Carbon-Carbon Bond Formation of Trifluoroacetyl Amides with Grignard Reagents via C(O)-CF3 Bond Cleavage

Article abstract of DOI:10.1021/acs.joc.9b00583

The reaction of trifluoroacetyl amides with Grignard reagent for the substitution of CF₃ group with various alkyl or aryl groups is described. A variety of aryl, quinolin-8-yl, and (hetero)alkyl functional groups as well as F, Cl, and Br atoms are well tolerated. These moisture-stable and easily available trifluoroacetyl amides can be conveniently obtained and used as new versatile precursors for isocyanates. The control experiments show that the reaction proceeds via an isocyanate intermediate and/or alkoxide/amide dual anionic intermediate.

Full text of DOI:10.1021/acs.joc.9b00583

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Article
Carbon-Carbon Bond Formation of Trifluoroacetyl Amides
with Grignard Reagents via C(O)-CF3 Bond Cleavage
Longzhi Zhu, Liyuan Le, Mingpan Yan, Chak-Tong Au, Renhua Qiu, and Nobuaki Kambe
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00583 • Publication Date (Web): 05 Apr 2019
Downloaded from http://pubs.acs.org on April 6, 2019
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Carbon−Carbon Bond Formation of Trifluoroacetyl Amides
with Grignard Reagents via C(O)−CF3 Bond Cleavage
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Longzhi Zhu,† Liyuan Le,† Mingpan Yan,† Chak-Tong Au,‡ Renhua Qiu*,† Nobuaki
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Kambe*,†,§
†State Key Laboratory of Chemo/Biosensing and Chemometrics, College of Chemistry and Chemical
Engineering, Hunan University, Changsha, 410082, P. R. China
§Department of Applied Chemistry, Graduate School of Engineering, Osaka University, Suita, Osaka
565-0871, Japan
‡College of Chemistry and Chemical Engineering, Hunan Institute of Engineering, Xiangtan, 411104,
P.R. China
renhuaqiu@hnu.edu.cn (R.Q.), kambe@chem.eng.osaka-u.ac.jp (N.K.).
RECEIVED DATE (to be automatically inserted after your manuscript is accepted if
required according to the journal that you are submitting your paper to)
ABSTRACT
The reaction of trifluoroacetyl amides with Grignard reagent for the substitution of CF3
group with various alkyl or aryl groups is described. A variety of aryl, quinolin-8-yl, and
(hetero)alkyl functional groups as well as F, Cl, and Br atoms are well tolerated. These
moisture-stable and easily available trifluoroacetyl amides can be conveniently obtained
and used as new versatile precursors for isocyanates. The control experiments show that
the reaction proceeds via an isocyanate intermediate and/or alkoxide/amide dual anionic
intermediate.
INTRODUCTION
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As backbone of proteins, amide skeleton has a crucial role in biochemistry.1 It is also a
common functional group in pharmaceuticals2 and materials.3 With high accessibility and
abundant properties,4 amides have attracted much attention in terms of their manipulation
and utilization. Amides are used as precursors to provide aryl/alkyl carbonyl groups for the
formation of ketones,5 amides,6 esters,7 aromatic hydrocarbons8 and others9 via C(O)−N
bond cleavage.10,11 Also, through the cleavage of C(O)−C12 or C(O)−H13 bond, amides
provide aryl/alkyl amino units for complex amide synthesis. However, comparing with the
route of C(O)−N bond cleavage, the transformation through bond cleavage of these kinds,
especially C(O)−C bond, are usually difficult because of the inherent strength of the
C−C(O) bond.14
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Scheme 1. Transformation of Trifluoroacetyl Amides via C(O)−CF3 Bond Cleavage
By having the CX3 group (X = I, Br, Cl, F) eliminated, trihaloacetamide has emerged as
a powerful precursor for the provision of aryl/alkyl amino units.15-18 In contrast to the non-
fluorine CX3 analogues, trifluoroacetyl amide compounds can be easily isolated and are
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much more stable in open air. However, their application in producing CF3 and the related
amino coupling reagents are not well studied (Scheme 1).19 It is probably due to the inert
C(O)−CF3 bond which is hard to activate in comparison with the non-fluorine C(CX3)−C(O)
bonds. There are many examples on the formation of C(O)−N20 and C(O)−O21 bond
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making use of amino units generated from trifluoroacetyl amides released in the cleavage
of C(O)−CF3 bond (Scheme 1a). As for C(O)−C bond formation after C(O)−CF3 bond
cleavage, a highly active reagent is needed (Scheme 1b).12a,22 Smith and coworkers
performed a pioneering work on the intermolecular C(O)−C bond formation of
trifluoroacetanilides with organolithium reagents that led to the generation of anilides
(Scheme 1b1).12a However, the use of highly active reagent usually results in the drawbacks
of narrow substrate scope and poor tolerance of functional groups. For example, bromide
substituent among the starting materials is usually employed for further transformation, but
it is not tolerated in the above reaction that involves lithium reagents.
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Herein, as part of our continuous works on the development of cross-coupling reaction
utilizing Grignard reagents as key coupling partner23 as well as on the functionalization of
aminoquinoline,24 we disclose an efficient protocol for site-selective cleavage of C(O)−CF3
bond of a wide range of trifluoroacetyl amides by Grignard reagents (Scheme 1b2).
Trifluoroacetanilides, 2,2,2-trifluoro-N-(quinolin-8-yl)acetamide and N-alkyl-2,2,2-
trifluoroacetamide are well tolerated in this protocol. Furthermore, halogens are also
tolerated in the transformation. The present protocol provides a useful insight regarding the
mechanism of transformation of trifluoroacetyl amides with organometallic reagents.
RESULTS AND DISCUSSION
Initially,
2,2,2-trifluoro-N-(quinolin-8-yl)acetamide
(1a)
and
(p-
methylphenyl)magnesium bromide (2a) were selected as substrates for condition
optimization (Table 1). When the reaction was carried out at 25 C for 12 h in different
solvents, THF was found to be the best (entries 1−3). When the reaction was performed in
Et2O, the desired product 3a was not formed but rather 8-aminoquinoline was obtained in
80% yield. Further experiments revealed that the temperature had a profound effect on the
reaction and 70 C was the most suitable (entries 4−7). Decreasing the amount of 2a
resulted in low conversion of 1a, and if only 1.0 equiv of Grignard reagent was used, 1a
was fully recovered (entry 8). Increasing the amount of Grignard reagent to 4.0 equiv
resulted in the decrease of 3a yield, plausibly because of the competitive generation of
alcohol byproducts as a result of over addition of Grignard reagent (entry 10).
Table 1. Screening of Reaction Conditionsa
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a1a (0.3 mmol), 2a (1 M in THF, 0.9 mmol), anhydrous solvent (0.5 mL), N2 atmosphere; bGC yield,
c
using n-dodecane as internal standard; the number in parentheses is isolated yield; 8-aminoqunoline
was obtained in 80% yield. d1a was fully recovered.
With the optimized reaction conditions in hand, we investigated the substrate scopes
with respect to Grignard reagents (Scheme 2). For many kinds of aryl Grignard reagents,
the reaction proceeded smoothly for selective cleavage of trifluoromethyl group, leading
to satisfying yields of the corresponding amides (3a−g). With electron-donating group of
Grignard reagent at para position of the phenyl moiety (4-Me, 4-OMe), the corresponding
products (3a, 3e) were obtained in good yield (74%, 71%, respectively), whereas with
electron-withdrawing group (4-F, 4-Cl) would result in low yield of corresponding amides
(3f, 3g). Methyl group at different positions of phenyl Grignard reagents shows a steric
effect (3a−c), and if o-tolylmagnesium bromide was used, the desired product was obtained
in moderate yield (3c, 55%) after prolonged reaction. Alkyl Grignard reagents could also
be applied to this system, giving the desired products in moderate yields (3h−j). Besides,
cyclopropyl magnesium bromide and cyclopentyl magnesium bromide can also be
tolerated, giving the products in moderate yields (3i−j). Substituted aminoquinoline
derivatives were all compatible with this protocol, generating the corresponding products
in good yields (3k−n, 52%−70%). It should be noted that the bromide group at C5 position
of aminoquinoline remained unchanged (3l) without reacting with 2a. Furthermore, the
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coupling of 2,2,2-trifluoro-N-(quinolin-5-yl)acetamide with 2a can result in good yield of
3o (65%), indicating that the 8-aminoquinoline core is not necessary for the reaction. In
order to compare with the work of organolithium,12a 2,2,2-trifluoro-N-(quinolin-8-
yl)acetamide (1a) was tested with 2.0 equiv of phenyllithium at 0 C, and the target product
3d was obtained in only 40% yield. The reaction can be enlarged to 5 mmol scale with 3a
generated in 51% yield (668.0 mg).
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Scheme 2. Investigation of Grignard Reagent Scopea
Reaction conditions: a1a (0.3 mmol), 2 (3.0 equiv), anhydrous THF (0.5 mL), N2 atmosphere; isolated
yields. bThe reaction was performed in 5 mmol scale. c24 h. d1a was tested with 2 equiv of phenyllithium
at 0 C.
With the positive result of 3o, we extended the reaction system to various kinds of
trifluoromethyl N-aryl and N-alkyl amides (Scheme 3). As shown in Scheme 3, the
introduction of either electron-donating or electron-withdrawing substituents into the
benzamides did not significantly affect the transformation, generating the desired products
in good yields (5b−j). When bulky tert-butyl or triphenyl was introduced at the para
position of trifluoromethyl aniline, the desired products were obtained in modest yields
(5k−l). Amides containing a bicyclic moiety, such as naphthyl scaffold and
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tetrahydronaphthyl, afforded the desired amides 5m−n in good yields. Alkyl amides, such
as thienyl, benzyl, isobutyl, long chain and cyclohexyl amide could also give good yields
(5o−t). Tertiary amide 2,2,2-trifluoro-1-(piperidin-1-yl)ethan-1-one also afforded 5u in 62%
yield. However, the reaction of 2a with amides carrying a strong electron-withdrawing
group in the para position (5v−w) or a steric group at the ortho position (5x−y) failed to
give the related amide compounds.
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Scheme 3. Investigation of Amides Scopea
Reaction conditions: a1a (0.3 mmol), 2a (3.0 equiv), THF (0.5 mL), N2, isolated yield. b24 h. c2a (2.0
equiv).
Other perfluoroalkyl substituted amides (6, 7), also worked well with this system, giving
the desired product 3a in 60%, 65% yield, respectively (eq. 1).
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Scheme 4. Control Experiments
In order to verify the effect of trifluoromethyl group, the same reaction using N-
(quinolin-8-yl)acetamide (1aa) or N-(quinolin-8-yl)pivalamide (1ab) instead of 1a under
the standard reaction condition was performed (Scheme 4a, b). The desired methyl or
tertiary butyl leaving reaction did not take place, and in the case of 1aa, 8-aminoquinoline
was isolated in 68% yield, indicating the key role of strong electron-withdrawing
trifluoromethyl group played in the transformation. When trifluoroacetophenone (1ac) was
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tested, only the nucleophilic addition reaction took place (Scheme 4c).26 The corresponding
product 5m was observed in the yield of 93% by GC-MS when the moisture-sensitive 1-
isocyanatonaphthalene (4v) was reacted with 2a for the feasibility test (Scheme 4d). When
the reaction was conducted at room temperature rather than at 70 C, 5m was generated in
59% yield, indicating the readiness of nucleophilic addition. The good yield result
indicated that the isocyanate could be a possible intermediate. However, this does not yet
prove the isocyanate is indeed the intermediate. When (4-(9H-carbazol-9-
yl)phenyl)magnesium bromide (2m) was used to react with 1a, 9 was detected as a main
product by GC-MS (Scheme 4e).5f However, when 4g was tested with 2m, imine 10, which
can be transferred to the related amine and trifluoroacetyl ketone 9 in acidic condition (100%
GC yield), was formed in 30% yield (Scheme 4f). These experiments show that an
alkoxide/amide intermediate might exist in the reaction.
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Scheme 5. Possible Pathways
Although the exact reaction mechanism remains unclear, we propose here several
possible pathways based on the above results and literatures (Scheme 5).5g,12a,26 Initially
deprotonation of trifluoroacetyl amide (1 or 4) by Grignard reagent forms intermediate A.
It is noted that there is a high possibility of trifluoromethyl elimination to give isocyanate.27
Then isocyanate E undergoes nucleophilic addition with Grignard reagent and
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tautomerization to form the desired product 3 or 5 (route a).12a The intermediate A can also
be attacked by another equiv Grignard reagent to generate alkoxide/amide dual anionic
intermediate B. Then, B undergoes trifluoromethyl elimination to form the target product
3 or 5 (route b), or elimination of amine to form the corresponding amine and
trifluoroacetyl ketone D, which was detected in most of the reactions (route c). In another
pathway, intermediate B can undergo protonation and elimination of H2O to form imine F,
which probably would be transformed to the related amine and trifluoroacetyl ketone D
under acidic condition (route d).
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CONCLUSIONS
In summary, we have developed an efficient and convenient method for the conversion
of trifluoroacetyl amides to alkyl or aryl amides via the selective substitution of CF3 group
at the carbonyl carbon of amides under catalyst-free condition. A variety of aryl, quinolin-
8-yl, and (hetero)alkyl functional groups as well as F, Cl, and Br atoms are well tolerated.
These moisture-stable and easily available trifluoroacetyl amides can act as convenient and
versatile precursor for isocyanates. The control experiments show the reaction proceeds
via an isocyanate intermediate and/or alkoxide/amide dual anionic intermediate during the
reaction.
EXPERIMENTAL SECTION
General Information. All reactions were carried out under N2 atmosphere using standard
Schlenk techniques unless stated otherwise. The glassware was dried in an oven (110 °C)
and heated under reduced pressure before use. The thin layer chromatography (TLC)
analyses and column chromatography were performed using Anhui Liangchen silica gel
(200−300) with distilled solvents. NMR spectra were recorded on a Bruker Avance 400
spectrometer operating at 400 MHz (1H NMR) and 101 MHz (13C NMR) in CDCl3. Unless
1
noted otherwise, all H and 13C NMR chemical shifts were reported in ppm relative to
internal references of (CH3)4Si at 0.000 ppm and carbon resonance in chloroform-d1 at
77.00 ppm, respectively. The following abbreviations are used to describe peak patterns
where appropriate: singlet (s), doublet (d), triplet (t), multiplet (m), broad resonances (br).
Unless noted otherwise, the materials obtained from commercial suppliers were used
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without further purification. All solvents were redistilled. The concentration of Grignard
reagent was calculated via titration by I2.
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Typical Experimental Procedure for the Preparation of Starting Materials
Amides Derivatives (1, 4, 6, 7). The perfluoro-anhydride (11 mmol) was added
dropwise to a solution of 8-aminoquinoline derivatives or amines (10 mmol) in
CH2Cl2 (10 mL) at 0 °C. The mixture was stirred overnight at room temperature for
12 h. Then the mixture was washed with saturated aqueous NaHCO3, brine and
water. The organic layer was dried over MgSO4 and concentrated under reduced
pressure. The residue was purified by flash column chromatography on silica gel
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and eluted with EtOAc/petroleum to afford the corresponding amides 1, 4, 6 or 7.
General Procedure for the Cleavage of C(alkyl(F))
10 mL screw capped vial equipped with a magnetic stirring bar was added amides
4, 6 or ) (0.3 mmol), and anhydrous THF (0.5 mL) was added via syringe under
−C(O) Bond of Amides. To a
(
1
,
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N2 atmosphere. Then Grignard Reagent (0.9 mmol) of which the concentration was
calculated via titration by I2 was added slowly in 2 minutes. The reaction mixture
was placed in a pre-heated oil bath at 70 °C and vigorously stirred for 12 h. After
cooling to ambient temperature, the reaction was quenched by saturated ammonium
chloride (5 mL), and the mixture was subject to extraction by ethyl acetate (3 x 5
mL). The combined organic layers were dried over MgSO4 and subject to solvent
removal under reduced pressure. The as-obtained crude mixture was purified by
chromatography on silica gel (petroleum/EtOAc as eluent) to obtain the desired
product. In some cases, the products were purified by the PTLC method.
General Procedure for the Control Experiments. To a 10 mL screw capped vial
equipped with a magnetic stirring bar was added the substrate (0.3 mmol) under N2
atmosphere, and anhydrous THF (0.5 mL) was added via syringe. Then Grignard Reagent
(0.9 mmol or 0.6 mmol (with 4v)) with concentration calculated via titration by I2 was
added slowly in about 2 min. The reaction mixture was placed in a pre-heated oil bath at
70 °C and vigorously stirred for 12 h. After cooling to ambient temperature, the reaction
was quenched by saturated ammonium chloride (5 mL), and the mixture was subject to
extraction by ethyl acetate (3 x 5 mL). The organic layers were combined and dried over
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MgSO4 and then the solvent was removed under reduced pressure. The crude reaction
mixture was purified by chromatography on silica gel (petroleum ether /ethyl acetate as
eluent) to obtain the desired product.
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Analytical Data of Products
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4-methyl-N-(quinolin-8-yl)benzamide (3a).28 White solid, 58.2 mg, 74% yield (from 1a);
47.2 mg, 60% yield (from 6); 51.1 mg, 65% yield (from 7). Melt point: 115−116 C.
Purification by silica gel column chromatography (petroleum ether /ethyl acetate = 20:1
with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 10.69 (s, 1H), 8.93 (d, J =
7.5 Hz, 1H), 8.81 (s, 1H), 8.13 (d, J = 8.2 Hz, 1H), 7.97 (d, J = 7.4 Hz, 2H), 7.56 (t, J = 7.8
Hz, 1H), 7.49 (d, J = 8.1 Hz, 1H), 7.43 (dd, J = 5.1, 2.7 Hz, 1H), 7.32 (d, J = 7.5 Hz, 2H),
2.42 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 165.3, 148.1, 142.2, 138.6, 136.3,
134.6, 132.2, 129.4, 127.9, 127.4, 127.2, 121.6, 121.4, 116.3, 21.5. GC-MS: 262.
3-methyl-N-(quinolin-8-yl)benzamide (3b).28 Yellow solid, 52.7 mg, 67% yield. Melt
point:57−58 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 10.71 (s, 1H),
8.94 (d, J = 7.5 Hz, 1H), 8.85 (dd, J = 4.1, 1.3 Hz, 1H), 8.20 − 8.14 (m, 1H), 7.87 (d, J =
12.1 Hz, 2H), 7.61 − 7.50 (m, 2H), 7.48 − 7.37 (m, 3H), 2.48 (s, 3H). 13C{1H} NMR (101
MHz, CDCl3) δ (ppm) 165.6, 148.2, 138.8, 138.6, 136.3, 135.1, 134.6, 132.5, 128.6, 128.01,
127.95, 127.4, 124.2, 121.6, 121.5, 116.5, 21.4. GC-MS: 262.
2-methyl-N-(quinolin-8-yl)benzamide (3c).28 White solid, 43.3 mg, 55% yield. Melt point:
97−98 °C. Purification by silica gel column chromatography (petroleum ether /ethyl acetate
= 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 10.24 (s, 1H), 8.98
(d, J = 7.3 Hz, 1H), 8.83 − 8.75 (m, 1H), 8.20 (d, J = 8.2 Hz, 1H), 7.72 (d, J = 7.4 Hz, 1H),
7.66 − 7.56 (m, 2H), 7.51 − 7.39 (m, 2H), 7.35 (t, J = 7.5 Hz, 2H), 2.64 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm) 168.2, 148.2, 138.6, 136.7, 136.6, 136.3, 134.7, 131.3,
130.3, 128.0, 127.4, 127.2, 126.0, 121.7, 121.6, 116.5, 20.2. GC-MS: 262.
N-(quinolin-8-yl)benzamide (3d).28 White solid, 53.6 mg, 72% yield. Melt point: 83−85 °C.
Purification by silica gel column chromatography (petroleum ether /ethyl acetate = 20:1
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with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 10.74 (s, 1H), 8.94 (d, J =
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7.5 Hz, 1H), 8.88 − 8.80 (m, 1H), 8.16 (d, J = 8.2 Hz, 1H), 8.08 (d, J = 7.2 Hz, 2H), 7.61
− 7.51 (m, 5H), 7.45 (dd, J = 8.0, 4.1 Hz, 1H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm)
165.4, 148.2, 138.7, 136.3, 135.1, 134.5, 131.2, 128.7, 128.0, 127.4, 127.2, 121.6, 116.5.
One carbon is lost due to overlap. GC-MS: 248.
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4-methoxy-N-(quinolin-8-yl)benzamide (3e).29 White solid, 59.3 mg, 71% yield. Melt
point: 111−113 °C. Purification by silica gel column chromatography (petroleum ether
/ethyl acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 10.67
(s, 1H), 8.92 (d, J = 7.5 Hz, 1H), 8.83 (d, J = 1.5 Hz, 1H), 8.15 (d, J = 8.1 Hz, 1H), 8.05
(d, J = 8.2 Hz, 2H), 7.57 (t, J = 7.9 Hz, 1H), 7.50 (d, J = 8.1 Hz, 1H), 7.45 (dd, J = 7.3, 3.3
Hz, 1H), 7.03 (d, J = 8.2 Hz, 2H), 3.88 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm)
165.0, 162.4, 148.2, 138.7, 136.3, 134.7, 129.1, 127.9, 127.42, 127.36, 121.6, 121.3, 116.3,
113.9, 55.4. GC-MS: 278.
4-fluoro-N-(quinolin-8-yl)benzamide (3f).29 White solid, 51.9 mg, 65% yield. Melt point:
113−114 °C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 10.70 (s, 1H),
8.91 (d, J = 7.3 Hz, 1H), 8.85 (d, J = 3.8 Hz, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.10 (dd, J =
8.0, 5.6 Hz, 2H), 7.68 − 7.53 (m, 2H), 7.49 (dd, J = 8.2, 4.2 Hz, 1H), 7.29 − 7.18 (m, 2H).
19F NMR (376 MHz, CDCl3) δ (ppm) -107.67. 13C{1H} NMR (101 MHz, CDCl3) δ (ppm)
165.0 (d, J = 252.6 Hz), 164.4, 148.3, 138.8, 136.4, 134.5, 131.4 (d, J = 3.0 Hz), 129.7,
129.6, 128.0, 127.5, 121.8 (d, J = 5.7 Hz), 116.6, 115.9 (d, J = 22.0 Hz). GC-MS: 266.
4-chloro-N-(quinolin-8-yl)benzamide (3g).30 White solid, 52.5 mg, 62% yield. Melt point:
112−113 °C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 10.72 (s, 1H),
8.91 (d, J = 7.2 Hz, 1H), 8.85 (s, 1H), 8.20 (d, J = 8.2 Hz, 1H), 8.02 (d, J = 7.6 Hz, 2H),
7.66 − 7.42 (m, 5H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 164.3, 148.3, 138.7, 138.1,
136.4, 134.3, 133.5, 129.0, 128.7, 128.0, 127.4, 121.9, 121.7, 116.6. GC-MS: 283.
N-(quinolin-8-yl)pentanamide (3h).31 Yellow oil, 28.7 mg, 42% yield. Purification by
silica gel column chromatography (petroleum ether /ethyl acetate = 20:1 with 1%
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triethylamine). H NMR (400 MHz, CDCl3) δ (ppm) 9.83 (s, 1H), 8.81 (d, J = 7.1 Hz,
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2H), 8.17 (d, J = 8.2 Hz, 1H), 7.62 − 7.41 (m, 3H), 2.59 (t, J = 7.6 Hz, 2H), 1.91 − 1.72 (m,
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2H), 1.64 − 1.40 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H). C{1H} NMR (101 MHz, CDCl3) δ
(ppm) 171.9, 148.1, 138.3, 136.3, 134.5, 127.9, 127.4, 121.5, 121.3, 116.4, 38.0, 27.7, 22.4,
13.8. GC-MS: 228.
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N-(quinolin-8-yl)cyclopropanecarboxamide (3i).32 White solid, 19.1 mg, 30% yield. Melt
point: 74−76 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 10.00 (s, 1H),
8.74 (dd, J = 8.4, 4.3 Hz, 2H), 8.06 (dd, J = 8.3, 1.2 Hz, 1H), 7.49 − 7.35 (m, 3H), 1.81 −
1.73 (m, 1H), 1.17 − 1.12 (m, 2H), 0.91 − 0.84 (m, 2H). 13C{1H} NMR (101 MHz, CDCl3)
δ (ppm) 172.0, 147.8, 137.9, 136.0, 134.5, 127.7, 127.1, 121.3, 121.0, 116.1, 16.0, 7.9. GC-
MS: 212.
N-(quinolin-8-yl)cyclopentanecarboxamide (3j).33 White solid, 12.3 mg, 17% yield. Melt
point: 84−85 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 9.88 (s, 1H),
8.80 (d, J = 6.8 Hz, 2H), 8.16 (d, J = 8.2 Hz, 1H), 7.56 − 7.43 (m, 3H), 2.96 (p, J = 8.1 Hz,
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1H), 2.13 − 1.93 (m, 4H), 1.90 − 1.79 (m, 2H), 1.75 − 1.59 (m, 2H). C{1H} NMR (101
MHz, CDCl3) δ (ppm) 175.1, 148.1, 138.4, 136.3, 134.7, 127.9, 127.5, 121.5, 121.1, 116.3,
47.4, 30.6, 26.0. GC-MS: 240.
4-methyl-N-(2-methylquinolin-8-yl)benzamide (3k).34 White solid, 43.1 mg, 52% yield.
Melt point: 123−124 C. Purification by silica gel column chromatography (petroleum
ether /ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm)
10.66 (s, 1H), 8.78 (d, J = 7.3 Hz, 1H), 7.94 − 7.82 (m, 3H), 7.41-7.33 (m, 2H), 7.27 − 7.13
(m, 3H), 2.64 (s, 3H), 2.34 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 165.2, 157.0,
142.1, 138.0, 136.3, 134.0, 132.4, 129.4, 127.2, 126.3, 126.0, 122.3, 121.2, 116.3, 25.3,
21.4. HRMS (ESI) m/z: [M + H]+ calcd for C18H16N2O 277.1335; Found 277.1338.
N-(5-bromoquinolin-8-yl)-4-methylbenzamide (3l).35 White solid, 56.3 mg, 55% yield.
Melt point: 159−160 C. Purification by silica gel column chromatography (petroleum
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ether /ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm)
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10.65 (s, 1H), 8.89 − 8.77 (m, 2H), 8.52 (d, J = 8.5 Hz, 1H), 7.95 (d, J = 7.6 Hz, 2H), 7.82
(d, J = 8.4 Hz, 1H), 7.56 (dd, J = 8.4, 4.1 Hz, 1H), 7.33 (d, J = 7.7 Hz, 2H), 2.44 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 165.3, 148.7, 142.5, 139.4, 135.9, 134.6, 132.0,
130.9, 129.5, 127.3, 127.2, 122.7, 116.9, 114.2, 21.5. GC-MS: 341. HRMS (ESI) m/z: [M
+ H]+calcd for C17H13BrN2O 341.0284; Found 341.0281.
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4-methyl-N-(5-phenylquinolin-8-yl)benzamide (3m). White solid, 71.1 mg, 70% yield.
Melt point: 149−151 C. Purification by silica gel column chromatography (petroleum
ether /ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm)
10.82 (s, 1H), 8.98 (d, J = 7.8 Hz, 1H), 8.86 (s, 1H), 8.31 (d, J = 8.3 Hz, 1H), 8.01 (d, J =
7.6 Hz, 2H), 7.57 − 7.34 (m, 9H), 2.46 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm)
165.4, 148.0, 142.3, 139.2, 138.8, 134.8, 134.3, 134.1, 132.4, 130.1, 129.4, 128.5, 128.0,
127.4, 127.3, 126.3, 121.5, 116.1, 21.5. HRMS (ESI) m/z: [M + H]+calcd for C23H18N2O
339.1492; Found 339.1491.
N-(6-methoxyquinolin-8-yl)-4-methylbenzamide (3n).36 Yellow solid, 51.7 mg, 59% yield.
Melt point: 159−160 C. Purification by silica gel column chromatography (petroleum
ether /ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm)
10.67 (s, 1H), 8.66 (d, J = 1.8 Hz, 2H), 7.99 (dd, J = 22.3, 7.8 Hz, 3H), 7.39 (dd, J = 7.4,
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3.8 Hz, 1H), 7.33 (d, J = 7.5 Hz, 2H), 6.80 (s, 1H), 3.93 (s, 3H), 2.44 (s, 3H). C{1H}
NMR (101 MHz, CDCl3) δ (ppm) 165.4, 158.5, 145.6, 142.4, 135.5, 135.3, 134.9, 132.1,
129.4, 128.9, 127.2, 122.0, 108.8, 99.8, 55.6, 21.5. HRMS (ESI) m/z: [M + H]+calcd for
C18H16N2O2 293.1285; Found 293.1283.
4-methyl-N-(quinolin-5-yl)benzamide (3o). White solid, 51.1 mg, 65 % yield. Melt point:
205−206 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, DMSO) δ (ppm) 10.22 (s, 1H),
9.38 (s, 1H), 8.96 (d, J = 8.3 Hz, 1H), 8.51 (d, J = 7.4 Hz, 2H), 8.44 (d, J = 8.0 Hz, 1H),
8.31 (d, J = 6.6 Hz, 1H), 8.24 (t, J = 7.6 Hz, 1H), 8.04 − 7.92 (m, 1H), 7.84 (d, J = 7.3 Hz,
2H), 2.90 (s, 3H). 13C{1H} NMR (101 MHz, DMSO) δ (ppm) 166.6, 150.8, 149.3, 142.6,
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134.8, 132.4, 132.1, 129.5, 129.2, 128.2, 127.8, 124.7, 123.4, 121.3, 21.0. HRMS (ESI)
m/z: [M + H]+ calcd for C17H14N2O 263.1179; Found 263.1181.
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4-methyl-N-phenylbenzamide (5a).37 White solid, 38.0 mg, 60% yield. Melt point:
135−137 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 8.06 (s, 1H),
7.74 (d, J = 8.0 Hz, 2H), 7.63 (d, J = 8.0 Hz, 2H), 7.32 (t, J = 7.8 Hz, 2H), 7.21 (d, J = 7.9
Hz, 2H), 7.12 (t, J = 7.4 Hz, 1H), 2.39 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm)
165.8, 142.2, 138.0, 132.0, 129.3, 128.9, 127.0, 124.3, 120.3, 21.4. GC-MS: 211.
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4-methyl-N-(p-tolyl)benzamide (5b).37 White solid, 47.3 mg, 70% yield. Melt point:
150−151 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 7.90 (s, 1H),
7.74 (d, J = 7.5 Hz, 2H), 7.51 (d, J = 7.6 Hz, 2H), 7.24 (d, J = 8.1 Hz, 2H), 7.14 (d, J = 7.8
Hz, 2H), 2.40 (s, 3H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 165.6, 142.1,
135.5, 134.0, 132.1, 129.5, 129.3, 127.0, 120.3, 21.4, 20.9. GC-MS: 225.
4-methyl-N-(m-tolyl)benzamide (5c).37 White solid, 43.9 mg, 65% yield. Melt point:
106−107 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.91 (s, 1H),
7.75 (d, J = 7.4 Hz, 2H), 7.50 (s, 1H), 7.41 (d, J = 8.0 Hz, 1H), 7.30 − 7.19 (m, 3H), 6.95
(d, J = 7.4 Hz, 1H), 2.40 (s, 3H), 2.34 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm)
165.7, 142.2, 138.9, 137.9, 132.1, 129.3, 128.8, 127.0, 125.2, 120.8, 117.2, 21.5, 21.4.
HRMS (ESI) m/z: [M + H]+ calcd for C15H15NO 226.1226; Found 226.1225.
N-(2-ethylphenyl)-4-methylbenzamide (5d).38 White solid, 30.2 mg, 42% yield. Melt point:
124−126 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 7.95 (d, J =
7.7 Hz, 1H), 7.78 (d, J = 7.6 Hz, 2H), 7.72 (s, 1H), 7.27 (dd, J = 18.2, 7.6 Hz, 4H), 7.16 (t,
J = 7.4 Hz, 1H), 2.68 (q, J = 7.5 Hz, 2H), 2.43 (s, 3H), 1.28 (t, J = 7.5 Hz, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm) 165.7, 142.3, 135.2, 134.9, 132.2, 129.5, 128.6, 127.0,
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126.8, 125.5, 123.6, 24.4, 21.5, 13.9. HRMS (ESI) m/z: [M + H]+calcd for C16H17NO
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240.1383; Found 240.1382.
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N-(3,4-dimethylphenyl)-4-methylbenzamide (5e).39 White solid, 51.0 mg, 71% yield. Melt
point: 117−118 °C. Purification by silica gel column chromatography (petroleum ether
/ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.92
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(s, 1H), 7.73 (d, J = 7.5 Hz, 2H), 7.41 (s, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 7.6 Hz,
2H), 7.07 (d, J = 8.0 Hz, 1H), 2.38 (s, 3H), 2.22 (s, 6H). 13C{1H} NMR (101 MHz, CDCl3)
δ (ppm) 165.6, 142.0, 137.1, 135.7, 132.7, 132.2, 129.9, 129.2, 127.0, 121.6, 117.8, 21.4,
19.8, 19.1. GC-MS: 239. HRMS (ESI) m/z: [M + H]+ calcd for C16H17NO240.1383; Found
240.1385.
N-(2,3-dimethylphenyl)-4-methylbenzamide (5f). White solid, 46.6 mg, 65% yield. Melt
point: 138−140 C. Purification by silica gel column chromatography (petroleum ether
/ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.76
(d, J = 7.8 Hz, 2H), 7.71 − 7.63 (m, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 6.7 Hz, 2H),
2.41 (s, 3H), 2.30 (s, 3H), 2.26 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 165.7,
142.1, 135.0, 133.2, 132.1, 131.1, 129.7, 129.3, 127.3, 127.0, 123.5, 21.4, 20.9, 17.7.
HRMS (ESI) m/z: [M + H]+ calcd for C16H17NO 240.1383; Found 240.1388.
N-(4-methoxyphenyl)-4-methylbenzamide (5g).37 White solid, 57.9 mg, 80% yield. Melt
point: 158−160 C. Purification by silica gel column chromatography (petroleum ether
/ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.85
(s, 1H), 7.74 (d, J = 7.6 Hz, 2H), 7.51 (d, J = 8.3 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 6.88
(d, J = 8.3 Hz, 2H), 3.80 (s, 3H), 2.41 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm)
165.7, 156.5, 142.1, 132.1, 131.1, 129.3, 127.0, 122.1, 114.1, 55.5, 21.4. GC-MS: 241.
4-methyl-N-(4-phenoxyphenyl)benzamide (5h). White solid, 58.2 mg, 64% yield. Melt
point: 148−149 C. Purification by silica gel column chromatography (petroleum ether
/ethyl acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 7.98 (s,
1H), 7.75 (d, J = 7.7 Hz, 2H), 7.58 (d, J = 8.4 Hz, 2H), 7.32 (t, J = 7.5 Hz, 2H), 7.24 (d, J
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= 7.2 Hz, 2H), 7.08 (t, J = 7.3 Hz, 1H), 6.99 (d, J = 8.1 Hz, 4H), 2.40 (s, 3H). C{1H}
NMR (101 MHz, CDCl3) δ (ppm) 165.7, 157.5, 153.6, 142.3, 133.5, 132.0, 129.7, 129.4,
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127.0, 123.0, 122.0, 119.6, 118.4, 21.5. HRMS (ESI) m/z: [M + H]+ calcd for C20H17NO2
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304.1332; Found 304.1329.
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N-(4-fluorophenyl)-4-methylbenzamide (5i).40 White solid, 44.7 mg, 65% yield. Melt point:
180−183 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 7.83 (s, 1H),
7.76 (d, J = 7.4 Hz, 2H), 7.59 (dd, J = 6.9, 5.2 Hz, 2H), 7.27 (d, J = 8.7 Hz, 2H), 7.05 (t, J
= 8.0 Hz, 2H), 2.42 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 165.7, 159.5 (d, J
= 243.5 Hz), 142.5, 134.0, 131.8, 129.5, 127.0, 122.0 (d, J = 7.9 Hz), 115.7 (d, J = 22.5
Hz), 21.5. 19F NMR (376 MHz, CDCl3) δ (ppm) -117.83. GC-MS: 229.
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N-(4-chlorophenyl)-4-methylbenzamide (5j).40 Yellow solid, 51.6 mg, 70% yield. Melt
point: 200−202 C. Purification by silica gel column chromatography (petroleum ether
/ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.81
(s, 1H), 7.75 (d, J = 7.7 Hz, 2H), 7.59 (d, J = 8.1 Hz, 2H), 7.39 − 7.26 (m, 4H), 2.43 (s,
3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 165.6, 142.6, 136.6, 131.7, 129.5, 129.1,
127.0, 125.9, 121.4, 21.5. GC-MS: 246.
N-(4-(tert-butyl)phenyl)-4-methylbenzamide (5k). White solid, 36.1 mg, yield 45%. Melt
point: 136−138 C. Purification by silica gel column chromatography (petroleum ether
/ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.94
(s, 1H), 7.78 (d, J = 7.4 Hz, 2H), 7.59 (d, J = 7.7 Hz, 2H), 7.40 (d, J = 7.6 Hz, 2H), 7.27
(d, J = 7.9 Hz, 2H), 2.44 (s, 3H), 1.35 (s, 9H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm)
165.7, 147.4, 142.13, 135.4, 132.2, 129.3, 127.0, 125.8, 120.0, 34.4, 31.3, 21.4. HRMS
(ESI) m/z: [M + H]+calcd for C18H21NO 268.1696; Found 268.1694.
4-methyl-N-(4-tritylphenyl)benzamide (5l). White solid, 43.5 mg, 32% yield. Melt point:
258−260 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 7.78 (s, 1H),
7.74 (d, J = 7.6 Hz, 2H), 7.51 (d, J = 7.9 Hz, 2H), 7.29 − 7.18 (m, 19H), 2.41 (s, 3H).
13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 165.7 146.7, 143.0, 142.4, 135.8, 132.1, 131.8,
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131.1, 129.4, 127.5, 127.0, 125.9, 119.1, 64.6, 21.5. HRMS (ESI) m/z: [M + H]+ calcd for
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C33H27NO 454.2165; Found 454.2165.
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4-methyl-N-(naphthalen-1-yl)benzamide (5m).41 White solid, 51.2 mg, 66% yield. Melt
point: 171−172 C. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.30 (s, 1H), 7.93 − 7.78 (m, 6H),
7.69 (d, J = 8.2 Hz, 1H), 7.52 − 7.37 (m, 4H), 7.24 (d, J = 7.6 Hz, 3H), 2.41 (s, 3H). 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm) 166.3, 142.4, 134.1, 132.5, 131.8, 129.4, 128.7, 127.6,
127.2, 126.2, 126.0, 125.9, 125.7, 121.4, 120.9, 21.5. HRMS (ESI) m/z: [M + H]+ calcd for
C18H15NO 262.1226; Found 262.1221.
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4-methyl-N-(5,6,7,8-tetrahydronaphthalen-1-yl)benzamide (5n). White solid, 45.4 mg, 57%
yield. Melt point: 168−169 C. Purification by silica gel column chromatography
(petroleum ether /ethyl acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3)
δ (ppm) 7.76 (d, J = 6.8 Hz, 3H), 7.66 (s, 1H), 7.27 (d, J = 7.7 Hz, 2H), 7.15 (s, 1H), 6.94
(d, J = 7.5 Hz, 1H), 2.80 (d, J = 5.6 Hz, 2H), 2.65 (d, J = 6.1 Hz, 2H), 2.42 (s, 3H),1.81
(dd, J = 27.7, 5.3 Hz, 4H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 165.5, 142.2, 138.1,
135.5, 132.2, 129.4, 128.3, 127.0, 126.2, 125.8, 120.4, 29.7, 24.5, 22.8, 22.5, 21.5. GC-
MS: 265. HRMS (ESI) m/z: [M + Na]+ calcd for C18H19NO 288.1359; Found 288.1357.
(S)-4-methyl-N-(1-(naphthalen-1-yl)ethyl)benzamide (5o). White solid, 62.5 mg, 72%
yield. Melt point: 180−181 C. Purification by silica gel column chromatography
(petroleum ether /ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3)
δ (ppm) 8.13 (d, J = 7.9 Hz, 1H), 7.84 (d, J = 7.6 Hz, 1H), 7.78 (d, J = 8.1 Hz, 1H), 7.61 −
7.39 (m, 6H), 7.11 (d, J = 7.7 Hz, 2H), 6.49 (d, J = 7.1 Hz, 1H), 6.22 − 5.91 (m, 1H), 2.32
(s, 3H), 1.72 (d, J = 6.6 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 166.3, 141.7,
138.3, 133.9, 131.5, 131.2, 129.0, 128.7, 128.3, 126.9, 126.5, 125.8, 125.1, 123.4, 122.6,
45.1, 21.3, 20.7. HRMS (ESI) m/z: [M + H]+ calcd for C20H19NO 290.1539; Found
290.1536.
4-methyl-N-(2-(thiophen-2-yl)ethyl)benzamide (5p). White solid, 44.2 mg, 60% yield.
Melt point: 74−75 C. Purification by silica gel column chromatography (petroleum ether
/ethyl acetate = 20:1 with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.63
(d, J = 7.3 Hz, 2H), 7.23 − 7.13 (m, 3H), 6.96 (d, J = 3.2 Hz, 1H), 6.86 (s, 1H), 6.41 (s,
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1H), 3.70 (t, J = 5.1 Hz, 2H), 3.14 (t, J = 5.0 Hz, 2H), 2.38 (s, 3H). C{1H} NMR (101
MHz, CDCl3) δ (ppm) 167.4, 141.8, 141.3, 131.6, 129.2, 127.1, 126.8, 125.4, 124.0, 41.2,
29.9, 21.4. HRMS (ESI) m/z: [M + H]+ calcd for C14H15NOS 246.0947; Found 246.0944.
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N-benzyl-4-methylbenzamide (5q).37 White solid, 43.9 mg, 65% yield. Melt point:
120−122 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 7.69 (d, J =
7.4 Hz, 2H), 7.38 − 7.24 (m, 5H), 7.21 (d, J = 7.5 Hz, 2H), 6.52 (s, 1H), 4.62 (d, J = 5.2
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Hz, 2H), 2.38 (s, 3H). C{1H} NMR (101 MHz, CDCl3) δ (ppm) 167.3, 141.9, 138.3,
131.4, 129.7, 128.7, 127.8, 127.5, 126.9, 44.0, 21.4. GC-MS: 225.
N-isobutyl-4-methylbenzamide (5r).42 White solid, 35.0 mg, 61% yield. Melt point: 82−83
C. Purification by silica gel column chromatography (petroleum ether /ethyl acetate = 20:1
with 1% triethylamine). 1H NMR (400 MHz, CDCl3) δ (ppm) 7.67 (d, J = 7.4 Hz, 2H),
7.22 (d, J = 7.4 Hz, 2H), 6.29 (s, 1H), 3.27 (t, J = 6.0 Hz, 2H), 2.39 (s, 3H), 1.94 − 1.86
(m, 1H), 0.98 (s, 3H), 0.96 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3) δ (ppm) 167.5, 141.6,
132.0, 129.1, 126.8, 47.2, 28.6, 21.4, 20.1. GC-MS: 191.
N-dodecyl-4-methylbenzamide (5s). White solid, 56.5 mg, 62% yield. Melt point: 66−68
C. Purification by silica gel column chromatography (petroleum ether /ethyl acetate = 20:1
1
with 1% triethylamine). H NMR (400 MHz, CDCl3) δ (ppm) 7.65 (d, J = 7.5 Hz, 2H),
7.22 (d, J = 7.6 Hz, 2H), 6.12 (s, 1H), 3.43 (q, J = 6.6 Hz, 2H), 2.39 (s, 3H), 1.65 − 1.53
(m, 2H), 1.41 − 1.19 (m, 18H), 0.88 (t, J = 6.4 Hz, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ (ppm) 167.4, 141.60 132.0, 129.1, 126.8, 40.0, 31.9, 29.7, 29.62, 29.61, 29.57, 29.53,
29.3, 27.0, 22.7, 21.4, 14.1. One carbon was lost due to overlap. HRMS (ESI) M/Z: [M +
H]+ calcd for C20H33NO 304.2635; Found 304.2633.
N-cyclohexyl-4-methylbenzamide (5t).43 White solid, 42.4 mg, 65% yield. Melt point:
150−152 C. Purification by silica gel column chromatography (petroleum ether /ethyl
acetate = 20:1 with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 7.65 (d, J =
7.5 Hz, 2H), 7.21 (d, J = 7.6 Hz, 2H), 6.00 (s, 1H), 3.97 (d, J = 9.5 Hz, 1H), 2.39 (s, 3H),
2.02 (d, J = 11.9 Hz, 2H), 1.75 (d, J = 13.2 Hz, 2H), 1.65 (d, J = 12.9 Hz, 1H), 1.48 − 1.36
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(m, 2H), 1.29 − 1.14 (m, 3H). C{1H} NMR (101 MHz, CDCl3) δ (ppm) 166.5, 141.5,
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132.2, 129.9, 126.8, 48.5, 33.2, 25.6, 24.9, 21.37. GC-MS: 217.
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piperidin-1-yl(p-tolyl)methanone (5u).37,44 Colorless oil. 37.8 mg, 62% yield. Purification
by silica gel column chromatography (petroleum ether /ethyl acetate = 20:1 with 1%
triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 7.33 − 7.25 (m, 2H), 7.19 (d, J = 7.5
Hz, 2H), 3.69 (br, 2H), 3.36 (br, 2H) 2.37 (s, 3H), 1.67− 1.53 (m, 6H). 13C{1H} NMR (101
MHz, CDCl3) δ (ppm) 170.5, 139.4, 133.5, 128.9, 126.9, 48.8, 43.1, 26.4, 25.6, 24.6, 21.3.
GC-MS: 203.
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2,2,2-trifluoro-1-phenyl-1-(p-tolyl)ethan-1-ol (8).45 Colorless oil, 51.9 mg, 65% yield.
Purification by silica gel column chromatography (petroleum ether /ethyl acetate = 20:1
with 1% triethylamine).1H NMR (400 MHz, CDCl3) δ (ppm) 7.47 (s, 2H), 7.37 − 7.29 (m,
5H), 7.14 (d, J = 7.5 Hz, 2H), 2.86 (s, 1H), 2.32 (s, 3H). 13C{1H} NMR (101 MHz, CDCl3)
δ (ppm) 139.4, 138.5, 136.5, 129.4, 128.9, 128.5, 128.2, 127.4, 127.3, 126.8, 125.3 (q, J =
287), 79.3 (q, J = 28.7 Hz), 21.0. 19F NMR (376 MHz, CDCl3) δ (ppm) -74.24. GC-MS:
266.
1-(4-(9H-carbazol-9-yl)phenyl)-2,2,2-trifluoro-N-(4-methoxyphenyl)ethan-1-imine (10).
Yellow oil, 39.9 mg, 30% yield. Purification by silica gel column chromatography
(petroleum ether /ethyl acetate = 40:1 with 5% triethylamine). It’s unstable and
decomposes quickly. 1H NMR (400 MHz, CDCl3) δ (ppm) 8.13 (d, J = 7.7 Hz, 2H), 7.58
(d, J = 8.5 Hz, 2H), 7.48 (d, J = 8.4 Hz, 2H), 7.41 (d, J = 5.7 Hz, 4H), 7.34 − 7.28 (m, 2H),
6.86 − 6.79 (m, 4H), 3.78 (s, 3H). 19F NMR (376 MHz, CDCl3) δ (ppm) -69.58. 13C{1H}
NMR (101 MHz, CDCl3) δ (ppm) 158.0, 154.4 (q, J = 33.7 Hz), 140.2, 139.6, 139.4, 130.4,
129.2, 126.9, 126.1, 123.7, 123.4, 120.5, 120.4, 119.0 (q, J = 279.3 Hz), 114.2, 109.6, 55.4.
GC-MS: 444.
Author Contributions
The authors declare no competing financial interest.
ACKNOWLEDGMENT
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The authors thank the Natural Science Foundation of China (Nos. 21676076, 21878071),
the Hu-Xiang High Talent Project in Hunan Province (2018RS3042) and Recruitment
Program for Foreign Experts of China (WQ20164300353) for financial support. C.T. Au
thanks HNU for an adjunct professorship.
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Supporting Information:
Copies of the 1H, 13C, 19F spectra of 3, 5, 8, 10. This material is available free of charge via
the Internet at http://pubs.acs.org.
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