benzonitrile (3b): Light yellow solid (45 mg, 60%
yield); melting point: 101-103 ˚С. 1H NMR (400 MHz, CDCl3): δ 2.44 (s, 3H), 3.99 (s,
3H), 7.12-7.16 (m, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.59-7.63 (m, 1H), 7.72 (d, J = 8.4
13
Hz, 2H). C{H} NMR (100 MHz, CDCl3): δ 21.8, 56.5, 100.7, 113.3, 114.3, 121.3,
129.4, 130.5, 133.4, 133.5, 143.9, 145.1, 162.1, 193.4. HR MS (TOF MS, EI+) m/z
calcd. for C16H13NO2: 251.0946; found: 251.0944.
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2-fluoro-6-(4-methylbenzoyl)benzonitrile (3c): Yellow oil (44 mg, 62% yield). H
NMR (400 MHz, CDCl3) δ 2.46 (s, 3H), 7.31 (d, J = 7.6 Hz, 2H), 7.39-7.44 (m, 2H),
7.67-7.73 (m, 3H). 13C{H} NMR (100 MHz, CDCl3) δ 21.9, 101.0 (d, 2JC-F = 16.2 Hz),
111.9, 118.6 (d, 2JC-F = 19.5 Hz), 125.5 (d, 3JC-F = 3.9 Hz), 129.6, 130.5, 132.9, 134.1
(d, 3JC-F = 8.8 Hz), 143.6, 145.5, 164.0 (d, 1JC-F = 260.0 Hz), 192.1 (d, 4JC-F = 1.9 Hz).
HR MS (TOF MS, EI+) m/z calcd. for C15H10FNO: 239.0746; found: 239.0748.
2-chloro-6-(4-methylbenzoyl)benzonitrile (3d): White solid (33 mg, 43% yield);
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melting point: 134-136 ˚С. H NMR (400 MHz, CDCl3): δ 2.45 (s, 3H), 7.31 (d, J =
8.0 Hz, 2H), 7.51 (dd, J = 1.2, 7.6 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.68-7.72 (m,
3H). 13C{H} NMR (100 MHz, CDCl3): δ 21.9, 112.4, 114.0, 127.5, 129.6, 130.6,
131.8, 132.8, 132.9, 138.8, 144.4, 145.6, 192.4. HR MS (TOF MS, EI+) m/z calcd.
for C15H10ClNO: 255.0451; found: 255.0455.
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2-(4-methylbenzoyl)-1-naphthonitrile (3e): Light yellow oil (62 mg, 76% yield). H
NMR (400 MHz, CDCl3) δ 2.44 (s, 3H), 7.30 (d, J = 8.0 Hz, 2H), 7.64 (d, J = 8.4 Hz,
1H), 7.69-7.79 (m, 4H), 7.99 (d, J = 8.0 Hz, 1H), 8.14 (d, J = 8.4 Hz, 1H), 8.37 (d, J =
8.0 Hz, 1H). 13C{H} NMR (100 MHz, CDCl3) δ 21.9, 109.3, 115.8, 124.9, 126.1,
128.7, 128.8, 129.5, 130.7, 132.5, 132.6, 133.5, 133.6, 142.4, 145.2, 194.2. HR MS
(TOF MS, EI+) m/z calcd. for C19H13NO: 271.0997; found: 271.0994.
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2,4-dimethyl-6-(4-methylbenzoyl)benzonitrile (3f): Yellow oil (41 mg, 55% yield).
1H NMR (400 MHz, CDCl3) δ 2.42 (s, 3H), 2.44 (s, 3H), 2.59 (s, 3H), 7.21 (s, 1H),
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7.28 (s, 1H), 7.30 (d, J = 0.8 Hz, 2H), 7.71 (d, J = 8.4 Hz, 2H). C{H} NMR (100
MHz, CDCl3) δ 20.7, 21.7, 21.8, 108.8, 116.4, 127.7, 129.4, 130.5, 132.9, 133.7,
142.6, 142.7, 143.4, 144.9, 194.2. HR MS (TOF MS, EI+) m/z calcd. for C17H15NO:
249.1154; found: 249.1156.
dimethyl 2'-cyano-[1,1'-biphenyl]-2,3'-dicarboxylate (3g): Yellow oil (41 mg, 93%
yield). 1H NMR (400 MHz, CDCl3) δ 3.71 (s, 3H), 4.00 (s, 3H), 7.31 (dd, J = 1.2, 7.6
Hz, 1H), 7.52-7.58 (m, 2H), 7.62-7.70 (m, 2H), 7.12-7.15 (m, 2H). 13C{H} NMR (100
MHz, CDCl3) δ 52.2, 52.9, 112.4, 116.1, 129.1, 129.3, 129.7, 130.9, 131.0, 131.5,
132.4, 132.6, 133.1, 139.5, 148.4, 164.9, 166.6. HR MS (TOF MS, EI+) m/z calcd.
for C17H13NO4: 295.0845; found: 295.0841.
2',3-dinitro-[1,1'-biphenyl]-2-carbonitrile (3h): Yellow solid (30 mg, 75% yield);
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melting point: 188-190 ˚С. H NMR (400 MHz, CDCl3): δ 7.45 (dd, J = 1.4, 7.8 Hz,
1H), 7.69-7.76 (m, 2H), 7.80-7.89 (m, 2H), 8.30 (dd, J = 1.0, 8.2 Hz, 1H), 8.37 (dd, J
13
= 1.2, 8.4 Hz, 1H). C{H} NMR (100 MHz, CDCl3) δ 107.6, 113.3, 124.8, 125.6,
131.0, 131.8, 131.9, 133.1, 134.1, 134.2, 146.2, 147.4, 149.3. HR MS (TOF MS, EI+)
m/z calcd. for C13H7N3O4: 269.0437; found:269.0432.
2-chloro-6-(2-methylbenzoyl)benzonitrile (3i): Yellow solid (59 mg, 77% yield);
melting point: 110-112 ˚С. 1H NMR (400 MHz, CDCl3): δ 2.52 (s, 3H), 7.23-7.31 (m,
2H), 7.35 (d, J = 7.6, 1H), 7.45-7.50 (m, 2H), 7.59 (t, J = 8.0 Hz, 1H), 7.70 (dd, J =
1.2, 8.0 Hz, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 20.9, 112.5, 113.9, 125.6, 128.6,
130.8, 132.0, 132.4, 132.5, 132.8, 135.7, 139.3, 139.6, 144.4, 194.5. HR MS (TOF
MS, EI+) m/z calcd. for C15H10ClNO: 255.0451; found: 255.0456.
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2,6-bis(4-methylbenzoyl)benzonitrile (3j): Light yellow solid (41 mg, 40% yield);
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melting point: 164-166 ˚С. H NMR (400 MHz, CDCl3): δ 2.45 (s, 6H), 7.31 (d, J =
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8.0 Hz, 4H), 7.71-7.79 (m, 7H). 13C{H} NMR (100 MHz, CDCl3): δ 21.9, 110.0,
114.7, 129.6, 130.6, 131.5, 133.1, 143.9, 145.5, 193.2. HR MS (TOF MS, EI+) m/z
calcd. for C23H17NO2: 339.1259; found:339.1263.
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4-methoxy-2,6-bis(4-methylbenzoyl)benzonitrile (3k): White solid (42 mg, 38%
yield); melting point: 166-168 ˚С. 1H NMR (400 MHz, CDCl3): δ 2.44 (s, 6H), 3.91 (s,
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3H), 7.18 (s, 2H), 7.30 (d, J = 8.0 Hz, 4H), 7.75 (d, J = 8.0 Hz, 4H). C{H} NMR
(100 MHz, CDCl3): δ 21.9, 56.2, 101.3, 114.9, 116.2, 129.6, 130.6, 132.9, 145.6,
145.8, 161.6, 193.1. HR MS (TOF MS, EI+) m/z calcd. for C24H19NO3: 369.1365;
found: 369.1362.
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2-benzoyl-6-methylbenzonitrile (4a): Light yellow oil (43 mg, 65% yield). H NMR
(400 MHz, CDCl3): δ 2.65 (s, 3H), 7.43 (dd, J = 1.2, 7.2 Hz, 1H), 7.48-7.58 (m, 4H),
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7.62-7.66 (m, 1H), 7.81 (m, 2H). C{H} NMR (100 MHz, CDCl3): δ 20.8, 111.8,
116.0, 127.2, 128.6, 130.4, 131.6, 132.6, 133.8, 136.1, 142.1, 143.8, 194.2. HR MS
(TOF MS, EI+) m/z calcd. for C15H11NO: 221.0841; found: 221.0843.
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2-methyl-6-(2-methylbenzoyl)benzonitrile (4b): Yellow oil (69 mg, 98% yield). H NMR
(400 MHz, CDCl3): δ 2.46 (s, 3H), 2.62 (s, 3H), 7.21 (t, J = 7.4 Hz, 1H), 7.27-7.31 (m,
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2H), 7.35-7.37 (m, 1H), 7.42 (td, J = 7.6, 1.6 Hz, 1H), 7.48-7.52 (m, 2H). C{H}
NMR (100 MHz, CDCl3): δ 20.7, 20.9, 111.9, 116.1, 125.4, 128.3, 130.5, 131.6,
131.7, 131.9, 133.2, 136.6, 139.1, 142.4, 144.1, 196.1. HR MS (TOF MS, EI+) m/z
calcd. for C16H13NO: 235.0997; found: 235.0994.
2-methyl-6-(3-methylbenzoyl)benzonitrile (4c): Orange yellow oil (70 mg, 99%
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yield). H NMR (400 MHz, CDCl3) δ 2.41 (s, 3H), 2.64 (s, 3H), 7.35-7.45 (m, 3H),
7.50-7.58 (m, 3H), 7.66 (s, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 20.8, 21.4, 111.8,
116.1, 127.1, 127.8, 128.5, 130.7, 131.6, 132.5, 134.7, 136.1, 138.6, 142.3, 143.7,
194.4. HR MS (TOF MS, EI+) m/z calcd. for C16H13NO: 235.0997; found: 235.0992.
2-(2-methoxybenzoyl)-6-methylbenzonitrile (4d): Light yellow oil (65 mg, 86%
yield). 1H NMR (400 MHz, CDCl3): δ 2.63 (s, 3H), 3.65 (s, 3H), 6,97 (d, J = 8.4 Hz,
1H), 7.05-7.09 (m, 1H), 7.39-7.58 (m, 5H). 13C{H} NMR (100 MHz, CDCl3): δ 20.8,
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55.6, 111.1, 111.7, 116.3, 120.9, 127.3, 127.6, 131.1, 131.5, 132.7, 134.0, 143.0,
143.5, 158.5, 194.0. HR MS (TOF MS, EI+) m/z calcd. for C16H13NO2: 251.0946;
found: 251.0948.
2-(4-methoxybenzoyl)-6-methylbenzonitrile (4e): Yellow oil (43 mg, 58% yield).
1H NMR (400 MHz, CDCl3): δ 2.64 (s, 3H), 3.89 (s, 3H), 6.94-6.98 (m, 2H), 7.40 (d,
J = 7.6 Hz, 1H), 7.49 (d, J = 7.2 Hz, 1H), 7.55 (t, J = 7.6 Hz, 1H), 7.79-7.83 (m, 2H).
13C{H} NMR (100 MHz, CDCl3) δ 20.8, 55.6, 111.7, 113.9, 116.1, 126.7, 128.9,
131.6, 132.0, 132.9, 142.9, 143.6, 164.2, 192.9. HR MS (TOF MS, EI+) m/z calcd.
for C16H13NO2: 251.0946; found: 251.0949.
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2-(2-fluorobenzoyl)-6-methylbenzonitrile (4f): Light yellow oil (47 mg, 66% yield).
1H NMR (400 MHz, CDCl3): δ 2.65 (s, 3H), 7.12-7.17 (m, 1H), 7.31 (td, J = 1.2, 7.6
Hz, 1H), 7.46-7.48 (m, 1H), 7.52-7,55 (m, 2H), 7.57-7.63 (m, 1H), 7.73 (td, J = 1.6,
2
7.6 Hz, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 20.8, 111.2, 116.0, 116.5 (d, JC-F
=
21.7 Hz), 124.7 (d, 3JC-F = 3.8 Hz), 125.6 (d, 2JC-F = 13.2 Hz), 127.6 (d, 4JC-F = 2.1 Hz),
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131.5 (d, JC-F = 2.0 Hz), 131.8, 133.4, 135.0 (d, JC-F = 8.4 Hz), 142.0, 143.9, 161.0
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(d, JC-F = 253.1 Hz), 191.2. HR MS (TOF MS, EI+) m/z calcd. for C15H10FNO:
239.0746; found: 239.0745.
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2-(4-fluorobenzoyl)-6-methylbenzonitrile (4g): Yellow oil (24 mg, 33% yield). H
NMR (400 MHz, CDCl3): δ 2.65 (s, 3H), 7.15-7.20 (m, 2H), 7.42 (d, J = 7.6 Hz, 1H),
7.52-7.60 (m, 2H), 7.84-7.88 (m, 2H). 13C{H} NMR (100 MHz, CDCl3): δ 20.8,
111.8, 115.9 (d, 2JC-F = 22.2 Hz), 115.9, 126.9, 131.7, 132.5 (d, 3JC-F = 3.0 Hz), 132.6,
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133.0 (d, JC-F = 9.9 Hz), 141.9, 143.9, 166.2 (d, JC-F = 255.9 Hz), 192.7. HR MS
(TOF MS, EI+) m/z calcd. for C15H10FNO: 239.0746; found: 239.0746.
2-(2-chlorobenzoyl)-6-methylbenzonitrile (4h): Light yellow solid (35 mg, 46%
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yield); melting point: 108-110 °C. H NMR (400 MHz, CDCl3): δ 2.66 (s, 3H),
7.39-7.57 (m, 7H). 13C{H} NMR (100 MHz, CDCl3): δ 20.9, 111.7, 116.0, 127.1,
128.8, 130.4, 130.4, 131.8, 132.2, 132.5, 134.1, 137.3, 140.4, 144.6, 193.2; HR MS
(TOF MS, EI+) m/z calcd. for C15H10ClNO: 255.0451; found: 255.0448.
2-(4-chlorobenzoyl)-6-methylbenzonitrile (4i): Light yellow solid (32 mg, 42%
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yield); melting point: 158-160 ˚С; H NMR (400 MHz, CDCl3): δ 2.65 (s, 3H), 7.41
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(d, J = 7.2 Hz, 1H), 7.48 (d, J = 8.4 Hz, 2H), 7.52-7.59 (m, 2H), 7.76 (d, J = 8.4 Hz,
2H). 13C{H} NMR (100 MHz, CDCl3): δ 20.8, 111.8, 115.9, 127.0, 129.1, 131.7,
132.7, 134.4, 140.5, 141.6, 144.0, 193.0. HR MS (TOF MS, EI+) m/z calcd. for
C15H10ClNO: 255.0451; found: 255.0450.
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2-(3-fluorobenzoyl)-6-methylbenzonitrile (4j): Light yellow oil (40 mg, 57% yield).
1H NMR (400 MHz, CDCl3): δ 2.66 (s, 3H), 7.32-7.37 (m, 1H), 7.42 -7.60 (m, 6H).
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13C{H} NMR (100 MHz, CDCl3): δ 20.8, 111.9, 115.9, 116.8 (d, JC-F = 22.7 Hz),
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120.9 (d, JC-F = 20.9 Hz), 126.3 (d, JC-F = 2.5 Hz), 127.2, 130.3 (d, JC-F = 6.4 Hz),
131.7, 132.9, 138.1 (d, 3JC-F = 6.4 Hz), 141.4, 144.1, 162.7 (d, 1JC-F = 247.5 Hz), 192.9
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(d, JC-F = 3.2 Hz). HR MS (TOF MS, EI+) m/z calcd. for C15H10FNO: 239.0746;
found: 239.0749.
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2-benzoyl-6-methoxybenzonitrile (4k): Yellow oil (49 mg, 70% yield). H NMR
(400 MHz, CDCl3): δ 4.01 (s, 3H), 7.15-7.18 (m, 2H), 7.47-7.51 (m, 2H), 7.60-7.65
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(m, 2H), 7.81-7.83 (m, 2H). C{H} NMR (100 MHz, CDCl3): δ 56.5, 100.8, 113.5,
114.2, 121.4, 128.6, 130.4, 133.5, 133.9, 135.9, 143.5, 162.1, 193.7. HR MS (TOF
MS, EI+) m/z calcd. for C15H11NO2: 237.0790; found: 237.0788.
2-methoxy-6-(2-methylbenzoyl)benzonitrile (4l): Yellow oil (73 mg, 97% yield). 1H
NMR (400 MHz, CDCl3): δ 2.49 (s, 3H), 3.99 (s, 3H), 7.12 (dd, J = 0.8, 7.6 Hz, 1H),
7.17 (dd, J = 0.4, 8.4 Hz, 1H), 7.23 (t, J = 7.6 Hz, 1H), 7.30-7.33 (m, 2H), 7.44 (td, J
= 1.2, 7.2 Hz, 1H), 7.56-7.60 (m, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 20.8, 56.5,
100.8, 114.2, 122.5, 125.4, 130.7, 131.8, 132.0, 133.5, 136.5, 139.2, 143.8, 162.4,
195.6. HR MS (TOF MS, EI+) m/z calcd. for C16H13NO2: 251.0946; found: 251.0946.
2-methyl-6-(2,4,6-trimethylbenzoyl)benzonitrile (4m): White solid (50 mg, 64%
yield); melting point: 192-194 ˚С. 1H NMR (400 MHz, CDCl3): δ 2.10 (s, 6H), 2.33 (s,
3H), 2.67 (s, 3H), 6.90 (s, 2H), 7.35 (dd, J = 0.6, 7.6 Hz, 1H), 7.47 (t, J = 7.6 Hz, 1H),
13
7.54 (dd, J = 0.6, 7.6 Hz, 2H). C{H} NMR (100 MHz, CDCl3): δ 19.6, 20.9, 21.2,
111.2, 116.4, 128.7, 129.1, 132.0, 134.4, 134.8, 135.8, 139.5, 140.4, 145.1, 198.1. HR
MS (TOF MS, EI+) m/z calcd. for C18H17NO: 263.1310; found: 263.1311.
2-(3,5-dimethylbenzoyl)-6-methylbenzonitrile (4n): Light yellow oil (48 mg, 65%
yield). 1H NMR (400 MHz, CDCl3): δ 2.36 (d, J = 4.0 Hz, 6H), 2.65 (s, 3H), 7.26 (s,
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1H), 7.39-7.40 (m, 3H), 7.49-7.57 (m, 2H): C{H} NMR (100 MHz, CDCl3) δ 20.8,
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21.2, 111.8, 116.0, 127.0, 128.2, 131.5, 132.3, 135.6, 136.2, 138.3, 142.6, 143.7,
194.6. HR MS (TOF MS, EI+) m/z calcd. for C17H15NO: 249.1154; found: 249.1158.
2-(2-naphthoyl)-6-methylbenzonitrile (4o): Light yellow solid (57 mg, 70% yield);
melting point: 184-186 ˚С. 1H NMR (400 MHz, CDCl3): δ 2.67 (s, 3H), 7.48-7.65 (m,
5H), 7.88-8.01 (m, 4H), 8.20 (s, 1H). 13C{H} NMR (100 MHz, CDCl3): δ 20.9, 111.9,
116.1, 125.1, 127.0, 127.2, 127.9, 128.8, 129.1, 129.7, 131.6, 132.2, 132.5, 133.1,
133.4, 135.9, 142.4, 143.9, 194.2. HR MS (TOF MS, EI+) m/z calcd. for C19H13NO:
271.0997; found: 271.0998.
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2-(2-methylbenzoyl)-1-naphthonitrile (4p): Yellow oil (72 mg, 89% yield). H
NMR (400 MHz, CDCl3): δ 2.54 (s, 3H), 7.22-7.25 (m, 1H), 7.32-7.37 (m, 2H),
7.45-7.49 (m, 1H), 7.64 (d, J = 8.4 Hz, 1H), 7.69-7.79 (m, 2H), 7.98 (d, J = 7.2 Hz,
13
1H), 8.11 (d, J = 8.4 Hz, 1H), 8.40 (d, J = 8.8 Hz, 1H). C{H} NMR (100 MHz,
CDCl3): δ 20.9, 109.9, 115.6, 125.5, 126.4, 128.6, 129.1, 130.9, 131.8, 132.2, 132.6,
133.9, 136.6, 139.3, 142.2, 196.3. HR MS (TOF MS, EI+) m/z calcd. for C19H13NO:
271.0997; found: 271.0997.
2-acetyl-6-methylbenzonitrile (4q)[17]: White solid (13 mg, 27% yield); melting
point: 94-96 °С. 1H NMR (400 MHz, CDCl3): δ 2.63 (s, 3H), 2.68 (s, 3H), 7.52 (d, J =
13
7.2 Hz, 1H), 7.57 (t, J = 7.6 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H). C{H} NMR (100
MHz, CDCl3): δ 20.9, 28.0, 110.8, 116.8, 127.1, 131.9, 133.8, 140.6, 144.6, 196.7.
AUTHOR INFORMATION
Corresponding Author
*E-mail: chenwzz@zju.edu.cn
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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Financial supports from National Natural Science Foundation of China (Nos. 21572203 and J1210042) and
Zhejiang Provincial Natural Science Foundation of China (No. LZ16B020001) are gratefully acknowledged.
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Supporting Information. Spectra of H NMR, 13C NMR for new products and crystallographic data for 4d. This
material is available free of charge via the Internet at http://pubs.acs.org.
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