NHC-Cu(I)-Catalyzed Friedl?nder-Type Annulation of Fluorinated o-Aminophenones with Alkynes on Water: Competitive Base-Catalyzed Dibenzo[b,f][1,5]diazocine Formation

Article abstract of DOI:10.1021/acs.joc.7b01235

An efficient, easily scalable synthesis of 4-trifluoromethylquinolines and naphthydrines (as well as their difluoro- and perfluoro-analogues) as a result of tandem direct catalytic alkynylation/dehydrative condensation of o-aminofluoromethylketones (o-FMKs), for the first time catalyzed by NHC-copper(I) complexes on water, is reported. A wide range of terminal alkynes is tolerated under the reaction conditions, including β-lactam-, steroid-, and sugar-derived ones, leading to desired quinolines and naphthydrines with good yields. Further investigations proved that o-FMKs could be efficiently transformed into a rare class of heterocyclic compounds - dibenzo[b,f][1,5]diazocines - by a base-catalyzed condensation, also on water. The developed method was applied for gram-scale synthesis of a fluorinated analogue of G protein-coupled receptor antagonist (GPR91).

Full text of DOI:10.1021/acs.joc.7b01235

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Article
NHC-Cu(I)-Catalyzed Friedländer-Type Annulation of Fluorinated
o-Aminophenones with Alkynes on Water. Competitive
Base-Catalyzed Dibenzo[b,f][1,5]diazocine Formation
Pawe# Czerwi#ski, and Micha# Michalak
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01235 • Publication Date (Web): 07 Jul 2017
Downloaded from http://pubs.acs.org on July 7, 2017
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NHCꢀCu(I)ꢀcatalyzed Friedländerꢀtype annulation of fluorinated oꢀaminophenones
with alkynes on Water. Competitive baseꢀcatalyzed dibenzo[b,f][1,5]diazocine
formation
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Paweł Czerwiński and Michał Michalak*
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52, 01ꢀ224 Warsaw, Poland
*
michal.michalak@icho.edu.pl
Graphical abstract
Abstract: An efficient, easily scalable synthesis of 4ꢀtrifluoromethylquinolines and
naphthydrines (as well as their difluoroꢀ and perfluoroꢀanalogues) as a result of tandem
direct catalytic alkynylation/dehydrative condensation of oꢀaminofluoromethylketones (oꢀ
FMKs), for the first time catalyzed by NHCꢀcopper(I) complexes on water, is reported. A
wide range of terminal alkynes is tolerated under the reaction conditions, including βꢀ
lactamꢀ, steroidꢀ, and sugarꢀderived ones, leading to desired quinolines and
naphthydrines with good yields. Further investigations proved that oꢀFMKs could be
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efficiently transformed into
a
rare class of heterocyclic compounds
–
dibenzo[b,f][1,5]diazocines – by a baseꢀcatalyzed condensation, also on water. The
developed method was applied for gramꢀscale synthesis of a fluorinated analogue of G
proteinꢀcoupled receptor antagonist (GPR91).
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Keywords: oꢀaminofluorophenone, Friedländer reaction, copper, Nꢀheterocyclic
carbene, quinoline, naphthydrine, on water
Introduction
Fluorineꢀcontaining organic molecules, in particular fluorinated heterocycles,
constitute a privileged structural motif in many areas of modern society, including
1
material science, pharmaceutical industry, agrochemicals, fine chemicals, and most of
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all medicinal chemistry. More than 30% of all compounds present on the worldwide
1b,3
agrochemical and pharmaceutical market contain fluorine or fluorinated groups.
The
incorporation of fluorine into organic compounds strongly affects their biological
properties, simultaneously allowing for structural elaboration, and hence has become
crucial for modern drug development. It is wellꢀestablished that the presence of fluorine
2,3b,4
improves bioavailability and increases lipophilicity and metabolic stability.
Iconic
examples of the beneficial properties bestowed upon fluorinated compounds are
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Ezetimibe (inhibitor of cholesterol adsorption) and Efavirenz (nonꢀnucleoside inhibitor
of reverse transcriptase of HIV), which have been commercialized in the last decade.
Among a plethora of fluorinated heterocycles, quinolines and quinolones have
retained longꢀstanding interest of the synthetic community. Tremendous advances in
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the field of fluorination have naturally led to the discovery of fluorinated quinolines or
quinolones exhibiting remarkable biological properties, and some of them have been
introduced to the pharmaceutical market. Representative examples include fluoroquine
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®
and mefloquine (antimalarial drugs), brequinar (used in transplantation and for the
treatment of psoriasis and rheumatic arthritis), flosequinan (used for the treatment of
heart disease) and many derivatives of fluoroquinolones with a broad spectrum of
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antibacterial activity (Figure 1).
Figure 1. Representative structures of biologically active fluorineꢀcontaining quinolines
and quinolones.
Due to the importance of quinolines in natural product synthesis and medicinal
chemistry, many useful methods for their preparation have been developed to date.
Among classical methods leading to this heterocyclic scaffold, including the Skraup
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reaction, the Doebnerꢀvon Miller reaction, the GouldꢀJacobs reaction, the Condradꢀ
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Limpach reaction,
the Combes synthesis,
the Knorr synthesis,
and the
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Niementowski synthesis, the Friedländer reaction constitutes an obvious choice due
to its simplicity. Generally, the classical protocol for the latter involves an acidꢀ or a
baseꢀcatalyzed reaction between a 2ꢀaminocarbonyl compound with an αꢀmethylene
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16b
ketone. However, in most cases high temperature is required.
To avoid harsh
conditions and expand the scope of substrates in terms of functional group
compatibility, an alternative route based on tandem addition of terminal alkynes to 2ꢀ
aminobenzaldehydes and spontaneous cyclization has been developed and serves as
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an excellent alternative. Gold(I) complexes have most often been used as catalysts, in
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addition to sparse reports devoted to silver(I), iron(III), and copper salts (which
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necessitate the preactivation of the carbonyl group via an iminium ion). In this respect,
the application of oꢀaminotrifluoromethylketones (oꢀTFMKs) for the synthesis of
fluorinated quinolines is largely unexplored. To date, the application of a stoichiometric
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amount of Zn(OTf)2 and catalytic pyrophoric Ag/PCy3 have been reported with an
extremely narrow scope of substrates.
Scheme 1. Direct catalytic alkynylation of different electrophiles on water catalyzed by
NHCCuX complexes
Herein, we present the first application of Nꢀheterocyclic carbene copper(I) complexes
(
NHCCuX) as efficient catalysts (2 mol%) for the synthesis of fluorineꢀcontaining
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quinolines (CF3, CF H, CnF2n+1
)
and naphthydrines via direct catalytic
2
alkynylation/dehydrative cyclization sequence on water (Friedländerꢀtype reaction).
Recently, we have proved the effectiveness of Nꢀheterocyclic carbene copper(I)
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complexes
trifluoromethylketones
a successful transformation was based on the observation that NHCꢀcopper(I)
in
direct
catalytic
alkynylation
of
chiral
nitrones
and
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(TFMKs) on water (Scheme 1). The key rationale for
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complexes can form stable, monomeric (as confirmed by Xꢀray crystallography ),
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stable, highly reactive (e.g in triazole formation ) and moistureꢀinsensitive acetylides, in
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contrast to polymeric ones, generated from copper(I) salts themselves. Moreover,
strong σꢀdonor properties of the NHC ligands enhance the nucleophilicity of the Csp
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carbon atom of the acetylide, facilitating the addition to the electrophile. Bearing in
mind the successful application of NHCCuX complexes for the alkynylation of nitrones
and TFMKs, we anticipated that the same catalytic system, namely NHCCuX/water,
should deliver a practical route to fluorinated quinolines as a result of direct catalytic
alkynylation/dehydrative cyclization sequence.
Results and discussion
Scheme 2. Model reaction.
a
Table 1. Initial optimization of the reaction conditions
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Entry
1
Base (mol Solvent
Temperature Reaction
Yield of
Yield of
b
b
%)
(°C)
50
time (h)
48
3a (%)
4a (%)
Et N (20) DME,
ꢀ
ꢀ
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DCE,
toluene,
DMF,
DMSO,
pyridine
2
3
Et N (20) EtOH
50
48
48
10
23
n.d.
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3
Et N (20) H O/DME 50
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(20/1)
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Et N (20) H O/DME 100
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3
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(20/1)
TMG (20) H O/DME 100
2
(20/1)
TMG (2)
TMG (2)
H O/DME 100
2
(20/1)
H O/DME 100
2
(20/1)
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a
Reactions conditions: ketone 1a (1.0 mmol), alkyne 2a (1.2 mmol), NHCCuX (0.02
mmol), tetradecane (10 ꢁL), DME (0.1 mL), H O (2 mL) and appropriate amount of
2
b
base; conversion was based on GC with tetradecane as internal standard; isolated
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yield after chromatography; n.d.
Tetramethylguanidine.
–
not determined, TMG
–
1,1,3,3ꢀ
At the outset of our study, we selected the reaction of cyclopropylacetylene (2a) with
oꢀTFMK 1a (Scheme 2). First, we examined the effect of solvent on the model reaction.
When substrates were mixed together in common organic solvents (Table 1, entry 1) in
the presence of 2 mol% IPrCuCl and 20 mol% of Et N, only unreacted starting materials
3
were detected, even after 48 h at 50 °C. However, when EtOH was used, the expected
quinoline 3a was isolated with poor 10% yield after chromatography (Table 1, entry 2).
The best 42% yield was obtained when the reaction was conducted in a mixture of
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water and DME (v/v 20:1) at a higher temperature, which is consistent with our
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previous findings.
Surprisingly, dibenzo[b,f][1,5]diazocine 4a was also isolated as a
byꢀproduct with 43% yield. In order to improve the yield of quinoline 3a, we screened
carefully the influence of the type and the amount of base. After some experimentation,
it was found that the yield of quinoline 3a could be improved to 61% when 2 mol% of
1
,1,3,3ꢀtetramethylguanidine (TMG) were used. Dibenzo [b,f][1,5]diazocine 4a was
isolated with 21% yield in this case. These results clearly suggested that the formation
of dibenzo[b,f][1,5]diazocine 4a is a baseꢀcatalyzed process and its formation can be
suppressed by lowering the loading of TMG to an equimolar amount relative to the
NHCCuX complex used.
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Scheme 3. TMGꢀcatalyzed formation of dibenzo[b,f][1,5]diazocine 4.
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To the best of our knowledge, this is the first example of a baseꢀcatalyzed synthesis of
a dibenzo[b,f][1,5]diazocine on water. Similar compounds have been reported as byꢀ
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products by Wang during the synthesis of quinolines via the Friedländer reaction and
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by Warm in an attempt towards the largeꢀscale preparation of efavirenz. To confirm
the baseꢀcatalyzed mechanism, ketones 1 were treated with 20 mol% of TMG on water,
furnishing heterocycles 4a and 4b cleanly in 66% and 58% yield, respectively (Scheme
3
). Inquiries into the scope of formation of dibenzo[b,f][1,5]diazocines of type 4 are
underway with promising results.
Figure 2. NHC metal complexes used for quinoline 3a formation.
Table 2. The influence of the NHC carbene ligand and the counterion on the
alkynylation/cyclization sequence leading to quinoline 3a and diazocine 4a.
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Entry
NHCCuX (2
Conversion
Quinoline 3a
Diazocine 4a
a
b,c
b,c
mol%)
(%)
(%)
(%)
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IMesCuCl
IMesCuBr
SIMesCuCl
SIMesCuBr
IPrCuCl
94
91
95
91
91
92
90
87
95
94
91
94
90
96
94
42 (48)
51 (57)
35 (45)
33 (44)
44 (50)
46 (53)
37 (45)
32 (49)
53 (54)
48 (52)
26 (28)
44 (47)
37 (41)
49 (53)
71 (78)
39 (40)
28 (28)
40 (40)
35 (41)
16 (22)
31 (34)
32 (33)
22 (27)
30 (33)
31 (33)
61 (63)
35 (36)
47 (48)
33 (34)
7 (8)
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IPrCuBr
IPrCuI
SIPrCuCl
SIPrCuBr
SIPrCuI
1
1
0
1
[IMes] CuBF
2
4
12
[ICy] PF
2
6
1
1
1
3
4
5
[IPr] PF
2
6
PyIMesCuCl
IPr*CuCl
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d
d
1
6
IPr*CuCl
n.d.
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a
Reactions conditions: ketone 1a (1.0 mmol), alkyne 2a (1.2 mmol), NHCCuX (0.02
mmol), TMG (0.02 mmol), tetradecane (10 ꢁL), DME (0.1 mL), H O (2 mL), 16h, 100 °C;
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conversion was based on GC with tetradecane as internal standard; isolated yield
c
after chromatography; estimated yield based on GC from calibration curve is given in
d
parentheses (see ESI); reaction conducted on 5.0 mmol scale of 1a; n.d. – not
determined.
This unprecedented product distribution led us to examine the influence of the
electronic and steric nature of the NHC carbeneꢀcopper(I) complex in more detail (for
the structures of NHC complexes used, see Figure 2). Initially, we were pleased to find
that copper(I) complexes bearing IMes or SIMes carbene ligands also catalyze the
formation of quinoline 3a. However, no clear conclusion could be given regarding the
role of counterion in the copper complex (Table 2, entries 1ꢀ4). Quinoline 3a was
isolated with moderate 33–51% yield. In a series of more hindered unsaturated IPr or
SIPr complexes, the yield of the reaction could be slightly improved by changing the
counterion from iodide or chloride to bromide (Table 2, entry 6 and 9). Unfortunately, in
all cases dibenzo[b,f][1,5]diazocine 4a was also formed in significant quantities, up to
3
2%. Unexpectedly, dibenzo[b,f][1,5]diazocine 4a was isolated in higher yield when the
reaction was catalyzed by homoleptic ionic [ICy] CuBF . Other ionic complexes were
2
4
less effective. The best results in terms of conversion and yield were obtained when
sterically hindered complex IPr*CuCl was applied. Quinoline 3a was isolated in 71%
yield while dibenzo[b,f][1,5]diazocine was formed in low 7% yield (Table 2, Entry 15).
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Pleasingly, the same reaction conducted on 5.0 mmol scale furnished cleanly product in
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6% after chromatography (more than 1 g of 3a was isolated, Table 2, entry 16).
2
mol% IPr*CuCl
mol% TMG
O
CF3
2
Cl
R
Cl
CF3
NH2
H2O/DME 20/1
00 °C
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N
R
1
1
a
2
3
OCH3
OCH3
R =
OCH3
CH3
OCH3
3
b, 16 h, 66%
3c, 16 h, 64%
S
3d, 16 h, 53%
3e, 16 h, 77%
N
CF3
3
f, 16 h, 11%
3g, 16 h, 53%
3h, 16 h, 73%
3i, 16 h, 15%
O
O
nꢀC5H11
OH
3l, 16 h, 68%
F
3j, 16 h, 70%
3k, 16 h, 61%
3m, 16 h, 50%
O
O
O
O
O
O
O
N
Ph
H
O
3
n, 24 h, 68%
3o, 16 h, 55%
3p, 16 h, 63%
O
O
OAc
OAc
H
AcO
H
OAc
O
H
H
3
q, 48 h, 28%
O
3r, 16 h, 83%
17
TBSO
H
H
H
16
Fe
H 15
H
NH
O
CH3O
3x, 16 h, 67%
3y, 16 h, 52%
3z, 48 h, 62%
Scheme 4. The scope of alkynes.
With the optimized conditions (2 mol% of IPr*CuCl and 2 mol% of TMG on water) in
hand, we explored the scope of alkynes. It was found that phenylacetylene and its
derivatives afforded products 3bꢀe with good yields when electronꢀdonating substituents
were present, while electronꢀwithdrawing groups such as CF gave poor yields (Scheme
3
4, 3i). Further investigations revealed that heterocyclic substituents were tolerated
under the reaction conditions. 3ꢀEthynylthiophene furnished product 3g cleanly in 53%
yield, while 3ꢀethynylpyridine in only 11% yield. Next, we turned our attention to alkylꢀ
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substituted alkynes. In those cases, quinolines 3jꢀp were formed in good yields in the
presence of alkene, ketone, ester, amide or free hydroxyl functional groups. To illustrate
the broad scope of substrates for the synthesis of trifluorometylquinolines further,
ferroceneꢀ, βꢀlactamꢀ, sugarꢀ, and steroidꢀderived alkynes were selected. Pleasingly, the
Friedländerꢀtype reaction furnished the respective heterocycles 3n, qꢀy in excellent.
Only glucose tetraacetate afforded product 3q in low 28% yield. It should be stressed
that the reported yield of quinoline formation in the range of 60ꢀ70% is still satisfactory,
bearing in mind the competitive selfꢀcondensation of oꢀTFMK leading to
dibenzo[b,f][1,5]diazocine 4a, observed in all cases.
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Figure 3. Representative examples of biologically active steroids bearing heterocyclic
substituent.
Finally, the developed methodology was applied for the synthesis of structurally
complex and pharmaceutically relevant estrone derivative 3z which is of high
importance from the perspective of medicinal applications. The class of compounds
consisting of a heterocyclic subunit (usually quinolone, isoquinoline or pyridine)
attached to the steroid core in position C17 (for numbering, see Scheme 4, structure 3z)
exhibit a broad spectrum of biological activities including antiangiogenic (e.g. natural
32
products of the cortistatin family ) or proven anticancer ones (e.g. semisynthetic
33
analogue of cardenolides – abiraterone, Figure 3). Recently, Corey has simplified the
structure of naturally occurring cortistatins bearing an unusual steroid scaffold to a
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simple androstane derivative and confirmed its prominent antiangiogenic activity.
34ꢀ35
Regarding the synthetic efforts towards cortistatin and its analogues,
the key
transformation involved a palladiumꢀcatalyzed (10–50 mol% of Pd) Stille coupling of a
sterically congested steroid vinyl iodide or enol triflate located in a neopentyl position.
The application of palladium and tin compounds to the synthesis of biologically active
molecules can affect biological evaluation due to toxic heavy metal contamination. The
developed method offers an attractive alternative for the construction of heterocycleꢀ
steroid hybrids via a palladiumꢀfree protocol. The respective estrone derivative 3z was
isolated in 62% yield using only 2 mol% of the IPr*CuCl complex.
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a
Scheme 5. The scope of fluoroketones. 5 mol% of IPr*OMeCuCl was used.
Next, we explored variously substituted oꢀTFMKs for the synthesis of quinolines.
Ketones bearing strongly and weakly electronꢀdonating groups, such as NMe , OMe,
2
Me, F, H as well as a naphthyl moiety furnished the corresponding quinolines 5a,c,d,fꢀh
and benzo[h]quinoline 5b in moderate to good yields (Scheme 5). Further improvement
of the formation of 5a was accomplished by fine tuning the electronic properties of NHC
OMe
36
ligand. Application of IPr* CuCl complex, introduced by Kobayashi, in place of
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IPr*CuCl resulted in increases in yield, up to 82%. Presumably, this can be attributed to
the electronꢀdonating properties of the methoxy group attached to the NHC ligand which
OMe
enhance the nucleophilicity of the copper acetylide. Similarly, IPr* CuCl appeared to
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be the complex of choice for the synthesis of fluorinated 1,6ꢀ and 1,8ꢀnaphythyridines
5iꢀk and 5l, accessible by other methods only with difficulty.
Further investigations were directed at the synthesis of difluoromethylꢀcontaining
quinolines. It is wellꢀestablished that CF H can act as a bioisostere of hydroxyl, Nꢀ
2
37
hydroxamic acid and thiol groups, which offers new routes for drug design. CF H
2
37ꢀ38
constitutes a good platform for lipophilic interactions as a hydrogen bond donor
and
may enhance membrane permeability, binding affinity and bioavailability. Although
direct introduction of CF H onto arenes has become the subject of intensive research in
2
39
40
41
42
recent years (including Pd, Ni, Cu or Zn catalyzed transformations), the
developed methods usually need harsh conditions and are incompatible with many
functional groups. Furthermore, the complexity of reagent mixtures used or catalytic
systems makes these approaches far from practical, especially on a large scale.
Bearing in mind the practical aspects, the developed protocol has revealed a simple
procedure of difluoromethylquinoline synthesis. Indeed, heating a mixture of
difluorometylketone and a terminal alkyne on water in the presence of 2 mol% IPr*CuCl
and 2 mol% of TMG afforded the respective quinolones 5nꢀo in good yields (52–77%),
also in the case of cholesterol derivative 5p. The same conditions appeared compatible
OMe
with the synthesis of perfluoroalkylꢀquinoline 5m. However, IPr* CuCl had to be used
to maintain a reasonable 56% isolated yield.
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R
HO OH
TMG
A
CFn
TMG•HCl
NH2
C
HO CFn
NHCCuCl
R
TMG
H2O
NHCCu
B
R
O
NH2
CFn
NH2
G
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ꢀ
H2O
D
TMG
FnC
CFn
NH
NHCCuO CFn
O
N
R
HN
H
R
TMG•HCl
NH2
CFn
E
F
Scheme 6. A plausible catalytic cycle; NHC – Nꢀheterocyclic carbene, TMG – 1,1,3,3ꢀ
Tetramethylguanidine
22
Based on our experiments and literature data, a plausible catalytic cycle of the
NHCCuXꢀcatalyzed Friedländer reaction leading to quinolines was proposed (Scheme
6
). The NHCCuX complex interacts with terminal alkyne A (via universally accepted πꢀ
activation mode) forming the mononuclear copper acetylide B and releasing an amine
hydrochloride simultaneously (if copper chloride complex is used). The structure of the
NHCꢀcopper acetylide was confirmed independently by NMR spectroscopy and Xꢀray
2
6b
25
crystallography (by Nolan and Jones, respectively). Next, the monomeric acetylide
B undergoes an addition to the fluorinated ketone D, affording copper alkoxide F which
is protonated by the strongest Brönsted acid present in the system – amine
hydrochloride. The protonation step regenerates the NHCCuCl complex and the amine
needed for the activation of terminal alkyne A, closing the catalytic cycle. The
spontaneous dehydrative cyclization of the propargyl alcohol G, which may be
22
enhanced by the NHCCuX complex via πꢀactivation or by the Brönsted acid, affording
quinoline H. It should be stressed that other side reactions, such as selfꢀcondensation
or hydratation could decrease the yield of quinoline H. For those reasons, an equivalent
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loading of the base and the NHCCuX complex has to be used to prevent the formation
of dibenzo[b,f][1,5]diazocine E (see, Table 1).
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Scheme 7. The application of the Friedländerꢀtype reaction to a gramꢀscale synthesis of
a fluorinated analogue of a G proteinꢀcoupled receptor antagonist (GPR91); TMG –
1
,1,3,3ꢀtetramethylguanidine, HOBt – 1ꢀhydroxybenzotriazole, EDC•HCl – 1ꢀethylꢀ3ꢀ(3ꢀ
dimethylaminopropyl)carbodiimide hydrochloride.
The utility of the developed method is further illustrated through a scalable synthesis
of a fluorinated analogue 13 of G proteinꢀcoupled receptor antagonist (known as
GPR91, Scheme 7). GPR91 belongs to a class of membrane proteins able to bind an
43
extracellular succinate – an intermediate in the Krebs cycle. The binding of succinate
to GPR91 can affect a wide array of physiological and pathological processes such as
inhibition of lipolysis, regulation of blood pressure, cardiac hypertrophy, angiogenesis in
44
retinal tissues, etc. Among nonꢀpeptide small organic molecules which serve as
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ligands for GPR91, naphthydrines coupled with biphenylꢀderived benzylamine, originally
45
synthesized and evaluated by Merck as inhibitors of Bradykinin B1 receptor (BK R),
1
46
have witnessed a growing interest. However, their fluorinated analogues have not
been investigated to date. Herein, we present a scalable convergent route to this class
of compounds. First, we synthesized fluorinated naphthydrine 5j applying the developed
method on a 0.5 mmol scale which afforded the product in 74% yield. Pleasingly, we
found that a 14ꢀfold increase in scale furnished the product cleanly with equally
excellent yield, further underlining the practical aspect of the developed method.
The intermediate benzylamine derivative 12 was synthesized by a twoꢀstep sequence.
The key biphenyl 11 was synthesized via Feꢀcatalyzed arylꢀaryl crossꢀcoupling under
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conditions developed by Knochel.
Arylcopper reagent 9, generated from the
respective nitrile 8, was coupled with iodoester 10 to afford biaryl 11 in 81% yield on
large scale (1.45 g). It should be noted that homocoupling product was observed when
the arylcopper species was generated from iodoester 10. Subsequent chemoselective
reduction of nitrile group to amine appeared to be challenging. BH and common metal
3
hydrides (NaBH in combination with CoCl , CuCl) appeared to be unsuccessful,
4
2
48
whereas the reduction in the presence of Raney nickel furnished secondary amine (for
details, see ESI). Gratifyingly, Pdꢀcatalyzed reduction in the presence of HCl in MeOH
cleanly afforded the respective amine hydrochloride 12 without chromatography on
gram scale. The obtained amine 12 was coupled with ester 5j (after hydrolysis of the
latter), mediated by the mixture of EDC•HCl/HOBt to give amide 13 with 63% yield after
two steps. The evaluation of biological activity of naphthydrine 13 and its analogues are
in progress.
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Conclusion
In summary, we developed an efficient synthesis of trifluoromethylquinolines (and
their difluoromethylꢀ and perfluoroalkylꢀ analogues) and naphthydrines via tandem direct
catalytic alkynylation of oꢀaminofluoromethylketones/condensation sequence, for the
first time on water in the presence of a catalytic amount of NHCꢀcopper(I) complexes.
The established method allows to obtain a series of fluorinated quinolines with good to
moderate yields. During the optimization of the reaction conditions, it was found that oꢀ
aminotrifluoromethylketones undergo baseꢀcatalyzed selfꢀcondensation leading to a
rare example of dibenzo[b,f][1,5]diazocine synthesis. Further experiments confirmed
that the formation of dibenzo[b,f][1,5]diazocines is catalyzed by a weak base on water.
The studies on the scope of the formation of dibenzo[b,f][1,5]diazocines are underway
with promising results.
10
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Experimental section
General remarks
NMR spectra were recorded in CDCl3 or DMSOꢀd6 solutions (unless indicated
otherwise); chemical shifts are quoted on the δ scale, ppm, with the solvent signal as
1
13
the internal standard (CHCl , H NMR 7.26 ppm; CDCl , C NMR 77.00 ppm, DMSOꢀd
6
3
3
1
3
2
.50 ppm, C NMR 39.40 ppm). High resolution mass spectra (HRMS) were taken
using EI technique or electrospray ionization (ESI). Column chromatography was
performed on Merck silica gel 60, 230ꢀ400 mesh. TLC was performed on aluminum
sheets, Merck 60F 254. Anhydrous solvents were obtained by distillation over CaCl2
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(
CH Cl ) or Na/benzophenone (THF, hexane, MTBE). Airꢀsensitive reactions were
2
2
performed in flameꢀdried glassware under atmosphere of argon. Organic extracts were
dried and solvents were evaporated in a rotary evaporator. Reagents were used as they
were purchased unless otherwise indicated (which is specified at beginning of each
section). The name of compounds were generated using ACD Lab Name 12.0 software.
Synthesis of Nꢀheterocyclic carbene copper(I) complexes
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[
IMes] CuPF , SIPrAgCl and IPrAuCl were commercially available from Aldrich and
2 6
49
26a
49
50
49
used as received. SIMesCuCl, SIMesCuBr,
IMesCuCl, IMesCuBr, SIPrCuCl,
51
51
52
53
49
51
51
SIPrCuBr,
SIPrCuI,
SIPrCuOTf,
SIPrOAc,
IPrCuCl,
IPrCuBr,
IPrCuI,
49
26b
54
IPr*CuCl, [ICy] CuPF ,
and [IPr] CuPF
6
were prepared followed by literature
2
6
2
procedure.
{
1,3ꢀbis[2,6ꢀbis(Diphenylmethyl)ꢀ4ꢀmethoxyphenyl]ꢀ1,3ꢀdihydroꢀ2Hꢀimidazolꢀ2ꢀ
OMe
ylidene}(chloro)copper IPr* CuCl was prepared applying literature procedure
49
developed by Cazin et. al. In a glove box, a 20ꢀmL screwꢀcap vial was charged with
OMe
K CO (281.9 mg, 2.04 mmol, 2.0 equiv), IPr* Cl (1.0 g, 1.02 mmol), CuCl (100.8 mg,
2
3
1.02 mmol, 1.0 equiv) and anhydrous acetone (10 mL). Next the vial was capped,
removed from the glove box and the resulting suspension was vigorously stirred for 20h
at 60 °C (temp. of oil bath). Then solvent was evaporated, DCM (20 mL) was added and
the resulting mixture was filtered through a pad of Celite (washing with DCM). The
crude copper(I) complex was dissolved in minimum volume of DCM (6 mL) and crashed
with nꢀpentane (28 mL). The obtained solid was filtered, washed with nꢀpentane (3 x 10
OMe
1
mL), and dried in vacuo to give IPr* CuCl as a white solid (933.3 mg, 88%). H NMR
(400 MHz, CD Cl ) δ 7.28–7.18 (m, 24H), 7.13–7.08 (m, 8H), 6.98–6.91 (m, 8H), 6.62
2
2
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(
s, 4H), 5.86 (s, 2H), 5.25 (s, 4H), 3.62 (s, 6H). H NMR data are in agreement with
36
those reported.
Synthesis of alkynes
10
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Cyclopropylethyne (2a), ethynylbenzene (2b), 1ꢀethynylꢀ4ꢀmethoxybenzene (2c), 5ꢀ
ethynylꢀ1,2,3ꢀtrimethoxybenzene
(2d),
1ꢀethynylꢀ4ꢀmethylbenzene
(2e),
3ꢀ
ethynylpyridine (2f), 3ꢀethynylthiophene (2g), 1ꢀethynylcyclohexene (2h), 1ꢀethynylꢀ4ꢀ
trifluoromethylbenzene (2i), octyꢀ1ꢀyne (2j), 4ꢀmethylpentꢀ1ꢀyne (2k), pentꢀ4ꢀyneꢀ1ꢀol
(2l), methyl hexꢀ5ꢀynoate (2m) and ethynylferrocene (2x) are commercially available
and used as received without further purification. 1ꢀ(4ꢀFluorophenyl)pentꢀ4ꢀylꢀ1ꢀone
24
55
56
(
2o), ethyl hexꢀ5ꢀynoate (7), (3β)ꢀcholestꢀ4ꢀenꢀ3yl hexꢀ5ꢀynoate (2r), 17ꢀethynylꢀ3ꢀ
57
methoxyestraꢀ1(10),2,4,16ꢀtetraene
(2z)
and
(3S,4R)ꢀ3ꢀ{(1R)ꢀ{[tertꢀ
5
8
butyl(dimethyl)silyl]oxo}ethylꢀ4ꢀpropꢀ2ꢀynꢀ1yl)azetidineꢀ2ꢀone (2y)
were prepared
followed by literature procedure.
Pentꢀ4ꢀynꢀ1ꢀyl 2,3,4,6ꢀtetraꢀOꢀacetylꢀαꢀDꢀmannopyranoside (2q) To a solution of
,2,3,4,6ꢀpentaꢀOꢀacetylꢀDꢀmannopyranose (4.37 g, 11.2 mmol), MS 3Å (4 g) in
1
anhydrous DCM (80 mL) and 4ꢀpentynꢀ1ꢀol (2l) (2.08 mL, 22.4 mmol, 2.0 equiv), cooled
to ꢀ10 °C, BF —Et O (11.2 mL, 89.6 mmol, 8.0 equiv) was added dropwise. The resulting
3
2
mixture was slowly allowed to reach rt and stirred for 16 h. The reaction mixture was
then quenched by addition of solid NaHCO (10 g) and stirred at rt. After 30 min. the
3
reaction mixture was washed with sat. aqueous NaHCO (3 x 50 mL), dried over
3
MgSO , and solvent was evaporated. The residue was chromatographed on silica FCC
4
(15ꢀ30% EtOAc/hexanes) to give a light yellow oil (1.55 g, 33%, CAS: 1327252ꢀ78ꢀ7, no
2
D
3
spectral data available for comparison were reported). [a] = 46.4 (c = 1.1, CHCl ); IR
3
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1
(
film) 3283, 2958, 2939, 2117, 1751 cm ; H NMR (400 MHz, CDCl ) δ 5.32 (dd, J =
3
1
0.0, 3.2 Hz, 1H), 5,29 (t, J = 9.6 Hz, 1H), 5.22 (dd, J = 3.2, 1.6 Hz, 1H), 4.80 (d, J = 1.6
Hz, 1H), 4.27 (dd, J = 12.2, 5.2 Hz, 1H), 4.10 (dd, J = 12.3, 2.4 Hz, 1H), 4.00 (ddd, J =
.6, 5.2, 2.4 Hz, 1H), 3.83 (ddd, J = 9.6, 7.2, 5.6 Hz, 1H), 3.55 (ddd, J = 9.6, 5.6, 5.6 Hz,
0
1
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4
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1H), 2.35–2.27 (m, 2H), 2.14 (s, 3H), 2.09 (s, 3H), 2.03 (s, 3H), 1.98 (s, 3H), 1.95 (t, J =
13
2
1
1
.6 Hz, 1H), 1.89–1.73 (m, 2H); C NMR (100 MHz, CDCl ) δ 170.6, 170.0, 169.8,
3
69.7, 97.6, 83.2, 69.6, 69.1, 69.0, 68.5, 66.5, 66.2, 62.4, 27.9, 20.8, 20.7, 20.6, 20.6,
+
5.2; HRMS (ESIꢀTOF) m/z: [M+Na]
Calcd for C H O Na 437.1424;
19 26 10
Found:437.1416.
Pentꢀ4ꢀynꢀ1ꢀyl αꢀDꢀmannopyranoside (14) To a stirred solution of pentꢀ4ꢀynꢀ1ꢀyl
,3,4,6ꢀtetraꢀOꢀacetylꢀαꢀDꢀmannopyranoside (2q) (875.0 mg, 2.24 mmol) in dry MeOH
20 mL), KOMe (15.7 mg, 0.224 mmol, 0.1 equiv) was added at rt and stirred for 3h.
2
(
Then solvent was evaporated and residue was passed through pad of silica (10%
MeOH/DCM) to give a colourless oil (474.4 mg, 86%). The obtained pentꢀ4ꢀynꢀ1ꢀyl αꢀDꢀ
23
mannopyranoside (14) was used without further purification in the next step. [a] = ꢀ
D
13
7
0.7 (c = 1.9, MeOH); C NMR (100 MHz, CD OD) δ 101.6, 84.3, 74.5, 72.7, 72.2,
3
+
69.9, 68.5, 66.9, 62.8, 29.6, 15.9; HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C H O Na
11
18
6
2
69.1001; Found: 269.0991.
(
3aS,4S,5aR,9aR,9bS)ꢀ2,2,8,8ꢀTetramethylꢀ4ꢀ(pentꢀ4ꢀynꢀ1ꢀ
yloxy)hexahydro[1,3]dioxolo[4,5]pyrano [3,2ꢀd][1,3]dioxine (2n) To a stirred rt
solution of the tetraol 14 (0.397 g, 1.71 mmol) in dry DMF (13 mL) under atmosphere of
argon, Me C(OMe) (1.32 mL, 10.9 mmol, 10.0 equiv) and pꢀTsOH (20.9 mg, 0.11
2
2
mmol, 0.1 equiv) were added at rt. The reaction mixture was stirred for 3 h before
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acetone (2.7 mL) was introduced. After 24 h the reaction was diluted with Et O (20 mL)
2
and washed with sat. NaHCO solution (2 x 20 mL). The organic layer was separated,
3
washed with H O (3 x 20 mL), brine (2 x 30 mL), dried over Na SO , filtered and
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4
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concentrated in vacuo. The residue was purified by chromatography on silica (5%
EtOAc/hexanes) to give diacetal 2n as a colourless oil (441.0 mg, 79%). α = ꢀ70.7 (c =
ꢀ1
1
1
.9, MeOH); IR (film) 3278, 2990, 2939, 2915, 2876, 2117 cm ; H NMR (400 MHz,
CDCl ) δ 5.00 (s, 1H), 4.18–4.09 (m, 2H), 3.87 (dd, J = 10.8, 5.6 Hz, 1H), 3.84–3.69 (m,
3
3
1
H), 3.63–3.44 (m, 2H), 2.30 (dt, J = 7.2, 2.8 Hz, 2H), 1.95 (t, J = 2.8 Hz, 1H), 1.86–
13
.74 (m, 2H), 1.54 (s, 3H), 1.51 (s, 3H), 1.42 (s, 3H), 1.34 (s, 3H); C NMR (100 MHz,
CDCl ) δ 109.4, 99.7, 97.8, 83.3, 76.1, 74.9, 72.7, 68.8, 65.9, 62.1, 61.4, 29.0, 28.2,
3
+
2
8.1, 26.1, 18.8, 15.2; HRMS (ESIꢀTOF) m/z: [M+Na] Calcd for C H O Na 349.1627;
17
26
6
Found: 349.1629.
Nꢀ[(1S)ꢀ1ꢀPhenylethyl]hexꢀ5ꢀynamide (2p) To a solution of 5ꢀhexynoic acid (1 g, 8.91
mmol) in DCM (20 mL), cooled to 0 °C, EDC (2.05 g, 10.7 mmol, 1.2 equiv) and (S)ꢀ
methylbenzylamine (1 g, 8.91 mmol, 1.2 equiv) were added, and stirred for 3h at rt.
Then reaction mixture was diluted with water (40 mL) and organic phase was
separated, washed with 5% HCl (2 x 20 mL), dried over MgSO and evaporated. The
aq
4
residue was passed through a pad of silica (eluted with 40% EtOAc/hexanes) to give a
23
D
waxy solid (1.83 g, 95%).
[α
]
= ꢀ92.7 (c = 0.94, CHCl ); IR (film) 3292, 3063, 2972,
3
ꢀ1 1
2
934, 2116, 1614, 1545 cm ; H NMR (400 MHz, CDCl ) δ 7.37–7.23 (m, 5H), 5.83 (br
3
s, J = 6.3 Hz, 1H), 5.19–5.06 (m, 1H), 2.37–2.19 (m, 4H), 1.96 (t, J = 2.6 Hz, 1H), 1.91–
13
1.80 (m, 2H), 1.48 (d, J = 6.9 Hz, 3H); C NMR (100 MHz, CDCl ) δ 171.2, 143.2,
3
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28.6, 127.3, 126.1, 83.5, 69.2, 48.7, 35.1, 24.1, 21.7, 17.8; HRMS (ESIꢀTOF) m/z:
+
[
M+Na] Calcd for C H NONa 238.1208; Found: 238.1204.
14 17
Synthesis of orthoꢀaminotrifluoromethylketones (oꢀTFMK’s) and their derivatives
containing difluoromethyl group and perfluoroalkyl chain
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ꢀ(2ꢀAminoꢀ5ꢀchlorophenyl)ꢀ2,2,2ꢀtrifluoroethanone (1a), 2,2ꢀdifluoroꢀ1ꢀ(morpholinꢀ4ꢀ
59
yl)ethanone
were prepared according to literature procedure. 1ꢀ(2ꢀAminoꢀ5ꢀ
chloropyridinꢀ3ꢀyl)ꢀ2,2ꢀdifluoroethanone is commercially available and was used as
received.
General procedure To a solution of amide (x mmol) and TMEDA (1.0 equiv), cooled to
ꢀ20 °C (or lower temp.) in MTBE (or THF), a solution of nꢀBuLi (2.2 equiv) was added
dropwise by means of syringe pump within 30 min. ꢀ 2h while the temperature was kept
below ꢀ10 °C (or lower as indicated). The mixture was aged at ꢀ5 – 5 °C for 2ꢀ4 h,
cooled below ꢀ30 °C (or ꢀ65 °) and CF CO Et (1.4 equiv) or other source of fluorinated
3
2
group was added. Then reaction mixture was stirred for 0.5 ꢀ 1h at rt, quenched with 5%
HCl (or 10% citric acid). Then solvents were evaporated. In some cases product was
separated by chromatography or crystallization from unreacted substrate. Then residue
was treated with 36% aqueous HCl or its solution in dioxane (4M in dioxane), and
stirred for 2ꢀ16h at 70ꢀ90 °C (temp. of oil bath). Then reaction mixture was neutralized
with sat. solution of K CO (or NaHCO ) and extracted with EtOAc. The combined
2
3
3
organic extracts were washed with brine, dried over MgSO and evaporated. The
4
residue was chromatographed on silica and further purified by crystallization (usually
from nꢀheptane) to give a pure orthoꢀaminofluorophenones and its derivatives.
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ꢀ(2ꢀAminoꢀ5ꢀmethoxyphenyl)ꢀ2,2,2ꢀtrifluoroethanone (1b) To a solution of amide Nꢀ
(4ꢀmethoxyphenyl)ꢀ2,2ꢀdimethylpropanamide (11.41 g, 55.1 mmol) in Et O (60 mL) and
2
TMEDA (8.5 mL, 55.1 mmol, 1.0 equiv), cooled to ꢀ20 °C, a solution of nꢀBuLi (48.5 mL,
21.2 mmol, 2.2 equiv, nꢀBuLi 2.5 M in hexanes) was added dropwise while the
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1
temperature was kept below 0 °C. The mixture was aged at 0ꢀ5 °C for 4 h and cooled
below ꢀ20 °C, and CF CO Et (8.0 mL, 67.2 mmol, 1.4 equiv) was added rapidly (internal
3
2
temp. reached 10 °C). Then reaction mixture was stirred for 1h at rt, quenched with 5%
HCl (40 mL). The aqueous phase was separated and extracted with MTBE (3 x 50 mL).
The residue was treated with 36% HCl (20 mL), and stirred for 16h at 90 °C (temp. of oil
bath). Then reaction mixture was cooled to 0 °C and washed with EtOAc to give a white
solid. The obtained solid was suspended in MTBE (40 mL) and treated with aq sat.
solution of NaOAc (80 mL). After 30 min. of vigorous stirring, organic phase was
separated, dried over MgSO , and evaporated. The residue was chromatographed on
4
1
silica (5ꢀ15% EtOAc/hexanes) to give an orange solid (1.64 g, 14%). H NMR (400 MHz,
CDCl ) δ 7.18–7.13 (m, 1H), 7.09 (dd, J = 9.1, 2.8 Hz, 1H), 6.69 (d, J = 9.1 Hz, 1H),
3
1
3
6
1
.23 (br s, 2H), 3.78 (s, 3H); C NMR (100 MHz, CDCl ) δ 180.1 (q, J = 33.0 Hz),
3
CF
50.0, 148.7, 127.4, 118.9, 117.1 (q, JCF = 289.8 Hz), 111.4 (q, JCF = 4.3 Hz), 110.4,
19
1
55.8; F NMR (376 MHz, CDCl ) δ ꢀ69.9. H NMR data are in agreement with those
3
60 13
reported.
C NMR spectra is described by authors without CꢀF coupling constants
and the accurate description and the copy of spectra are included in this experimental
section.
1
ꢀ(1ꢀAminonaphtaleneꢀ2yl)ꢀ2,2,2ꢀtrifluoroethanone (1c) To a solution of 2,2ꢀdimethylꢀ
Nꢀ(naphthalenꢀ1ꢀyl)propanamide (10.0 g, 44.0 mmol) in MTBE (80 mL) and TMEDA (6.8
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mL, 44.0 mmol, 1.0 equiv), cooled to ꢀ20 °C, a solution of nꢀBuLi (38.7 mL, 96.8 mmol,
2
2
2
.2 equiv, BuLi 2.5 M in hexane) was added dropwise by means of syringe pump within
h while the temperature was kept below ꢀ10 °C. The mixture was aged at ꢀ5 ꢀ 0 °C for
h and cooled below ꢀ30 °C, and CF CO Et (7.35 mL, 61.8 mmol, 1.4 equiv) was
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3
2
added rapidly (internal temp. reached 20 °C). Then reaction mixture was stirred for 1h at
rt, quenched with 5% HCl (40 mL) and solvents were evaporated. The residue was
treated with 36% HCl (20 mL), and stirred for 5h at 70 °C (temp. of oil bath). Then
reaction mixture was neutralized with sat. solution of K CO and extracted with EtOAc
2
3
(4 x 30 mL). The combined organic extracts were washed with brine (1 x 30 mL), dried
over MgSO , and evaporated. The residue was chromatographed on silica (toluene)
4
and further purified by crystallization (nꢀheptane) to give a brightꢀyellow solid (3.03 g,
ꢀ1
1
2
9%). M.p. 137.5–138.6 °C (nꢀheptane); IR (KBr) 3461, 3313, 1647, 1614 cm ; H NMR
(400 MHz, CDCl ) δ 8.01ꢀ7.70 (br s, 2H) overlapping 7.94ꢀ7.90 (pseudo dd, 1H) and
3
13
7
.75–7.71 (m, 1H), 7.69–7.71 (m, 2H), 7.55–7.48 (m, 1H), 7.05 (d, J = 9.1 Hz, 1H); C
NMR (100 MHz, CDCl ) δ 179.9 (JCF = 32.9 Hz), 153.3, 136.8, 130.6, 128.7, 126.1,
3
19
1
25.1 (JCF = 4.3 Hz), 122.6, 121.9, 117.5 (JCF = 289.4 Hz), 116.4, 105.3; F NMR (376
+
MHz, CDCl ) δ ꢀ69.2; HRMS (ESIꢀTOF) m/z: [M+H] Calcd for C H F NO 240.0636;
3
12
9 3
Found: 240.0632.
1
ꢀ(2ꢀAminoꢀ5ꢀfluorophenyl)ꢀ2,2,2ꢀtrifluoroethanone (1d) To a solution of Nꢀ(4ꢀ
fluorophenyl)ꢀ2,2ꢀdimethylpropanamide (9.37 g, 48.0 mmol) in MTBE (150 mL) and
TMEDA (7.4 mL, 48.0 mmol, 1.0 equiv), cooled to ꢀ20 °C, a solution of nꢀBuLi (45.8 mL,
1
09.0 mmol, 2.27 equiv, BuLi 2.38 M in hexanes) was added dropwise while the
temperature was kept below 0 °C. The mixture was aged at 0ꢀ5 °C for 2 h and cooled
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below ꢀ20 °C, and CF CO Et (8.0 mL, 67.2 mmol, 1.4 equiv) was added rapidly (internal
3
2
temp. reached 10 °C). Then reaction mixture was stirred for 1h at rt, quenched with 5%
HCl (40 mL) and solvents were evaporated. The residue was treated with 36% HCl (20
mL), and stirred for 3h at 70 °C (temp. of oil bath). Then reaction mixture was cooled to
0 °C and washed with EtOAc to give a white solid. The obtained solid was suspended in
MTBE (40 mL) and treated with aq sat. solution of NaOAc (80 mL). After 30 min. of
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vigorous stirring, organic phase was separated, dried over MgSO , and evaporated. The
4
1
residue was crystallized from nꢀheptane to give a brightꢀyellow solid (7.65 g, 77%). H
NMR (400 MHz, CDCl ) δ 7.45–739 (m, 1H), 7.21–714 (m, 1H), 6.70 (dd, J = 9.2, 4.5
3
13
Hz, 1H), 6.36 (br s, 2H, NH); C NMR (100 MHz, CDCl ) δ 180.7 (dq, J = 34.0, 3.3
3
CF
Hz, C=O), 153.2 (d, JCF = 238.4 Hz), 150.0, 125.7 (d, JCF = 24.3 Hz), 118.9 (d, JCF = 7.1
Hz), 116.8 (q, JCF = 289.5 Hz), 115.3 (dq, JCF = 23.4, 4.3 Hz), 110.0 (d, JCF = 6.6 Hz);
19
F NMR (376 MHz, CDCl ) δ ꢀ70.1, ꢀ127.1. CAS registry number ꢀ 214288ꢀ07ꢀ0, no
3
spectroscopic data are available for comparison.
1ꢀ(2ꢀAminophenyl)ꢀ2,2,2ꢀtrifluoroethanone (1e) To a solution of 2,2ꢀdimethylꢀNꢀ
phenylpropanamide (7.80 g, 44.0 mmol) in MTBE (100 mL) and TMEDA (6.8 mL, 44.0
mmol, 1.0 equiv), cooled to ꢀ20 °C, a solution of nꢀBuLi (38.7 mL, 96.8 mmol, 2.2 equiv,
nꢀBuLi 2.5 M in hexane) was added dropwise by means of syringe pump within 2h while
the temperature was kept below ꢀ10 °C. The mixture was aged at 25 °C for 3 h (yellow
solid has formed), cooled below ꢀ25 °C, and CF CO Et (7.35 mL, 61.8 mmol, 1.4 equiv)
3
2
was added rapidly (internal temp. reached 0 °C). Then reaction mixture was stirred for
6h at rt and quenched with 5% HCl (100 mL). The organic phase was separated and
1
solvents were evaporated. The residue was chromatographed on silica (5ꢀ10%
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EtOAc/hexanes) to give a yellow oil (5.1 g) and unreacted substrate (1.6 g). The crude
TFMK was treated with 36% HCl (20 mL) at rt (white solid was formed immediately) and
stirred for 3h at 90 °C (temp. of oil bath, yellow solution has been formed at 70 °C).
Then reaction mixture was neutralized with sat. solution of Na CO and extracted with
0
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1
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2
3
EtOAc (4 x 30 mL). The combined organic extracts were washed with brine (1 x 30 mL),
dried over MgSO , and evaporated. The residue was purified by crystallization (nꢀ
4
1
heptane, 8 mL, ꢀ40 °C, 2h) to give a bright yellow solid (2.66 g, 32%). H NMR (400
MHz, CDCl ) δ 7.82–7.73 (m, 1H), 7.43–7.36 (m, 1H), 6.77–6.68 (m, 2H), 6.45 (br s, 2H,
3
13
NH); C NMR (100 MHz, CDCl ) δ 180.8 (q, J = 33.1 Hz), 151.1, 136.6, 131.3 (q, JCF
3
CF
19
=
4.1 Hz), 117.4, 117.1 (q, JCF = 289.7 Hz), 116.4, 111.2; F NMR (376 MHz, CDCl ) δ
3
1
60 13
ꢀ
69.6. H NMR data are in agreement with those reported.
C NMR spectra is
described by authors without CꢀF coupling constants and the accurate description and
the copy of spectra are included in this experimental section.
1
ꢀ[2ꢀAminoꢀ5ꢀ(trifluoromethyl)phenyl]ꢀ2,2,2ꢀtrifluoroethanone (1f) To a solution of
2,2ꢀdimethylꢀNꢀ[4ꢀ(trifluoromethyl)phenyl]propanamide (10.8 g, 44.0 mmol) in MTBE
130 mL) and TMEDA (6.8 mL, 44.0 mmol, 1.0 equiv), cooled to ꢀ20 °C, a solution of nꢀ
(
BuLi (38.7 mL, 96.8 mmol, 2.2 equiv, nꢀBuLi 2.5 M in hexane) was added dropwise by
means of syringe pump within 1h while the temperature was kept below ꢀ20 °C. The
mixture was aged at 0 ꢀ 5 °C for 2 h (a brownꢀblack solid has been formed), cooled
below ꢀ25 °C, and CF CO Et (7.35 mL, 61.8 mmol, 1.4 equiv) was added rapidly
3
2
(internal temp. reached 0 °C). Then reaction mixture was stirred for 1h at rt, quenched
with 5% HCl (100 mL) and organic phase was separated and solvents were evaporated.
The yellowꢀgreen residue was treated with 36% HCl (100 mL), and stirred for 16h at 90
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°
C (temp. of oil bath). Then reaction mixture was neutralized with solid Na CO and
2
3
extracted with EtOAc (4 x 30 mL). The combined organic extracts were washed with
brine (1 x 30 mL), dried over MgSO , and evaporated. The residue was
4
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chromatographed on silica (10% EtOAc/hexanes) to give a bright yellow solid (4.44 g,
pure fraction). Additional 1.89 g of product was obtained by crystallization (nꢀheptane) of
1
mixed fraction after chromatography. (4.44 g + 1.89 g, 56%). H NMR (400 MHz, CDCl )
3
δ 8.05 (s, 1H), 7.58 (dd J = 8.9, 1.8 Hz, 1H), 6.83 (d, J = 2.2 Hz, 1H), 6.75 (br s, NH,
13
2
H); C NMR (100 MHz, CDCl ) δ 180.7 (q, J = 34.0 Hz), 154.7, 132.6 (q, JCF = 3.0
3
CF
Hz), 129.3 – 129.0 (m), 123.8 (q, JCF = 269.3 Hz), 118.6 (q, JCF = 33.4 Hz), 118.1, 116.7
19
1
(
q, JCF = 289.4 Hz), 109.9; F NMR (376 MHz, CDCl ) δ ꢀ62.3, ꢀ69.8. H NMR data are
3
60 13
in agreement with those reported.
C NMR spectra is described by authors without Cꢀ
F coupling constants and the accurate description and the copy of spectra are included
in this experimental section.
1
ꢀ[2ꢀAminoꢀ5ꢀ(dimethylamino)phenyl]ꢀ2,2,2ꢀtrifluoroethanone (1g) To a solution of
Nꢀ[4ꢀ(dimethylamino)phenyl]ꢀ2,2ꢀdimethylpropanamide (4.99 g, 22.66 mmol) and
TMEDA (45.34 mmol, 6.95 mL, 2.0 eq) in THF, cooled to ꢀ60 °C, nꢀBuLi (19.9 mL, 45.34
mmol, 2.2 equiv, 2.28 M in hexane) was added dropwise by means of syringe pump
within 30 min. (temp. has increased to ꢀ50 °C), and the reaction was stirred for 4h at 0 –
ꢀ5 °C degree (internal temperature; reaction mixture was stirred by means of
mechanical stirrer due to lithium dianion precipitation). Then reaction mixture was
cooled to ꢀ65 °C and CF CO Et (3.77 mL, 31.73 mmol, 1.4 equiv) was added within 5
3
2
min. (the internal temp. has risen to ꢀ35 °C). Then cooling bath was removed, and the
reaction mixture was allowed to warm up to 0 °C and stirred for additional 1h at this
ACS Paragon Plus Environment
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