Synthesis of: Meta-substituted anilines via a three-component reaction of acetone, amines, and 1,3-diketones

Article abstract of DOI:10.1039/c9ob02120e

A facile method for the synthesis of meta-substituted arylamines from acyclic precursors was developed. This method is based on three-component cyclo-condensation/aromatization of in situ generated imines of acetone with 1,3-diketones either under conventional heating or under microwave irradiation. The utility of this methodology is illustrated by the possibility of a gram scale synthesis of various anilines from readily available reagents.

Full text of DOI:10.1039/c9ob02120e

Organic &
Biomolecular Chemistry
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PAPER
Synthesis of meta-substituted anilines via a
three-component reaction of acetone, amines,
and 1,3-diketones†
Cite this: Org. Biomol. Chem., 2019,
17, 10030
a
Andrew R. Galeev, a Maksim V. Dmitriev, *a Ivan G. Mokrushin,
b,c
Irina V. Mashevskaya,a Andrey N. Maslivets a and Michael Rubin
*
A facile method for the synthesis of meta-substituted arylamines from acyclic precursors was developed.
This method is based on three-component cyclo-condensation/aromatization of in situ generated imines
of acetone with 1,3-diketones either under conventional heating or under microwave irradiation. The
utility of this methodology is illustrated by the possibility of a gram scale synthesis of various anilines from
readily available reagents.
Received 30th September 2019,
Accepted 12th November 2019
DOI: 10.1039/c9ob02120e
rsc.li/obc
Tasigna® (Nilotinib),23,24 Avodart® (Dutasteride),25,26 and
Tazemetostat.27,28 Other important examples are the topical
Introduction
It is hard to overstate the importance of aniline derivatives anesthetic Alcaine® (Proxymetacaine),29,30 the anti-inflamma-
which are commonly used for manufacturing commodity
chemicals,1 such as plastics, dyes, agrochemicals, pharmaceu-
ticals, and catalysts.2–6 They are also employed as convenient
building blocks in target-oriented organic synthesis, pharma-
ceutical chemistry, and drug discovery.7–11 Among other privi-
leged pharmacophoric scaffolds, the m-trifluoromethylaniline
motif is extensively used in medicinal chemistry due to the
fact that typically the introduction of fluorine (in particular,
the trifluoromethyl group) into biologically active scaffolds
may lead to dramatic changes in their physicochemical pro-
perties, increased metabolic stability, and improved pharmaco-
kinetic properties, and oftentimes could enhance the desired
biological effect.12–14 Furthermore, anilines with carbonyl sub-
stituents at the meta-position are also widely employed in med-
icinal chemistry,15–18 serving as pharmacophoric moieties of
biologically active agents or structural cores for their chemical
modification and diversification in drug discovery. For
example, there is a handful of successfully marketed medicinal
agents (Fig. 1) containing the m-trifluoromethylaniline or
m-carbonylaniline moiety including important anticancer
drugs Casodex® (Bicalutamide),19,20 Nexavar® (Sorafenib),21,22
aDepartment of Chemistry, Perm State University, ul. Bukireva 15, Perm, 614990,
Russian Federation. E-mail: dmax@psu.ru
bDepartment of Chemistry, North Caucasus Federal University, 1a Pushkin St.,
Stavropol 355009, Russian Federation
cDepartment of Chemistry, University of Kansas, 1567 Irving Hill Rd., Lawrence,
KS 66045-7582, USA. E-mail: mrubin@ku.edu; Tel: +1-785-864-5071
†Electronic supplementary information (ESI) available: Spectral data. CCDC
1905220–1905223 and 1960904. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c9ob02120e
Fig. 1 m-Substituted anilines in medicinal chemistry.
10030 | Org. Biomol. Chem., 2019, 17, 10030–10044
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tory agent Asacol® (Mesalazine),31,32 and the loop diuretic de novo assembly of m-substituted anilines could be achieved
Arelix® (Piretanide).33,34 From this perspective, it is not sur- via synthetic approaches based on formal [3 + 3] cyclo-
prising that synthetic efforts towards the m-substituted aniline addition–aromatization reactions (Scheme 1a–c). Thus, recently,
core continue to be the focus of attention of many research Guan’s57 and Yaragorla’s58 groups accessed biarylamines via
groups. Typically, molecules of this class are accessed via tran- cyclocondensation of push–pull enamines with enones fol-
sition metal-catalyzed C–N bond forming reactions, such as lowed by oxidation promoted by Cu(OAc)2 or chloranil
the Ullmann reaction and Buchwald–Hartwig and Chan–Lam (Scheme 1a). The synthesis of p-nitrosoanilines by the conden-
aminations.35–37 Another commonly used approach involves sation of amines, ketones and 2-hydroxyimino-1,3-diketones
the modification of an existing arylamine moiety via a has been developed (Scheme 1b).59–61 However, the reaction
sequence of steps, involving electrophilic aromatic substi- requires a long time (up to several months), often giving low
tution (SEAr), directed metalation, C–H activation or metal- yields. Kostyuk et al. reported the reaction of enamines with
catalyzed cross-coupling reactions. Most of these reactions, 1,3-dicarbonyl compounds or their surrogates, which is
however, allow for direct and selective functionalization of the limited to only activated push–pull enamines and a two-com-
ortho-position only. Functionalizations of the meta- and para- ponent strategy (Scheme 1c).62–64 We envisioned that these
positions of the arylamine core are much less straightforward, cyclization methods could be potentially employed for the
and typically require the installation and subsequent removal highly efficient assembly of m-substituted anilines.
of temporary directing groups.38–41 In general, meta- Potentially, a three-component one-pot and metal-free cyclo-
functionalization of arylamines is rather problematic for both condensation protocol could be designed (Scheme 1d). Herein
electrophilic substitution methods and transition-metal-cata- we wish to report on our progress towards this goal.
lyzed reactions.40,41 Alternative approaches, involving the de
novo assembly of the arylamine core from non-aromatic pre-
cursors still remain insufficiently explored. There are several
different synthetic strategies known that employ formal [4 + 2]
Results and discussion
cycloaddition reactions.42–46 Another method is based on the Initially, we decided to test our design of the three-component
dehydrogenative aromatization of cyclohexenones or their cascade transformation by employing benzoylpyruvate 1a as
derivatives.47–51 The synthesis of arylamines from 1,5-dicarbo- the 1,3-dicarbonyl component. To this end, 1a was stirred with
nyl compounds and alkyl or dialkylamines has also been equimolar amounts of aniline (2a) in acetone at 55 °C for 24 h.
reported.52–55 An example was reported, describing the syn- However, the target aniline structure 3aa was formed in a dis-
thetic efforts focused on the synthesis of nitroanilines from appointingly low yield (Table 1, entry 1) along with enamine
dinitropyridone.56 Arguably, the greatest potential for the 3aa′ resulting from the concurrent attack of aniline on the
highly electrophilic carbonyl group at C2 of pyruvate 1a.65
Taking into account that the formation of enamines is revers-
ible, and that the formation of the aromatic ring should be
thermodynamically favored, we wondered if the addition of
catalytic amounts of acids might help drive the reaction to
completion. Indeed, the addition of a weak protic acid (AcOH,
30 mol%) improved the yield of 3aa (entry 2). Addition of
formic acid, however, led to the predominant formation of
enamine 3aa′, while benzoic acid improved the formation of
both 3aa and 3aa′ compounds. Strong acids (TFA and TsOH,
entries 5 and 6) drastically shifted the distribution of the pro-
ducts, resulting in the predominant formation of the side
product 3aa′ and only trace amounts of the desired aniline
3aa. It should be pointed out that the use of aniline hydro-
chloride also led to the formation of enamine 3aa′ as a major
product. Next, we tested the possibility of promoting the cycli-
zation process by employing Lewis acids. To this end, the reac-
tion was carried out in the presence of ZnCl2 (entry 7),
Cu(OAc)2 or FeCl3 (not shown in Table 1), all of which provided
equally poor results. Our next attempt to improve the cycliza-
tion outcome involved the use of basic catalysts. For this
purpose, the reaction between 1a, aniline (2a), and acetone
was carried out in the presence of 30 mol% of triethylamine
(entry 8). Unfortunately, this approach also proved to be unsuc-
cessful and resulted in the predominant formation of aryla-
Scheme 1
mine 3ha. This molecule, in which the ester function was con-
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Table 1 Optimization of the three-component reaction by employing
pyruvate 1a
from acylpyruvic acids. We also tested the reactions with alkyl-
amines and dialkylamines, which afforded the desired pro-
ducts 3ae, 3bf in good yields (Scheme 2).
In these cases, the utilization of microwave irradiation was
successful and allowed for notable increase of reaction rates
without detrimental effect on chemoselectivity. Products 3ae,
3ag, 3ce, 3cj were obtained according to this modified protocol
in 15 min at 150 °C in high yields. It should be stressed that the
developed reaction conditions were compatible with unpro-
tected amino alcohols and amino acids (3ag, 3ah). The utility of
this method for the modification of more complex amines was
also demonstrated by the example of the formation of N-aryl
substituted cytisine 3ai. Encouraged by these initial results, we
planned on extension of the method to synthesize derivatives
of other acylpyruvates (1c–f): acetyl, pivaloyl, cinnamoyl, and
furoyl. In most cases, the reactions proceeded smoothly to
provide the desired products in good yields. It was also demon-
strated that the carbonyl group at the C2 of the 1,3-dicarbonyl
substrate could also be activated by a carboxamide functionality
(3ga, 3ha, 3gk). It is should be stressed that an EWG group adja-
cent to one of the carbonyls in the 1,3-diketone is a requisite for
the successful implementation of this reaction, as was con-
firmed by the inefficient reaction with dibenzoylmethane or
benzoylacetone, in which trace amounts of the desired products
(under the optimized conditions) were detected.
Yieldb, %
Entry
Additive
3aa
3aa′
1
2
3
4
5
6
7
8
None
30 mol% AcOH
30 mol% HCO2H
30 mol% PhCO2H
30 mol% TFA
10 mol% TsOH·H2O
10 mol% ZnCl2
30 mol% Et3N
30 mol% AcOH, 125 mg MS 4Å
30 mol% AcOH, 250 mg MS 4Å
30 mol% AcOH, 250 mg MS 4Å
14
32
17
34
9
11
16
11
16
16
55
38
42
53
42
9
9c
10c
11c,d
63
5
3
3
69
73 (60e)
a Reagents and conditions: 1a (0.50 mmol), aniline (0.50 mmol), and
acetone (0.5 mL) in a capped vial for 1 d. b NMR yields using 1,4-
dimethoxybenzene as an internal standard. c 2 d. d Aniline (0.55 mmol)
was used. e Isolated yield.
To examine the compatibility of this method with the substi-
tution at the α-position of 1,3-diketones, the reaction with
α-methyl substituted benzoylpyruvate (1i) was performed.
Unexpectedly, the only isolable product formed in this reaction
was identified as m-carbamoylaniline 3ia. Most likely, this
verted into the N-phenylamide group, was produced in 25% product was formed via the reaction of amines with
NMR yield, while ester 3aa and enamine 3aa′ were formed in α-substituted aroylpyruvates affording dihydroxypyrrolones (3ia′,
insignificant amounts (entry 8). Much better results were Scheme 3) first,68 which underwent ring cleavage to produce the
obtained in experiments carried out in the presence of 4 Å corresponding amides of aroylpyruvic acids. Subsequent trans-
molecular sieves (MS) added to the reaction mixture in order formation of these amides provides products such as 3ia. We
to remove the water produced as a by-product.66,67 To our also tested the reaction of 1,3-diketones bearing a halogen atom
delight, the combination of MS and acetic acid increased the at the α-position targeting further functionalization of the
regioselectivity towards the formation of the arylamine 3aa would-be product via transition metal-catalyzed cross-coupling
(entries 9 and 10). A small excess of amine 2 also slightly reactions. Unfortunately, under various conditions these experi-
improved the yield, although this reaction required a longer ments (see the ESI† for details) did not afford p-halo-substituted
time to reach completion (entry 11, optimal conditions).
With the optimized conditions in hand, we began to
anilines, providing only dehalogenated analogs instead.
At the next stage of our investigation, in order to access
explore the scope of the method. We tested the reaction of m-trifluoromethylated anilines, the reaction of 1,3-diketones
series of different acylpyruvates 1 with acetone and a variety of 4a–d bearing the trifluoromethyl group with various amines
amines 2 (Scheme 2). It should be pointed out that the was examined (Scheme 4). It should be pointed out that the
efficiency of the cyclocondensation process and reaction rates interaction of trifluoromethyl 1,3-diketones with arylamines
were directly dependent on the amine nucleophilicity required prolonged heating. For example, product 5al was iso-
employed. Thus, aniline required 2 days to achieve full conver- lated in a yield of 17% after 4 days at 55 °C. Heating at higher
sion (3aa, 60% yield), while the more reactive o-aminophenol temperatures under microwave irradiation accelerated the
achieved full conversion in just 30 min (3ab, 91% yield). It reaction drastically, and more importantly, reduced the
should be pointed out that sterically hindered mesithylamine amount of side products (see the discussion on the mecha-
was also successfully involved in this reaction (3ad, 73% yield). nistic rationale below). The yield of products 5 also depended
In order to reduce the reaction time, the effect of microwave on the nucleophilicity of arylamines. Thus, the reaction
irradiation was examined, but it was found that increasing the of the least nucleophilic (among the tested arylamines)
reaction temperature up to 150 °C increased the amount of p-trifluoromethylaniline (2n) proceeded to completion in
side products including enamines and carboxamides derived 1 h at 150 °C, affording product 5an in 54% yield. Both alkyl-
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Scheme 2 a Method A: 1 (0.50 mmol), 2 (0.55 mmol), AcOH (0.15 mmol), MS 4Å (250 mg) and acetone (0.5 mL) in a capped vial at 55 °C. Method B:
1 (0.5 mmol), 2 (0.55 mmol), AcOH (0.15 mmol), MS 4Å (250 mg) and acetone (2 mL) in a vial under microwave irradiation at 150 °C. b Isolated yields
are provided. c 2.0 mmol scale. d At RT. e 0.2 mmol scale. f 0.25 mmol scale (2 equiv. of aniline were used).
and dialkylamines were successfully utilized in the synthesis
of the corresponding anilines which were obtained in
good to excellent yields under either conventional heating
or microwave irradiation. The possibility of employing
α-methylsubstituted diketones in this method was demon-
strated by the preparation of adducts 5da and 5dk.
Unfortunately, the application of weakly nucleophilic nitro-
gen-based heterocycles in the reaction with 1,3-diketones did
not result in the desired products (see the ESI† for the tested
heterocycles). Nevertheless, we were able to obtain product
5aq from 2-aminopyridine (2q) under microwave irradiation
(for 1 h at 150 °C) or under heating in a steel bomb (for 5 h
Scheme 3
at 150 °C). By employing this method, we also managed to
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Scheme 4 a Method A: 4 (0.50 mmol), 2 (0.55 mmol), AcOH (0.15 mmol), MS 4Å (250 mg) and acetone (0.5 mL) in a capped vial at 55 °C. Method
B: 4 (0.5 mmol), 2 (0.55 mmol), AcOH (0.15 mmol), MS 4Å (250 mg) and acetone (2 mL) in a vial under microwave irradiation at 150 °C. b Isolated
yields are provided. c In a steel bomb at 150 °C. d 1.00 mmol scale.
access the symmetric product 5ar by the double-fold inter-
During the next stage of our investigation, we tested the
action of 4a and acetone with piperazine (2r); however, it was reaction of higher homologs of acetone. Interaction of
not possible to carry out the reaction selectively in a ratio of benzoyl pyruvate 1a with butan-2-one (MEK, 6a) and morpho-
1 : 1 to obtain the corresponding mono-adduct.
line (2k), carried out at 55 °C, led to the formation of a
Although we synthesized anilines with some readily remova- mixture of regioisomeric products 7 and 7′ in a ratio of 2 : 1.
ble protecting groups (N-Bn and N-t-Bu), the assembly of ani- The predominant formation of regiomer 7 suggests the initial
lines with an unprotected primary amino group proved unsuc- formation of less sterically hindered (kinetic) enamines.
cessful. To this end, we tested two different NH3 sources According to LC-MS analysis, the test reactions of more steri-
(aqueous NH3 and NH4OAc); however, none of them provided cally hindered ketones (such as isobutyl methyl ketone and
satisfactory results. Typically, complex mixtures of products were diethyl ketone), carried out at 55 °C or at reflux, led to the
obtained with the predominant formation of pyridine, resulting formation of aroylpyruvic amides as the main products
from Hantzsch-type cyclization (see the ESI† for details).
(Scheme 5).
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Fig. 2 Scale-up experiments on formal (3
+
3)-cyclocondensation.
Reaction conditions: 1 (10 mmol), 2 (11 mmol), AcOH (3.0 mmol), MS
4 Å (2.5 g) and acetone (10 mL) were stirred at 55 °C. Isolated yields of
the purified compounds are shown.
were isolated on a gram scale without reducing the yields after
simple crystallization (Fig. 2).
A plausible mechanistic rationale for the studied transform-
ation is shown in Scheme 6. It is reasonable to propose the
aldol addition of the in situ generated imine of acetone66 to
the more electrophilic activated carbonyl group at the C2 of
the 1,3-diketone as the initial stage. Next, the newly formed
enamine (intermediate A) could undergo 6-enolendo-exo-trig
cyclization (pathway 1) to form exo-cyclic imine (intermediate B).
Acid-assisted dehydration should provide intermediate C or
C′ (via pathway 1 or 1′), and subsequent elimination of a
second molecule of water would lead to its aromatization into
aniline (3 or 5). Alternatively, elimination of the first equi-
valent of water could take place in the molecule of intermedi-
Scheme 5 Method A: 1 or 4 (0.50 mmol), 2 (0.55 mmol), AcOH
(0.15 mmol), MS 4A (250 mg) and ketone 6 (0.5 mL) in a capped vial at
55 °C. a TSA·H2O (10 mol %) used as a catalyst instead of AcOH.
The reaction of diketone 4a with MEK (6a) and morpholine
(2k) takes place in a regioselective manner, providing product
8ka in 70% yield. A similar reaction with benzylamine (2e)
affords the mixture of regioisomeric products 8ea and 8ea′ in a
ratio of 4 : 1 (Scheme 5). An attempt to employ the more steri-
cally hindered isobutyl methyl ketone (6b) resulted in a very
sluggish reaction, in which full conversion of diketone (4a)
was not achieved even after 5 days, but aniline derivative 8kb
was isolated as the sole product in a poor yield. The reaction
of diketone 4a with diethyl ketone 6c and morpholine (2k),
carried out at 55 °C, as confirmed using LC-MS analysis, led to
the formation of a mixture of stable intermediates that did not
transform into final products even after prolonged heating. To
implement the dehydration step (see the discussion on the
mechanistic rationale below) we attempted to employ a stron-
ger tosic acid as a catalyst, which allowed the isolation of 49%
of the target product 8kc after 5 days of heating (Scheme 5).
It should be pointed out that the developed synthetic proto-
col can be easily scaled up. For example, products 3jk, 3ee
Scheme 6
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three-component (3 + 3)-cyclocondensation cascade reaction
by employing readily available reagents: acetone (or MEK),
amines, and 1,3-diketones. The reaction can be carried out
under conventional heating as well as under microwave
irradiation and scaled up easily, allowing the synthesis of a
wide range of arylamines containing electron-withdrawing sub-
stituents in the meta-position, including a trifluoromethyl
group or synthetically useful functionalities such as an ester or
an amide group.
Experimental
General information
1H, 13C and 19F NMR spectra were recorded on a Bruker
Avance III HD spectrometer (at 400, 101, or 377 MHz, respect-
ively) at 40 °C in CDCl3 or DMSO-d6 using the residual solvent
peak (CDCl3: δH = 7.26 ppm, δC = 77.16 ppm; DMSO-d6: δH
2.50 ppm; δC = 39.5 ppm) and PhCF3 (CDCl3: δF = −62.6 ppm;
DMSO-d6: δF =
−60.9 ppm)71 or C6F6 (CDCl3: δF
=
Scheme 7
=
−161.64 ppm; DMSO-d6: δF = −162.45 ppm)71 as internal stan-
dards. Splitting patterns of apparent multiplets were desig-
nated as s (singlet), d (doublet), t (triplet), q (quartet), m (mul-
tiplet), br (broadened), etc. FT-IR spectra were recorded as
ate A to afford intermediate D (pathway 2). The latter could
undergo 6-enolendo-exo-trig cyclization to form intermediate
C′; however, an alternative mechanism involving isomerization
and 6π-electrocyclization is also possible.40
mulls or neat samples in mineral oil by employing
a
When trifluoromethyl-substituted 1,3-diketones, in particu-
lar, 4a, reacted with o-aminophenol (or other aromatic amines)
at 55 °C, the formation of sufficiently stable intermediates
with a molecular mass of 353 a.m.u. (9a), which is 18 a.m.u.
higher than that of the target product, was observed by LC-MS.
This mass could correspond to the structures of intermediates
C, C′ or D (in reactions of acylpyruvates, such intermediates
were not detected). Prolonged heating resulted in an increase
in the proportion of the side product with a mass of 262 a.m.
u. (via hydrolysis of the aminophenol moiety), which did not
ultimately convert into the target product. Since the structure
of this side product (9b) could provide valuable information
on the mechanism, we isolated this material and established
its structure by single crystal X-ray diffraction. A trifluoro-
methyl alcohol moiety stable to oxidation41,69,70 or dehydration
was revealed, which explains the predominant formation of
this material. From the reaction performed at −10 °C, we also
isolated the type C intermediate 9a (Scheme 7). Unfortunately,
due to its high lability, it was difficult to obtain this material
in a sufficiently pure form. Overall, our observations indicated
that most likely pathway 1 is operational, at least for the reac-
tions of trifluoromethyl 1,3-diketones. It should be pointed out
that cyclohexanone 9b proved to be suitable for the straight-
forward synthesis of unprotected anilines (9c, Scheme 7)
without the formation of unwanted pyridines compared to the
direct reaction of 1,3-diketones with NH4OAc (vide supra).
PerkinElmer Spectrum Two spectrometer. Melting points were
measured with Mettler Toledo MP70 Melting Point apparatus.
Reaction progress was monitored by LC-MS on a Waters
Acquity UPLC I-Class instrument equipped with a PDA eλ
detector and a Xevo TQD detector in ESI + ionization mode.
High-resolution mass spectra were measured using a Bruker
microTOF-QTM ESI-TOF mass spectrometer. X-ray structural
analyses of compounds 3ab, 3ae, 5bc, 8ka and 9b were per-
formed on an Xcalibur Ruby diffractometer using a Mo X-ray
source (MoKα 0.71073 Å), by scanning at 295(2) K. Microwave-
assisted reactions were performed in standard reaction vessels,
sealed with silicone septa, in a Monowave 300 (Anton Paar)
instrument equipped with an internal IR probe. Column
chromatography was performed on silica gel (Acros Organics,
35–70 μm or 60–200 μm). TLC was performed on silica gel 60
F254 plates (Merck); spots were visualized with UV light
(254 nm) and iodine vapors. 4 Å MS were activated prior to use
by heating in a vacuum. β-Diketones (1 and 4) were purchased
from commercial vendors or were synthesized according to the
known procedures.72,73
General procedure A (conventional heating). A microreactor
vessel of an appropriate volume was charged with 4 Å mole-
cular sieves (250 mg), AcOH (9 μL, 30 mol%), amine 2
(0.55 mmol, 1.1 equiv.), and a solution of β-diketone 1 or 4
(0.5 mmol, 1 equiv.) in an appropriate amount of ketone
(acetone or 6, 0.5 mL). The vessel was sealed with a silicone
septum and heated at 55 °C (in a preheated aluminium block)
for a specified time, as shown in Schemes 2 and 4. The reac-
tion progress was monitored by LC-MS. When the reaction was
Conclusion
In conclusion, we have developed a convenient synthetic completed, the molecular sieves were filtered off and washed
method to access meta-substituted anilines via a metal-free several times with warm acetone. The combined organic solu-
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tions were evaporated, and the residue was purified by prepara- 123.7, 121.3, 120.4, 118.9, 115.9, 115.9, 52.4. IR (mineral oil),
tive column chromatography or re-crystallization.
cm−1: 3396, 3250, 1684, 1595. HRMS (ESI) m/z calcd for
Scale-up procedure. A 50 mL round bottomed flask equipped C20H18NO3+ (M + H)+: 320.1281, found: 320.1288.
with a reflux condenser and a drying tube was charged with a
Methyl 5-((4-chlorophenyl)amino)-[1,1′-biphenyl]-3-carboxylate
solution of β-diketone 1 (10 mmol, 1.0 equiv.) in acetone
(3ac)
(10 mL), 4 Å molecular sieves (2.5 g), AcOH (180 μL), and an
appropriate amount of amine 2 (11 mmol, 1.1 equiv.). The Method A (0.5 mmol scale), purified by crystallization from
mixture was placed in a preheated oil bath and stirred at 55 °C EtOH, peach solid (85 mg, 50%), mp 139–142 °C. 1H NMR
for a specified time, as shown in Fig. 2. After the reaction was (400 MHz, CDCl3) δ 7.84 (t, J = 1.6 Hz, 1H), 7.66 (dd, J = 2.3, 1.4
completed, the molecular sieves were filtered off, the solution Hz, 1H), 7.61–7.54 (m, 2H), 7.48–7.40 (m, 3H), 7.40–7.32 (m,
was concentrated in a vacuum and the residual material was 1H), 7.30–7.17 (m, 2H), 7.13–6.98 (m, 2H), 5.74 (br. s, 1H), 3.93
purified by re-crystallization.
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.1, 143.9, 143.0,
Reaction in a bomb. A stainless steel bomb charged with 141.3, 140.2, 132.2, 129.7 (2C), 129.0 (2C), 128.0, 127.3 (2C),
β-diketone 4 (0.5 mmol, 1.0 equiv.), acetone (2 mL), 4 Å mole- 126.8, 121.4, 120.4, 120.0 (2C), 117.4, 52.4. IR (mineral oil),
cular sieves (250 mg), AcOH (9 μL, 30 mol%), and amine cm−1: 3386, 1707, 1590, 1540. HRMS (ESI) m/z calcd for
(0.55 mmol, 1.1 equiv.) was heated at 150 °C (preheated oven) C20H17ClNO2+ (M + H)+: 338.0942, found: 338.0951.
for 5 h. After the reaction was completed, the molecular sieves
Methyl 5-((4-chlorophenyl)amino)-4′-methyl-[1,1′-biphenyl]-3-
were filtered off, the solution was concentrated in a vacuum
carboxylate (3bc)
and the residual material was purified by column
chromatography.
General procedure
Method A (0.5 mmol scale), purified by crystallization from
B
(microwave activation).
A
vessel EtOH–H2O, pale yellow solid (54 mg, 31%), mp 140–143 °C. 1H
charged with β-diketone 1 or 4 (0.5 mmol, 1.0 equiv.), acetone NMR (400 MHz, CDCl3) δ 7.84 (t, J = 1.5 Hz, 1H), 7.65 (dd, J =
(2 mL), 4 Å molecular sieves (250 mg), AcOH (9 μL, 30 mol%), 2.3, 1.4 Hz, 1H), 7.48 (d, J = 8.1 Hz, 2H), 7.45–7.39 (m, 1H),
and amine 2 (0.55 mmol, 1.1 equiv.) was placed in a microwave 7.31–7.19 (m, 4H), 7.06 (d, J = 8.8 Hz, 2H), 4.94 (br. s, 1H), 3.93
oven and heated at 150 °C for an appropriate time (Schemes 2 (s, 3H), 2.40 (s, 3H) 13C NMR (101 MHz, CDCl3) δ 167.1, 143.8,
and 4). When the reaction was completed, the molecular 143.0, 141.4, 137.9, 137.3, 132.1, 129.7 (2C), 129.7 (2C), 127.1
sieves were filtered off and washed several times with warm (2C), 126.7, 121.2, 120.3, 119.9 (2C), 117.2, 52.3, 21.3. IR
acetone. The solution was evaporated, and the residue was pur- (mineral oil), cm−1: 3362, 1711, 1607, 1584, 1525. HRMS (ESI)
+
ified by column chromatography.
m/z calcd for C21H19ClNO2 (M + H)+: 352.1099, found:
352.1099.
Methyl 5-(phenylamino)-[1,1′-biphenyl]-3-carboxylate (3aa)
Methyl 5-(mesitylamino)-[1,1′-biphenyl]-3-carboxylate (3ad)
Method A (0.5 mmol scale), purified by column chromato-
graphy (toluene, Rf 0.42), beige solid (91 mg, 0.30 mmol, 60%), Method A (0.5 mmol scale), purified by column chromato-
1
mp 90–92 °C. H NMR (400 MHz, CDCl3) δ 7.84 (t, J = 1.5 Hz, graphy (toluene–hexane = 2 : 1, Rf 0.26), colorless oil (125 mg,
1H), 7.72 (dd, J = 2.3, 1.5 Hz, 1H), 7.65–7.57 (m, 2H), 7.48 (dd, 73%, solidifies on standing (semisolid). 1H NMR (400 MHz,
J = 2.3, 1.6 Hz, 1H), 7.47–7.42 (m, 2H), 7.40–7.30 (m, 3H), CDCl3) δ 7.66 (t, J = 1.5 Hz, 1H), 7.59–7.49 (m, 2H), 7.44–7.38
7.19–7.13 (m, 2H), 7.06–6.98 (m, 1H), 5.78 (br. s, 1H), 3.93 (s, (m, 2H), 7.38–7.29 (m, 1H), 7.21 (dd, J = 2.4, 1.5 Hz, 1H), 6.97
3H). 13C NMR (101 MHz, CDCl3) δ 167.1, 144.2, 142.9, 142.5, (dq, J = 1.3, 0.7 Hz, 2H), 6.84 (dd, J = 2.4, 1.7 Hz, 1H), 5.15 (br.
140.4, 132.0, 129.7 (2C), 129.0 (2C), 127.9, 127.3 (2C), 122.2, S, 1H), 3.91 (s, 3H), 2.33 (d, J = 0.7 Hz, 3H), 2.22 (d, J = 0.6 Hz,
121.0, 120.2, 118.9 (2C), 117.3, 52.3. IR (mineral oil), cm−1
:
6H). 13C NMR (101 MHz, CDCl3) δ 167.5, 147.4, 142.7, 140.9,
136.1, 136.0, 134.9, 131.9, 129.6 (2C), 128.8 (2C), 127.7 (2C),
127.3 (2C), 118.2, 115.8, 113.3, 52.1, 21.0, 18.4 (2C). IR
(CHCl3), cm−1: 3420, 3200, 1714, 1597. HRMS (ESI) m/z calcd
for C23H24NO2+ (M + H)+: 346.1802, found: 346.1808.
+
3374, 1730, 1699, 1591. HRMS (ESI) m/z calcd for C20H18NO2
(M + H)+: 304.1332, found: 304.1335.
Methyl 5-((2-hydroxyphenyl)amino)-[1,1′-biphenyl]-3-
carboxylate (3ab)
Methyl 5-(benzylamino)-[1,1′-biphenyl]-3-carboxylate (3ae)
Method A (0.5 mmol scale) (should be isolated as soon as
possible, due to the high tendency of the o-aminophenol Method B (0.5 mmol scale), purified by column chromato-
moiety to undergo oxidation) purified by column chromato- graphy (toluene–acetone = 20 : 1; Rf 0.69), off-white/white solid
graphy (toluene–acetone = 10 : 1, Rf 0.34), yellow-orange solid (122 mg, 77%), mp 114–116 °C. Method A (2 mmol scale), puri-
1
(145 mg, 91%), mp 130–133 °C. H NMR (400 MHz, CDCl3) δ fied by crystallization from EtOH (414 mg, 65%). 1H NMR
7.79 (t, J = 1.5 Hz, 1H), 7.59–7.53 (m, 2H), 7.51 (dd, J = 2.3, 1.4 (400 MHz, CDCl3) δ 7.56 (t, J = 1.5 Hz, 1H), 7.51–7.41 (m, 2H),
Hz, 1H), 7.46–7.39 (m, 2H), 7.39–7.29 (m, 1H), 7.28–7.23 (m, 7.38–7.14 (m, 9H), 6.94 (dd, J = 2.4, 1.6 Hz, 1H), 4.50 (br. s,
1H), 7.22–7.19 (m, 1H), 7.13–7.05 (m, 1H), 7.01 (dd, J = 8.0, 1.6 1H), 4.33 (s, 2H), 3.82 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
Hz, 1H), 6.92 (td, J = 7.6, 1.6 Hz, 1H), 6.08 (s, 1H), 5.65 (s, 1H), 167.5, 148.4, 142.7, 140.9, 138.9, 131.8, 128.9 (2C), 128.9 (2C),
3.91 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.4, 150.4, 146.0, 127.8 (2C), 127.7, 127.6, 127.3 (2C), 118.3, 116.3, 113.0, 52.2,
142.9, 140.3, 131.9, 129.0, 128.9 (2C), 127.9, 127.2 (2C), 125.9, 48.7. IR (mineral oil), cm−1: 3388, 1709, 1605, 1526. HRMS
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(ESI) m/z calcd for C21H20NO2 (M + H)+: 318.1489, found: 0.20 mmol, 1.0 equiv.) were added to a solution of 1a (41 mg,
+
318.1497.
0.20 mmol, 1.0 equiv.) in acetone (0.5 mL). The resultant solu-
tion was stirred at 55 °C for 2 d; after the reaction was com-
pleted, the solution was evaporated, and purified by column
chromatography (toluene–MeOH = 10 : 1, Rf 0.19), affording a
Methyl 4′-methyl-5-(piperidin-1-yl)-[1,1′-biphenyl]-3-
carboxylate (3bf)
Method A (0.5 mmol scale), purified by column chromato- light-orange oil (49 mg, 61%). 1H NMR (400 MHz, CDCl3) δ
graphy (toluene–acetone = 50 : 1, Rf 0.59), red-orange solid 7.73 (t, J = 1.5 Hz, 1H), 7.56–7.48 (m, 2H), 7.45–7.37 (m, 3H),
1
(99 mg, 64%), mp 49–51 °C. H NMR (400 MHz, CDCl3) δ 7.73 7.37–7.28 (m, 2H), 7.13 (dd, J = 2.5, 1.6 Hz, 1H), 6.55 (dd, J =
(t, J = 1.5 Hz, 1H), 7.60 (dd, J = 2.5, 1.4 Hz, 1H), 7.55–7.50 (m, 9.0, 1.3 Hz, 1H), 6.14 (dd, J = 6.9, 1.4 Hz, 1H), 4.19 (d, J = 15.6
2H), 7.33 (dd, J = 2.5, 1.6 Hz, 1H), 7.29–7.21 (m, 2H), 3.94 (s, Hz, 1H), 4.01 (ddd, J = 15.6, 6.7, 1.1 Hz, 1H), 3.90 (s, 3H),
3H), 3.33–3.20 (m, 4H), 2.41 (s, 3H), 1.82–1.71 (m, 4H), 3.85–3.78 (m, 1H), 3.73 (ddt, J = 11.4, 3.3, 1.6 Hz, 1H),
1.70–1.57 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 167.6, 152.6, 3.23–3.00 (m, 3H), 2.77–2.56 (m, 1H), 2.09–2.01 (m, 1H),
142.3, 138.3, 137.4, 131.4, 129.5 (2C), 127.2 (2C), 119.5, 119.1, 1.99–1.85 (m, 1H). 13C NMR (101 MHz, CDCl3) δ 167.2, 163.5,
115.9, 52.1, 50.6 (2C), 25.9 (2C), 24.4, 21.2. IR (mineral oil), 151.8, 150.5, 142.6, 140.7, 139.2, 131.5, 128.9 (2C), 127.8, 127.3
cm−1: 1728, 1596, 1570, 1516. HRMS (ESI) m/z calcd for (2C), 120.7, 120.4, 117.1, 116.5, 105.8, 57.2, 57.0, 52.2, 50.1,
C20H24NO2+ (M + H)+: 310.1802, found: 310.1809.
35.4, 28.0, 25.6. IR (CHCl3), cm−1: 1718, 1651, 1595, 1548.
HRMS (ESI) m/z calcd for C25H25N2O3 (M + H)+: 401.1860,
+
Methyl 5-((2-hydroxyethyl)amino)-[1,1′-biphenyl]-3-carboxylate
(3ag)
found: 401.1852.
Methyl 3-(benzylamino)-5-methylbenzoate (3ce)
Method B (0.5 mmol scale), purified by column chromato-
graphy (toluene–acetone = 2 : 1, Rf 0.52), light-yellow solid Method B (0.5 mmol scale), purified by column chromato-
(123 mg, 91%), mp 83–86 °C. 1H NMR (400 MHz, CDCl3) δ 7.63 graphy (toluene–acetone = 10 : 1, Rf 0.73), off-white solid
(t, J = 1.5 Hz, 1H), 7.60–7.55 (m, 2H), 7.47–7.39 (m, 2H), (84 mg, 66%), mp 64–66 °C. 1H NMR (400 MHz, CDCl3) δ
7.39–7.32 (m, 1H), 7.30 (dd, J = 2.4, 1.4 Hz, 1H), 7.03 (dd, J = 7.40–7.26 (m, 5H), 7.24 (tt, J = 1.4, 0.7 Hz, 1H), 7.16 (ddd, J =
2.4, 1.6 Hz, 1H), 3.91 (s, 3H), 3.90–3.84 (m, 2H), 3.39 (dd, J = 2.3, 1.5, 0.6 Hz, 1H), 6.65 (ddd, J = 2.3, 1.5, 0.7 Hz, 1H), 4.35 (s,
5.7, 4.8 Hz, 2H), 3.00 (br. s, 2H). 13C NMR (101 MHz, CDCl3) δ 2H), 4.31 (br. s, 1H), 3.88 (s, 3H), 2.30 (dd, J = 0.7, 0.6 Hz, 3H).
167.6, 148.8, 142.7, 140.9, 131.8, 128.9 (2C), 127.7, 127.3 (2C), 13C NMR (101 MHz, CDCl3) δ 167.7, 148.2, 139.3, 139.1, 131.2,
118.2, 116.5, 112.8, 61.4, 52.2, 46.3. IR (mineral oil), cm−1
:
128.8 (2C), 127.7 (2C), 127.5, 120.0, 118.3, 111.2, 52.0, 48.6,
21.6. IR (mineral oil), cm−1: 3384, 1708, 1605, 1526. HRMS
+
3380, 1710, 1595, 1525. HRMS (ESI) m/z calcd for C16H18NO3
(M + H)+: 272.1281, found: 272.1288.
(ESI) m/z calcd for C16H18NO2 (M + H)+: 256.1332, found:
+
256.1336.
(5-(Methoxycarbonyl)-[1,1′-biphenyl]-3-yl)-L-proline (3ah)
Methyl 3-(cyclohexylamino)-5-methylbenzoate (3cj)
Method A (2 mmol scale). The solvent was evaporated and the
residue was poured into NaHCO3 (sat; 5 mL) and extracted Method B (0.5 mmol scale), purified by column chromato-
with Et2O (3 × 5 mL), the water layer was acidified (with conc. graphy (toluene–acetone = 50 : 1, Rf 0.39), light-yellow solid
1
HCl, pH ca. 2–3), and the formed precipitate was filtered off, (95 mg, 77%), mp 70–71 °C. H NMR (400 MHz, CDCl3) δ 7.15
affording a peach solid (333 mg, 51%), mp 69–72 °C. An (tt, J = 1.4, 0.7 Hz, 1H), 7.06 (ddd, J = 2.3, 1.5, 0.6 Hz, 1H), 6.57
additional portion of 3ah could be isolated by the extraction of (tt, J = 1.6, 0.8 Hz, 1H), 3.88 (s, 3H), 3.58 (br. s, 1H), 3.30 (tt, J =
the acidified supernatant with ethyl acetate (3 × 5 mL), 10.1, 3.8 Hz, 1H), 2.30 (dd, J = 0.7, 0.6 Hz, 3H), 2.12–1.98 (m,
affording 105 mg (16%) with purity ca. 90%. 1H NMR 2H), 1.85–1.72 (m, 2H), 1.71–1.57 (m, 1H), 1.49–1.33 (m, 2H),
(400 MHz, CDCl3) δ 8.15 (br. s, 1H), 7.64 (d, J = 1.3 Hz, 1H), 1.31–1.07 (m, 3H). 13C NMR (101 MHz, CDCl3) δ 167.8, 147.6,
7.57 (d, J = 7.1 Hz, 2H), 7.41 (t, J = 7.4 Hz, 2H), 7.36–7.30 (m, 139.1, 131.2, 119.0, 118.5, 111.3, 51.9, 51.7, 33.5 (2C), 26.0,
1H), 7.25 (d, J = 1.8 Hz, 1H), 6.95 (t, J = 1.9 Hz, 1H), 4.38 (dd, J 25.1 (2C), 21.5. IR (mineral oil), cm−1: 3369, 1726, 1707, 1603,
+
= 8.3, 2.6 Hz, 1H), 3.90 (s, 3H), 3.66 (td, J = 8.4, 3.1 Hz, 1H), 1530. HRMS (ESI) m/z calcd for C15H22NO2 (M + H)+:
3.44 (q, J = 8.0 Hz, 1H), 2.45–2.23 (m, 2H), 2.22–1.91 (m, 2H). 248.1645, found: 248.1645.
13C NMR (101 MHz, CDCl3) δ 178.6, 167.7, 147.2, 142.7, 141.1,
Methyl 3-methyl-5-morpholinobenzoate (3ck)
131.7, 128.9 (2C), 127.7, 127.4 (2C), 117.5, 115.3, 112.2, 61.0,
52.2, 48.9, 31.1, 23.9. IR (mineral oil), cm−1: 1717, 1598. HRMS Method A (0.5 mmol scale), purified by column chromato-
(ESI) m/z calcd for C19H20NO4 (M + H)+: 326.1387, found: graphy (toluene–EtOAc = 10 : 1, Rf 0.33), pale yellow oil
+
326.1389.
(59 mg, 50%). 1H NMR (400 MHz, CDCl3) δ 7.40 (m, 2H),
6.95 (d, J = 2.2 Hz, 1H), 3.89 (s, 3H), 3.89–3.85 (m, 4H),
3.25–3.11 (m, 4H), 2.36 (m, 3H). 13C NMR (101 MHz, CDCl3)
δ 167.5, 151.2, 139.3, 131.2, 122.4, 121.2, 114.1, 66.9 (2C),
Methyl 5-((1R,5S)-8-oxo-1,5,6,8-tetrahydro-2H-1,5-
methanopyrido[1,2-a][1,5]diazo1(4H)-yl)-[1,1′-biphenyl]-3-
carboxylate (3ai)
Method A (0.2 mmol scale). Procedure: 125 mg of 4 Å mole- (ESI) m/z calcd for C13H18NO3 (M + H)+: 236.1281, found:
cular sieves, 3.6 μL of AcOH and cytisine (2i; 38 mg, 236.1284.
52.2, 49.7 (2C), 21.7. IR (CHCl3), cm−1: 1716, 1599. HRMS
+
10038 | Org. Biomol. Chem., 2019, 17, 10030–10044
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Methyl 3-(tert-butyl)-5-morpholinobenzoate (3dk)
7.68–7.61 (m, 2H), 7.59–7.55 (m, 2H), 7.52 (p, J = 1.6 Hz, 2H),
7.47–7.40 (m, 3H), 7.40–7.28 (m, 5H), 7.19–7.11 (m, 3H), 7.02
(tt, J = 7.3, 1.1 Hz, 1H), 4.92 (s, 1H). 13C NMR (101 MHz,
CDCl3) δ 166.0, 144.7, 143.4, 142.1, 140.4, 138.1, 137.2, 129.7
(2C), 129.2 (2C), 129.0 (2C), 128.1, 127.3 (2C), 124.8, 122.6,
120.5 (2C), 119.4 (2C), 118.9, 117.9, 115.0. HRMS (ESI) m/z
calcd for C25H21N2O+ (M + H)+: 365.1648, found: 365.1642.
Method A (0.5 mmol scale), purified by column chromato-
graphy (toluene–acetone = 10 : 1, Rf 0.47), light-yellow oil (soli-
1
difies in a fridge; 79 mg, 57%). H NMR (400 MHz, CDCl3) δ
7.62 (t, J = 1.6 Hz, 1H), 7.41 (dd, J = 2.5, 1.4 Hz, 1H), 7.19–7.07
(m, 1H), 3.90 (s, 3H), 3.90–3.84 (m, 4H), 3.38–3.12 (m, 4H),
1.34 (s, 9H). 13C NMR (101 MHz, CDCl3) δ 167.7, 152.6, 151.3,
130.9, 119.0, 118.1, 114.1, 67.0 (2C), 52.1, 49.8 (2C), 35.2, 31.5
(3C). IR (CHCl3), cm−1: 1716, 1598. HRMS (ESI) m/z calcd for
C16H24NO3+ (M + H)+: 278.1751, found: 278.1750.
5-Morpholino-N-(p-tolyl)-[1,1′-biphenyl]-3-carboxamide (3gk)
Method A (0.5 mmol scale), purified by crystallization from
1
EtOH, off-white solid (135 mg, 73%), mp 182–184 °C. H NMR
Methyl (E)-3-(benzylamino)-5-styrylbenzoate (3ee)
(400 MHz, CDCl3) δ 7.93 (s, 1H), 7.66–7.56 (m, 2H), 7.53 (d, J =
8.4 Hz, 2H), 7.49–7.41 (m, 4H), 7.40–7.34 (m, 1H), 7.23 (dd, J =
2.5, 1.5 Hz, 1H), 7.16 (d, J = 8.2 Hz, 2H), 4.12–3.60 (m, 4H),
3.39–3.17 (m, 4H), 2.34 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
166.1, 152.1, 143.1, 141.0, 137.0, 135.6, 134.4, 129.7 (2C), 129.0
(2C), 128.0, 127.4 (2C), 120.5 (2C), 117.7, 116.9, 113.7, 66.9
(2C), 49.3 (2C), 21.0. IR (mineral oil), cm−1: 1640, 1590, 1525.
Method A (2 mmol scale). The reaction mixture was filtered
through a short column of silica gel, and purified by crystalli-
zation from EtOH, light-yellow solid (299 mg, 44%), mp
129–131 °C. Method A (10 mmol scale), purified by crystalliza-
1
tion from EtOH (1.625 g, 47%). H NMR (400 MHz, CDCl3) δ
7.60 (td, J = 1.5, 0.5 Hz, 1H), 7.50 (dtd, J = 7.7, 1.7, 1.0 Hz, 2H),
7.46–7.19 (m, 9H), 7.11 (d, J = 16.3 Hz, 1H), 7.03 (d, J = 16.3
Hz, 1H), 6.95–6.91 (m, 1H), 4.50 (br. s, 1H), 4.41 (s, 2H), 3.91
(s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.4, 148.3, 138.9,
138.8, 137.3, 131.7, 129.8, 128.9 (2C), 128.8 (2C), 128.4, 127.9,
127.8 (2C), 127.7, 126.8 (2C), 117.6, 115.4, 113.4, 52.2, 48.7. IR
(mineral oil), cm−1: 3373, 1708, 1595, 1520. HRMS (ESI) m/z
calcd for C23H22NO2+ (M + H)+: 344.1645, found: 344.1633.
HRMS (ESI) m/z calcd for C24H25N2O2 (M + H)+: 373.1911,
+
found: 373.1914.
2-Methyl-N-phenyl-5-(phenylamino)-[1,1′-biphenyl]-
3-carboxamide (3ia)
Method A (0.25 mmol scale). Procedure: 125 mg of 4 Å mole-
cular sieves, 4 μL of AcOH (30 mol%) and aniline (2a; 24 μL,
0.286 mmol, 1.1 equiv.) were added to a solution of ethyl
3-methyl-2,4-dioxo-4-phenylbutanoate (1i; 61 mg, 0.26 mmol, 1
equiv.) in acetone (0.5 mL). The resultant solution was heated
at 55 °C. When the reaction was completed, the molecular
sieves were filtered off and washed several times with warm
acetone. The solution was evaporated, and the residue was pur-
ified by column chromatography (toluene–EtOAc = 25 : 1, Rf
Methyl 3-(benzylamino)-5-(furan-2-yl)benzoate (3fe)
Method A (0.5 mmol scale), purified by column chromato-
graphy (toluene, Rf 0.36), light-yellow solid (119 mg, 77%), mp
104–106 °C. 1H NMR (400 MHz, CDCl3) δ 7.71 (t, J = 1.5 Hz,
1H), 7.45 (dd, J = 1.8, 0.8 Hz, 1H), 7.42–7.26 (m, 5H), 7.25 (dd,
J = 2.4, 1.4 Hz, 1H), 7.14 (dd, J = 2.4, 1.5 Hz, 1H), 6.66 (dd, J =
3.4, 0.8 Hz, 1H), 6.46 (dd, J = 3.4, 1.8 Hz, 1H), 4.40 (s, 2H), 4.24
(br. s, 1H), 3.91 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 167.3,
153.6, 148.6, 142.3, 139.0, 132.1, 131.8, 128.8 (2C), 127.7 (2C),
127.5, 114.8, 112.7, 112.2, 111.8, 105.8, 52.2, 48.4. IR (mineral
oil), cm−1: 3398, 1728, 1707, 1604, 1525. HRMS (ESI) m/z calcd
for C19H18NO3+ (M + H)+: 308.1281, found: 308.1284.
1
0.28), affording a grey solid (26 mg, 54%), mp 122–125 °C. H
NMR (400 MHz, CDCl3) δ 7.67–7.55 (m, 3H), 7.45–7.32 (m, 5H),
7.31–7.22 (m, 4H), 7.21–7.03 (m, 5H), 6.96 (t, J = 7.4 Hz, 1H),
5.10 (br. s, 1H), 2.27 (s, 3H). 13C NMR (101 MHz, CDCl3) δ
168.6, 144.9, 142.5, 141.4, 140.9, 139.0, 138.1, 129.7 (2C), 129.2
(4C), 128.3 (2C), 127.4, 125.9, 124.8, 122.1, 121.1, 120.1 (2C),
118.7 (2C), 115.2, 17.0. IR (CCl4), cm−1: 3401, 3289, 1652, 1594.
HRMS (ESI) m/z calcd for C26H23N2O+ (M + H)+: 379.1805,
found: 379.1811.
5-(Phenylamino)-N-(p-tolyl)-[1,1′-biphenyl]-3-carboxamide (3ga)
Method A (0.5 mmol scale), purified by column chromato-
graphy (toluene–acetone = 30 : 1, Rf 0.24), light-yellow solid
(136 mg, 72%), mp 76–79 °C. 1H NMR (400 MHz, CDCl3) δ 7.87
(s, 1H), 7.60–7.52 (m, 2H), 7.55–7.48 (m, 4H), 7.48–7.38 (m,
3H), 7.41–7.32 (m, 1H), 7.35–7.26 (m, 2H), 7.21–7.12 (m, 4H),
7.02 (tt, J = 7.5, 1.1 Hz, 1H), 4.67 (br. s, 1H), 2.34 (s, 3H). 13C
NMR (101 MHz, CDCl3) δ 165.9, 144.5, 143.3, 142.1, 140.4,
137.3, 135.5, 134.4, 129.7 (2C), 129.7 (2C), 129.0 (2C), 128.0,
127.3 (2C), 122.6, 120.5 (2C), 119.4 (2C), 118.9, 118.1, 115.1,
21.0. IR (mineral oil), cm−1: 3344, 1652, 1590. HRMS (ESI) m/z
calcd for C26H23N2O+ (M + H)+: 379.1805, found: 379.1810.
Methyl 4′-chloro-5-morpholino-[1,1′-biphenyl]-3-carboxylate (3jk)
Method A (10 mmol scale), purified by crystallization from EtOH,
1
off-white solid (2.34 g, 71%), mp 97–99 °C. H NMR (400 MHz,
CDCl3) δ 7.72 (t, J = 1.5 Hz, 1H), 7.58 (dd, J = 2.5, 1.4 Hz, 1H),
7.52 (d, J = 8.8 Hz, 2H), 7.41 (d, J = 8.7 Hz, 2H), 7.22 (dd, J = 2.5,
1.6 Hz, 1H), 3.93 (s, 3H), 3.91–3.87 (m, 4H), 3.31–3.20 (m, 4H).
13C NMR (101 MHz, CDCl3) δ 167.2, 152.0, 141.5, 139.4, 134.0,
131.9, 129.1 (2C), 128.6 (2C), 119.9, 118.6, 115.8, 66.9 (2C), 52.3,
49.4 (2C). IR (mineral oil), cm−1: 1727, 1602. HRMS (ESI) m/z
calcd for C18H19ClNO3+ (M + H)+: 332.1048, found: 332.1052.
N-Phenyl-5-(phenylamino)-[1,1′-biphenyl]-3-carboxamide (3ha)
N-Phenyl-3-(thiophen-2-yl)-5-(trifluoromethyl)aniline (5aa)
Method A (0.5 mmol scale), isolated by trituration with EtOH
(toluene–EtOAc = 10 : 1, Rf 0.45), beige solid (119 mg, 65%), Method B (0.5 mmol scale), purified by column chromato-
mp = 148–149 °C. 1H NMR (400 MHz, CDCl3) δ 7.91 (s, 1H), graphy (toluene, Rf 0.87), grey solid (121 mg, 76%), mp
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47–49 °C. 1H NMR (400 MHz, CDCl3) δ 7.52–7.30 (m, 6H), 7.19 7.50–7.44 (m, 2H), 7.44–7.38 (m, 2H), 7.38–7.35 (m, 1H),
(ddd, J = 2.3, 1.5, 0.7 Hz, 1H), 7.18–7.14 (m, 2H), 7.13–7.05 (m, 7.32–7.28 (m, 2H), 7.21 (ddd, J = 2.3, 1.5, 0.7 Hz, 1H),
2H), 5.85 (br. s, 1H). 13C NMR (101 MHz, CDCl3) δ 144.9, 7.12–7.04 (m, 2H), 5.84 (br. s, 1H). 13C NMR (101 MHz, CDCl3)
143.0, 141.7, 136.6, 132.6 (q, J = 32.2 Hz), 129.8 (2C), 128.3, δ 144.4, 143.7, 140.7, 139.9, 132.6 (q, J = 32.0 Hz), 129.8 (2C),
125.8, 124.3, 124.1 (q, J = 272.7 Hz), 122.8, 119.6 (2C), 116.9, 129.1 (2C), 128.3, 127.5, 127.3 (2C), 124.2 (q, J = 272.6 Hz),
114.7 (q, J = 4.0 Hz), 112.1 (q, J = 3.9 Hz). 19F NMR (377 MHz, 120.6 (2C), 118.7, 116.6 (q, J = 3.9 Hz), 112.5 (q, J = 3.8 Hz). 19
CDCl3, PhCF3) δ −62.9. IR (mineral oil), cm−1: 3390, 1609, NMR (377 MHz, CDCl3, PhCF3) δ −62.7. IR (mineral oil), cm−1
F
:
1594, 1538. HRMS (ESI) m/z calcd for C17H13F3NS+ (M + H)+: 3397, 1612, 1589, 1520. HRMS (ESI) m/z calcd for
320.0715, found: 320.0706.
C19H14ClF3N+ (M + H)+: 348.0761, found: 348.0750.
3-(Thiophen-2-yl)-N-(p-tolyl)-5-(trifluoromethyl)aniline (5al)
N-Benzyl-5-(trifluoromethyl)-[1,1′-biphenyl]-3-amine (5be)
Method B (0.5 mmol scale), purified by column chromato- Method B (0.5 mmol scale), purified by column chromato-
graphy (toluene, Rf 0.88), apricot solid (134 mg, 80%), mp graphy (toluene, Rf 0.82), light-orange oil (132 mg, 80%).
102–104 °C. 1H NMR (400 MHz, CDCl3) δ 7.37–7.32 (m, 3H), Method A (0.5 mmol scale) yielded 135 mg (82%). 1H NMR
7.31 (q, J = 1.2 Hz, 1H), 7.21–7.13 (m, 2H), 7.13–7.01 (m, 4H), (400 MHz, CDCl3) δ 7.68–7.54 (m, 2H), 7.55–7.32 (m, 8H), 7.26
5.78 (br. s, 1H), 2.36 (s, 3H). 13C NMR (101 MHz, CDCl3) δ (td, J = 1.6, 0.8 Hz, 1H), 7.01 (t, J = 1.9 Hz, 1H), 6.90 (ddd, J =
145.7, 143.2, 138.9, 136.5, 132.9, 132.6 (q, J = 32.0 Hz), 130.3 2.2, 1.5, 0.7 1H), 4.43 (s, 2H), 4.30 (br. s, 1H). 13C NMR
(2C), 128.2, 125.7, 124.2, 124.2 (q, J = 272.7 Hz), 120.7 (2C), (101 MHz, CDCl3) δ 148.8, 143.3, 140.6, 138.7, 132.2 (q, J = 31.7
116.2, 114.1 (q, J = 4.0 Hz), 111.3 (t, J = 3.9 Hz), 20.9. 19F NMR Hz), 128.9(4C), 128.0, 127.7, 127.7 (2C), 127.3 (2C), 124.5 (q, J =
(377 MHz, CDCl3, C6F6) δ −62.9. IR (mineral oil), cm−1: 3404, 272.6 Hz), 114.6, 113.3 (q, J = 3.9 Hz), 108.2 (q, J = 3.9 Hz),
1599, 1515. HRMS (ESI) m/z calcd for C18H15F3NS+ (M + H)+: 48.4. 19F NMR (377 MHz, CDCl3, PhCF3) δ −62.6. IR (CHCl3),
334.0872, found: 334.0863.
cm−1: 3423, 1611, 1521. HRMS (ESI) m/z calcd for C20H17F3N+
(M + H)+: 328.1308, found: 328.1311.
N-(4-Methoxyphenyl)-3-(thiophen-2-yl)-5-(trifluoromethyl)
aniline (5am)
N-(tert-Butyl)-5-(trifluoromethyl)-[1,1′-biphenyl]-3-amine (5bo)
Method B (0.5 mmol scale), purified by column chromato- Method B (0.5 mmol scale), purified by column chromato-
graphy (toluene, Rf 0.67), apricot solid (148 mg, 85%), mp graphy (toluene, Rf 0.52), light-orange oil (121 mg, 82%). 1H
80–82 °C. 1H NMR (400 MHz, CDCl3) δ 7.33–7.28 (m, 3H), NMR (400 MHz, CDCl3) δ 7.65–7.52 (m, 2H), 7.50–7.42 (m, 2H),
7.25–7.20 (m, 1H), 7.18–7.11 (m, 2H), 7.11–7.07 (m, 1H), 7.00 7.41–7.30 (m, 1H), 7.20 (td, J = 1.6, 0.8 Hz, 1H), 7.11 (d, J = 2.0
(ddd, J = 2.2, 1.5, 0.7 Hz, 1H), 6.98–6.91 (m, 2H), 5.67 (br. s, Hz, 1H), 6.97 (d, J = 1.9 Hz, 1H), 4.07 (br. s, 1H), 1.43 (s, 9H).
1H), 3.84 (s, 3H). 13C NMR (101 MHz, CDCl3) δ 156.6, 146.8, 13C NMR (101 MHz, CDCl3) δ 147.8, 143.0, 140.8, 132.0 (q, J =
143.3, 136.4, 134.2, 132.5 (q, J = 32.0 Hz), 128.2, 125.6, 124.2 (q, 31.6 Hz), 129.0 (2C), 127.9, 127.3 (2C), 124.6 (q, J = 272.5 Hz),
J = 272.6 Hz), 124.1, 123.9 (2C), 115.1 (3C), 113.5 (q, J = 3.9 Hz), 118.0, 113.3 (q, J = 3.9 Hz), 111.5 (q, J = 3.9 Hz), 51.7, 30.1 (3C).
110.3 (q, J = 3.9 Hz), 55.7. 19F NMR (377 MHz, CDCl3, PhCF3) δ 19F NMR (377 MHz, CDCl3, PhCF3) δ −62.6. IR (CHCl3), cm−1
:
−62.9. IR (mineral oil), cm−1: 3397, 1599, 1513. HRMS (ESI) m/z 3428, 1606, 1578, 1526. HRMS (ESI) m/z calcd for C17H19F3N+
calcd for C18H15F3NOS+ (M + H)+: 350.0821, found: 350.0809.
(M + H)+: 294.1464, found: 294.1461.
3-(Thiophen-2-yl)-5-(trifluoromethyl)-N-(4-(trifluoromethyl)
phenyl)aniline (5an)
2-((3-(Thiophen-2-yl)-5-(trifluoromethyl)phenyl)amino)ethan-
1-ol (5ag)
Method B (0.5 mmol scale), purified by column chromato- Method B (0.5 mmol scale), purified by column chromato-
graphy (toluene, Rf 0.86), off-white solid (104 mg, 54%), mp graphy (toluene–acetone, 4 : 1, Rf 0.32), off-white solid (96 mg,
59–60 °C. 1H NMR (400 MHz, CDCl3) δ 7.60–7.54 (m, 2H), 67%), mp 77–78 °C. 1H NMR (400 MHz, CDCl3) δ 7.36–7.28 (m,
7.51–7.45 (m, 2H), 7.40–7.32 (m, 2H), 7.31–7.23 (m, 1H), 2H), 7.20 (tt, J = 1.6, 0.8 Hz, 1H), 7.08 (dd, J = 5.1, 3.6 Hz, 1H),
7.17–7.08 (m, 3H), 6.04 (br. s, 1H). 13C NMR (101 MHz, CDCl3) 7.02–6.96 (m, 1H), 6.77 (ddd, J = 2.3, 1.5, 0.7 Hz, 1H), 4.19 (br.
δ 145.5, 143.0, 142.5, 137.0, 133.0 (q, J = 32.4 Hz), 128.4, 127.2 s, 1H), 3.89 (dd, J = 5.7, 4.8 Hz, 2H), 3.37 (dd, J = 5.7, 4.8 Hz,
(q, J = 3.7 Hz, 2C), 126.2, 124.5 (q, J = 271.0 Hz), 123.9 (q, J = 2H), 1.73 (br. s, 1H). 13C NMR (101 MHz, CDCl3) δ 149.0,
272.7 Hz), 123.6 (q, J = 32.8 Hz), 119.1, 117.0 (2C), 116.6 (q, J = 143.4, 136.3, 132.4 (q, J = 31.9 Hz), 128.2, 125.5, 124.3 (q, J =
3.9 Hz), 114.2 (q, J = 3.9 Hz). 19F NMR (377 MHz, CDCl3, 272.7 Hz), 124.0, 113.5, 112.2 (q, J = 4.0 Hz), 108.4 (q, J = 3.9
PhCF3) δ −61.6, −62.9. IR (neat), cm−1: 3437, 3405, 1600, 1526. Hz), 61.2, 45.9. 19F NMR (377 MHz, CDCl3, PhCF3) δ −62.9. IR
HRMS (ESI) m/z calcd for C18H10F6NS− (M − H)−: 386.0444, (mineral oil), cm−1: 3289, 1609, 1531, 1512. HRMS (ESI) m/z
found: 386.0442.
calcd for C13H13F3NOS+ (M + H)+: 288.0664, found: 288.0667.
N-(4-Chlorophenyl)-5-(trifluoromethyl)-[1,1′-biphenyl]-3-amine (5bc) N-(Furan-2-ylmethyl)-3-(thiophen-2-yl)-5-(trifluoromethyl)
aniline (5ap)
Method B (0.5 mmol scale), purified by column chromato-
graphy (toluene, Rf 0.88), apricot solid (118 mg, 68%), mp Method B (0.5 mmol scale), purified by column chromato-
82–84 °C. 1H NMR (400 MHz, CDCl3) δ 7.60–7.54 (m, 2H), graphy (toluene, Rf 0.73), pale yellow solid (97 mg, 60%), mp
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36–39 °C. 1H NMR (400 MHz, CDCl3) δ 7.40 (dd, J = 1.9, 4-(3-Ethyl-4-methyl-5-(trifluoromethyl)phenyl)morpholine (5dk)
0.8 Hz, 1H), 7.35–7.30 (m, 2H), 7.24 (td, J = 1.6, 0.8 Hz, 1H),
Method A (0.5 mmol scale), purified by column chromato-
graphy (toluene, Rf 0.27), colorless oil (76 mg, 56%). H NMR
7.09 (dd, J = 5.1, 3.6 Hz, 1H), 7.03 (t, J = 1.9 Hz, 1H), 6.82
(ddd, J = 2.3, 1.5, 0.7 Hz, 1H), 6.36 (dd, J = 3.2, 1.9 Hz, 1H),
6.30 (dq, J = 3.3, 0.8 Hz, 1H), 4.39 (s, 2H), 4.33 (br. s, 1H).
13C NMR (101 MHz, CDCl3) δ 151.9, 148.3, 143.5, 142.4,
136.2, 132.4 (q, J = 31.9 Hz), 128.2, 125.5, 124.3 (q, J = 272.7
Hz), 124.0, 113.5, 112.4 (q, J = 4.0 Hz), 110.6, 108.6 (q, J = 3.9
Hz), 107.6, 41.3. 19F NMR (377 MHz, CDCl3, PhCF3) δ −62.84.
IR (mineral oil), cm−1: 3393, 1609, 1514, 1504. HRMS (ESI)
m/z calcd for C16H13F3NOS+ (M + H)+: 324.0664, found:
324.0663.
1
(400 MHz, CDCl3) δ 7.05 (d, J = 2.7 Hz, 1H), 6.91 (d, J = 2.6 Hz,
1H), 4.02–3.67 (m, 4H), 3.35–2.96 (m, 4H), 2.68 (q, J = 7.5 Hz,
2H), 2.33 (q, J = 1.7 Hz, 3H), 1.23 (t, J = 7.6 Hz, 3H). 13C NMR
(101 MHz, CDCl3) δ 149.1, 145.5, 130.0 (q, J = 28.3 Hz), 125.7,
125.0 (q, J = 274.2 Hz), 119.3, 111.3 (q, J = 6.2 Hz), 66.9 (2C),
49.6 (2C), 27.2, 14.7, 13.9 (q, J = 2.6 Hz). 19F NMR (377 MHz,
CDCl3, C6F6) δ −60.12. IR (CHCl3), cm−1: 1615. HRMS (ESI) m/z
calcd for C14H19F3NO+ (M + H)+: 274.1413, found: 274.1418.
N-(3-(Thiophen-2-yl)-5-(trifluoromethyl)phenyl)pyridin-2-
amine (5aq)
1-(3-(Thiophen-2-yl)-5-(trifluoromethyl)phenyl)piperidine (5af)
Method B (0.5 mmol scale), purified by column chromato-
graphy (toluene, Rf 0.82), orange oil (140 mg, 90%). H NMR
Method A (0.5 mmol scale; steel bomb, 150 °C), purified by
column chromatography (toluene–EtOAc, 25 : 1, Rf 0.28), light
yellow solid (65 mg, 40%), mp 71–73 °C. Method B (0.5 mmol
scale), purified by column chromatography, light yellow solid
1
(400 MHz, CDCl3) δ 7.34 (dd, J = 3.6, 1.2 Hz, 1H), 7.33–7.26 (m,
3H), 7.10 (dd, J = 5.1, 3.6 Hz, 1H), 7.09–7.06 (m, 1H), 3.37–3.23
(m, 4H), 1.84–1.70 (m, 4H), 1.68–1.58 (m, 2H). 13C NMR
(101 MHz, CDCl3) δ 152.7, 143.9, 136.1, 132.2 (q, J = 31.7 Hz),
128.1, 125.4, 124.5 (q, J = 272.7 Hz), 124.0, 116.6, 113.2 (d, J =
4.3 Hz), 111.6 (q, J = 3.9 Hz), 50.2 (2C), 25.8 (2C), 24.3. 19F
NMR (377 MHz, CDCl3, PhCF3) δ −62.7. IR (neat), cm−1: 1687,
1602, 1531. HRMS (ESI) m/z calcd for C16H17F3NS+ (M + H)+:
312.1028, found: 312.1032.
1
(70 mg, 44%). H NMR (400 MHz, CDCl3) δ 8.26 (ddd, J = 5.1,
2.0, 0.9 Hz, 1H), 7.81 (t, J = 1.9 Hz, 1H), 7.67–7.62 (m, 1H), 7.57
(ddd, J = 8.4, 7.2, 1.9 Hz, 1H), 7.48 (td, J = 1.6, 0.8 Hz, 1H), 7.36
(dd, J = 3.6, 1.2 Hz, 1H), 7.33 (dd, J = 5.1, 1.2 Hz, 1H), 7.21 (br.
s, 1H), 7.10 (dd, J = 5.1, 3.6 Hz, 1H), 6.88 (dd, J = 8.4, 1.0 Hz,
1H), 6.83 (ddd, J = 7.3, 5.1, 0.9 Hz, 1H). 13C NMR (101 MHz,
CDCl3) δ 155.1, 147.9, 142.8, 141.8, 138.4, 136.5, 132.4 (q, J =
32.3 Hz), 128.3, 126.0, 124.4, 124.1 (q, J = 272.7 Hz), 119.9,
116.6 (q, J = 4.1 Hz), 116.1, 115.0 (q, J = 3.9 Hz), 109.7. 19F
(E)-N-Benzyl-3-styryl-5-(trifluoromethyl)aniline (5ce)
NMR (377 MHz, CDCl3, C6F6) δ −62.7. IR (mineral oil), cm−1
:
Method A (0.5 mmol scale; steel bomb, 150 °C), purified by
column chromatography (toluene–hexane, 1 : 2.5, Rf 0.30), off-
white solid (92 mg, 52%), mp 75–77 °C. Method B (0.5 mmol
scale), purified by column chromatography, off-white solid
1611, 1598, 1547. HRMS (ESI) m/z calcd for C16H12F3N2S+ (M +
H)+: 321.0668, found: 321.0668.
1
1,4-Bis(3-(thiophen-2-yl)-5-(trifluoromethyl)phenyl)piperazine
(5ar)
(94 mg, 52%). H NMR (400 MHz, CDCl3) δ 7.55–7.48 (m, 2H),
7.44–7.27 (m, 8H), 7.18 (tt, J = 1.3, 0.6 Hz, 1H), 7.10 (d, J = 16.3
Hz, 1H), 7.02 (d, J = 16.3 Hz, 1H), 6.93 (t, J = 1.7 Hz, 1H), 6.81
(ddd, J = 2.2, 1.5, 0.7 Hz, 1H), 5.08 (br. s, 1H), 4.40 (s, 2H). 13C
NMR (101 MHz, CDCl3) δ 148.0, 139.4, 138.2, 137.0, 132.2 (q, J
= 31.8 Hz), 130.4, 129.0 (2C), 128.9 (2C), 128.2, 127.9 (2C),
127.9, 127.9, 126.8 (2C), 124.4 (q, J = 272.4 Hz), 114.3, 113.2 (q,
J = 4.0 Hz), 109.2 (q, J = 4.0 Hz), 48.9. 19F NMR (376 MHz,
CDCl3, PhCF3) δ −62.8. IR (mineral oil), cm−1: 3419, 1715,
1636, 1604, 1517. HRMS (ESI) m/z calcd for C22H19F3N+ (M +
H)+: 354.1464, found: 354.1467.
Method A (1 mmol scale), after completion, water was added,
and the formed precipitate filtered off and washed with EtOH,
off-white solid (316 mg, 59%), mp 211–213 °C. 1H NMR
(400 MHz, CDCl3) δ 7.42–7.28 (m, 8H), 7.15–7.05 (m, 4H), 3.48
(s, 8H). 13C NMR (101 MHz, CDCl3, all signals are 2C) δ 151.8,
143.4, 136.5, 132.5 (q, J = 31.8 Hz), 128.3, 125.8, 124.3, 124.3
(q, J = 272.7 Hz), 116.7, 114.5 (d, J = 4.2 Hz), 111.7 (t, J =
4.1 Hz), 49.0. 19F NMR (377 MHz, CDCl3, C6F6) δ −62.7.
IR (mineral oil), cm−1: 1601. HRMS (ESI) m/z calcd for
C26H21F6N2S2+ (M + H)+: 539.1045, found: 539.1065.
3-Ethyl-4-methyl-N-phenyl-5-(trifluoromethyl)aniline (5da)
Methyl 6-methyl-5-morpholino-[1,1′-biphenyl]-3-carboxylate (7)
and methyl 4-methyl-5-morpholino-[1,1′-biphenyl]-
3-carboxylate (7′)
Method B (0.5 mmol scale), purified by column chromato-
graphy (toluene–hexane = 1 : 4, Rf 0.42), colorless oil (91 mg,
1
65%). H NMR (400 MHz, CDCl3) δ 7.33–7.27 (m, 2H), 7.23 (d,
J = 2.5 Hz, 1H), 7.12–7.02 (m, 3H), 7.01–6.88 (m, 1H), 5.76 (s, Method A (0.5 mmol scale), isolated as a mixture of isomers
1H), 2.67 (q, J = 7.5 Hz, 2H), 2.36 (q, J = 1.7 Hz, 3H), 1.23 (t, J = (ratio 2 : 1, NMR) via column chromatography (toluene–EtOAc
1
7.5 Hz, 3H). 13C NMR (101 MHz, chloroform-d) δ 145.8, 142.9, = 50 : 1, Rff 0.12 and 0.13), colorless oil (60 mg, 38%). H NMR
140.8, 130.3 (q, J = 28.9 Hz), 129.7 (2C), 127.1, 124.8 (q, J = (400 MHz, CDCl3) δ (7, major) 7.74 (d, J = 1.7 Hz, 1H), 7.70 (d, J
274.2 Hz), 121.8, 121.3, 118.2 (2C), 113.6 (q, J = 6.1 Hz), 26.9, = 1.7 Hz, 1H), 7.47–7.33 (overlapped m, 3H), 7.34–7.26 (m,
14.6, 14.1 (q, J = 2.6 Hz). 19F NMR (376 MHz, CDCl3, C6F6) δ 2H), 3.91 (s, 3H), 3.91–3.88 (overlapped m, 4H), 3.07–3.00 (m,
−60.34. HRMS (ESI) m/z calcd for C16H17F3N+ (M + H)+: 4H), 2.27 (s, 3H); (7′, minor) 7.81 (d, J = 1.9 Hz, 1H), 7.62–7.56
280.1308, found: 280.1311.
(m, 2H), 7.49–7.33 (overlapped m, 4H), 3.92 (s, 3H), 3.91–3.88
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(overlapped m, 4H), 3.00–2.94 (m, 4H), 2.57 (s, 3H). 13C NMR 30.6, 22.4 (2C). 19F NMR (377 MHz, CDCl3, C6F6) δ −62.28. IR
(101 MHz, CDCl3) δ (7, major) 167.2, 152.0, 144.1, 141.7, 136.3, (CHCl3), cm−1
: 1579, 1522. HRMS (ESI) m/z calcd for
129.3 (2C), 128.3 (2C), 128.3, 127.3, 126.4, 119.1, 67.4 (2C), C18H21F3NOS+ (M + H)+: 356.1290, found: 356.1302.
52.7 (2C), 52.1, 16.4; (7′, minor) 168.7, 152.8, 140.5, 139.4,
N-Benzyl-2,6-dimethyl-3-(thiophen-2-yl)-5-(trifluoromethyl)
aniline (8ec)
133.3, 132.7, 128.9 (2C), 127.6, 127.1 (2C), 123.9, 121.4, 67.4
(2C), 52.7 (2C), 52.0, 15.3. IR (CHCl3), cm−1: 1717, 1602, 1572.
+
HRMS (ESI) m/z calcd for C19H22NO3 (M + H)+: 312.1594, Method A (0.5 mmol scale), 0.1 equiv. of TSA·H2O was used as
found: 312.1605.
the catalyst instead of AcOH. Before column chromatography,
0.3 equiv. of triethylamine was added to neutralize TSA and
the mixture was purified by column chromatography (hexane–
toluene = 4 : 1, Rf 0.29), colorless oil (89 mg, 49%). 1H NMR
4-(2-Methyl-3-(thiophen-2-yl)-5-(trifluoromethyl)phenyl)
morpholine (8ka)
Method A (0.5 mmol scale), purified by column chromato- (400 MHz, CDCl3) δ 7.45 (s, 1H), 7.43–7.30 (m, 6H), 7.11 (dd, J
graphy (toluene, Rf 0.35), white solid (114 mg, 70%), mp = 5.2, 3.5 Hz, 1H), 7.04 (dd, J = 3.5, 1.2 Hz, 1H), 4.16 (s, 2H),
1
100–102 °C. H NMR (400 MHz, CDCl3) δ 7.43 (d, J = 1.8 Hz, 3.59 (s, 1H), 2.47 (q, J = 1.5 Hz, 3H), 2.37 (d, J = 0.9 Hz, 3H).
1H), 7.39 (dd, J = 5.1, 1.2 Hz, 1H), 7.28 (d, J = 1.8 Hz, 1H), 7.12 13C NMR (101 MHz, CDCl3) δ 147.8, 142.5, 139.5, 133.6, 133.4,
(dd, J = 5.0, 3.5 Hz, 1H), 7.08 (dd, J = 3.5, 1.2 Hz, 1H), 128.9 (3C), 128.2 (2C), 127.8, 127.7 (q, J = 29.2 Hz), 127.2,
3.96–3.88 (m, 4H), 3.14–2.91 (m, 4H), 2.42 (d, J = 1.0 Hz, 3H). 127.2, 125.7, 124.7 (q, J = 273.7 Hz), 122.9 (q, J = 6.2 Hz), 53.4,
13C NMR (101 MHz, CDCl3) δ 152.6, 142.2, 136.9, 135.6, 128.8 16.7, 14.3 (q, J = 2.5 Hz). 19F NMR (377 MHz, CDCl3, C6F6) δ
(q, J = 32.2 Hz), 127.4, 127.3, 126.0, 124.3 (q, J = 272.1 Hz), −60.30. IR (CHCl3), cm−1: 3381, 1567. HRMS (ESI) m/z calcd
122.5 (q, J = 3.9 Hz), 115.3 (q, J = 3.8 Hz), 67.3 (2C), 52.5 (2C). for C20H19F3NS+ (M + H)+: 362.1185, found: 362.1179.
19F NMR (377 MHz, CDCl3, C6F6) δ −62.19. IR (CHCl3), cm−1
:
2-((3-Hydroxy-5-(thiophen-2-yl)-3-(trifluoromethyl)cyclohexa-
1,5-dien-1-yl)amino)phenol (9a)
1582. HRMS (ESI) m/z calcd for C16H17F3NOS+ (M + H)+:
328.0977, found: 328.0969.
A solution of 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione
(4a; 666 mg, 3.00 mmol, 1.00 equiv.) and o-aminophenol (2b;
338 mg, 3.10 mmol, 1.03 equiv.) in acetone (5 mL) was placed
in a fridge (−10 °C, overnight). The reaction mixture was evap-
N-Benzyl-2-methyl-3-(thiophen-2-yl)-5-(trifluoromethyl)aniline
(8ea) and N-benzyl-2-methyl-5-(thiophen-2-yl)-3-
(trifluoromethyl)aniline (8ea′)
Method A (0.5 mmol scale), isolated as a mixture of isomers orated, and ca. 10 mL of CHCl3 was added. The formed pre-
(ratio 4 : 1, NMR) via column chromatography (toluene–hexane cipitate was filtered off, affording 428 mg of an yellow-orange
= 1 : 3, Rf 0.35), colorless oil (128 mg, 74%). 1H NMR solid, which contained the title product 9a (ca. 85%), 9b,
(400 MHz, CDCl3) δ (8ea, major) 7.53–7.33 (m, 6H), 7.16–7.12 o-aminophenol, and 2-((3-(thiophen-2-yl)-5-(trifluoromethyl)
(m, 2H), 7.06 (dd, J = 3.5, 1.2 Hz, 1H), 6.94 (s, 1H), 4.46 (s, 2H), phenyl)amino)phenol, as shown by LC-MS. NMR analysis
4.28 (s, 1H), 2.25 (s, 3H); (8ea′, minor) 7.53–7.33 (m, 6H), resulted in complicated spectra, due to significant decompo-
7.30–7.27 (m, 2H), 7.11–7.07 (m, 2H), 4.49 (s, 2H), 4.28 (s, 1H), sition of 9a. HRMS (ESI) m/z calcd for C17H15F3NO2S+ (M +
2.31 (d, J = 1.4 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ (8ea, H)+: 354.0770, found: 354.0775.
major) 146.8, 142.5, 138.5, 135.4, 129.0 (2C), 128.9 (q, J = 31.9
Hz), 127.9 (2C), 127.8, 127.3, 127.2, 125.8, 124.6 (q, J = 272.2
Hz), 124.5, 116.9, 106.1, 48.8, 14.6; (8ea′, minor) 147.3, 144.1,
5-Hydroxy-3-(thiophen-2-yl)-5-(trifluoromethyl)cyclohex-2-en-1-
one (9b)
138.5, 133.2, 130.1 (q, J = 29.3 Hz), 129.0 (2C), 128.1, 127.8 A solution of 4,4,4-trifluoro-1-(thiophen-2-yl)butane-1,3-dione
(3C), 125.0, 124.8 (q, J = 274.1 Hz), 123.5, 119.8, 112.7, 111.2, (4a; 1.11 g, 5.00 mmol, 1.00 equiv.) and o-aminophenol (2b;
48.8, 12.9 (q, J = 2.5 Hz). 19F NMR (376 MHz, CDCl3, C6F6) δ 109 mg, 1.00 mmol, 0.20 equiv.) in acetone (3 mL) was heated
−59.66 (minor), −62.38 (major). IR (CHCl3), cm−1: 3470, 3440, at 55 °C for 1 day. Water was added to the reaction mixture, and
1588. HRMS (ESI) m/z calcd for C19H17F3NS+ (M + H)+: the formed precipitate was filtered off and washed with warm
348.1028, found: 348.1031.
hexane, affording a peach-yellow solid (922 mg, 70%), mp
152–154 °C. H NMR (400 MHz, CDCl3) δ 7.49 (dd, J = 5.0, 1.1
Hz, 1H), 7.43 (dd, J = 3.8, 1.1 Hz, 1H), 7.12 (dd, J = 5.2, 3.8 Hz,
1H), 6.52 (d, J = 1.5 Hz, 1H), 2.86 (br. s, 1H), 3.13 (s, 2H),
1
4-(2-Isopropyl-3-(thiophen-2-yl)-5-(trifluoromethyl)phenyl)
morpholine (8kb)
Method A (0.5 mmol scale), purified by column chromatography 2.83–2.73 (m, 2H). 13C NMR (101 MHz, CDCl3) δ 194.2, 146.8,
(toluene–hexane = 1 : 1, Rf 0.30), colorless liquid (47 mg, 26%). 141.8, 129.9, 128.7, 128.3, 125.1 (q, J = 284.3 Hz), 121.6, 74.4 (q,
1H NMR (400 MHz, CDCl3) δ 7.62–7.56 (m, 1H), 7.43 (dq, J = 2.1, J = 29.8 Hz), 42.4, 33.6. 19F NMR (377 MHz, CDCl3, C6F6) δ
0.7 Hz, 1H), 7.36 (ddd, J = 5.2, 1.2, 0.5 Hz, 1H), 7.07 (ddd, J = −83.6. IR (mineral oil), cm−1: 3307, 1645, 1594. HRMS (ESI) m/z
5.2, 3.5, 0.5 Hz, 1H), 6.97 (ddd, J = 3.5, 1.2, 0.5 Hz, 1H), 3.88 (s, calcd for C11H10F3O2S+ (M + H)+: 263.0348, found: 263.0349.
4H), 3.43 (p, J = 7.0 Hz, 1H), 2.90 (s, 4H), 1.35 (d, J = 7.0 Hz,
3-(Thiophen-2-yl)-5-(trifluoromethyl)aniline hydrochloride (9c)
6H). 13C NMR (101 MHz, CDCl3) δ 154.0, 149.6, 142.4, 136.7,
128.7 (q, J = 32.5 Hz), 127.4, 127.0, 126.5 (q, J = 3.8 Hz), 125.9, Procedure: NH4OAc (5 mmol, 385 mg, 10 equiv.) was added to
124.0 (q, J = 272.1 Hz), 121.9 (q, J = 3.5 Hz), 67.3 (2C), 54.7 (2C), a solution of 9b (0.50 mmol, 131 mg, 1.00 equiv.) in EtOH
10042 | Org. Biomol. Chem., 2019, 17, 10030–10044
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(2 mL), and the formed mixture was heated at 60 °C for 4 days. 12 H. J. Böhm, D. Banner, S. Bendels, M. Kansy, B. Kuhn,
After completion, the mixture was diluted with water (10 mL)
and extracted with dichloromethane (2 × 10 mL). The organic
K. Müller, U. Obst-Sander and M. Stahl, ChemBioChem,
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phase was evaporated, and CHCl3 was added to the residue, 13 E. P. Gillis, K. J. Eastman, M. D. Hill, D. J. Donnelly and
followed by 1.20 equiv. of conc. HCl. The formed precipitate N. A. Meanwell, J. Med. Chem., 2015, 58, 8315–8359.
was filtered off, affording an apricot solid (98 mg, 70%), mp 14 J. Wang, M. Sánchez-Roselló, J. L. Aceña, C. del Pozo,
1
225–228 °C. H NMR (400 MHz, DMSO-d6) δ 7.62 (dd, J = 5.1,
1.2 Hz, 1H), 7.59 (dd, J = 3.7, 1.2 Hz, 1H), 7.53–7.44 (m, 2H),
A. E. Sorochinsky, S. Fustero, V. A. Soloshonok and H. Liu,
Chem. Rev., 2013, 114, 2432–2506.
7.20 (t, J = 1.6 Hz, 1H), 7.16 (dd, J = 5.1, 3.7 Hz, 1H), 5.65 (s, 15 C. Bardelle, T. Coleman, D. Cross, S. Davenport,
3H + H2O). 13C NMR (101 MHz, DMSO-d6) δ 142.2, 141.3,
135.8, 130.8 (q, J = 32.0 Hz), 128.6, 126.9, 125.2, 123.8 (q, J =
J. G. Kettle, E. J. Ko, A. G. Leach, A. Mortlock, J. Read and
N. J. Roberts, Bioorg. Med. Chem. Lett., 2008, 18, 5717–5721.
272.8 Hz), 118.8, 114.7, 113.6. 19F NMR (377 MHz, DMSO-d6, 16 K. W. Kuntz, J. E. Campbell, H. Keilhack, R. M. Pollock,
C6F6) δ −61.4. IR (mineral oil), cm−1: 1608, 1561. HRMS (ESI)
m/z calcd for C11H9F3NS+ (M + H − HCl)+: 244.0402, found:
244.0403.
S. K. Knutson, M. Porter-Scott, V. M. Richon,
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17 B. Lu, X. Shen, L. Zhang, D. Liu, C. Zhang, J. Cao, R. Shen,
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Conflicts of interest
There are no conflicts to declare.
18 F. Mu, D. J. Lee, D. E. Pryor, E. Hamel and M. Cushman,
J. Med. Chem., 2002, 45, 4774–4785.
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Acknowledgements
We gratefully acknowledge the Russian Foundation for Basic
Research (grant no. 18-33-01084) for the financial support.
X-ray analyses were performed under the financial support of
the Government of Perm Krai.
21 A.-L. Cheng, Y.-K. Kang, Z. Chen, C.-J. Tsao, S. Qin,
J. S. Kim, R. Luo, J. Feng, S. Ye, T.-S. Yang, J. Xu, Y. Sun,
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