Cu-Catalyzed C(sp2?H)-Trifluoromethylation of Aldehyde Hydrazones with Langlois Reagent

Article abstract of DOI:10.1002/ejoc.202100205

The C(sp²?H)-trifluoromethylation of hydrazones would give access to the α-trifluoromethylated hydrazones that can serve as intermediates in the synthesis of pharmaceutically interesting fluorinated compounds. Herein, we demonstrate the Cu-cata

Full text of DOI:10.1002/ejoc.202100205

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Cu-Catalyzed C(sp2À H)-Trifluoromethylation of Aldehyde
Hydrazones with Langlois Reagent
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Jatin Mehta,[a] Puspa Aryal,[a] and V. Prakash Reddy*[a]
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The C(sp2À H)-trifluoromethylation of hydrazones would give
access to the α-trifluoromethylated hydrazones that can serve
as intermediates in the synthesis of pharmaceutically interesting
fluorinated compounds. Herein, we demonstrate the Cu-cata-
lyzed C(sp2À H)-trifluoromethylation of the aldehyde hydrazones
using the readily available and cost effective Langlois reagent
(sodium trifluoromethanesulfinate). This reaction is broadly
applicable to a series of aromatic aldehyde N-aminomorpholine
hydrazones to give the corresponding C(sp2)-trifluoromethyl
hydrazones in moderate to high yields. The reaction generally
tolerates a series of electron-releasing as well as electron-
withdrawing substituents on the aromatic ring.
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Introduction
hydrazones, in contrast to the related imines, do not undergo
nucleophilic trifluoromethylations because the electrophilicity
of the imino carbon is attenuated due to the resonance
interaction of the adjacent amino group. Therefore, free-radical
trifluoromethylation of hydrazones has received renewed
attention as an alternative for the synthesis of the correspond-
ing C(sp2À H)-trifluoromethylated products.[21–26] Baud)oin,
Bouyssi, Monteiro, and coworkers reported C(sp2À H)-
trifluoromethylation of the aldehyde-hydrazones (1) using the
Togni’s reagent (1-trifluoromethyl-1,2-benziodoxol-3(1H)-one)
as the electrophilic trifluoromethylating reagent, which in the
presence of the Cu(I) catalyst, generates the trifluoromethyl free
radical as the reaction intermediate.[22,23] Moderate to high
yields of the trifluoromethylated hydrazones 2 were obtained in
this reaction. Studer and coworkers have achieved similar
C(sp2À H)-trifluoromethylation of aromatic aldehyde N,N-dimeth-
ylhydrazones using the Togni’s reagent and tetrabutylammo-
nium iodide (TBAI) as the radical initiator.[24] Feng and co-
workers have developed the free-radical trifluoromethylation of
the aldehyde hydrazones using the Langlois reagent (CF3SO2Na)
and PhI(OAc)2 as the radical initiator.[25] Xu and coworkers have
used photoredox catalysis for the trifluoronethylation of
hydrazones in the presence of trifluoromethanesulfonyl chloride
(CF3SO2Cl) (Scheme 1).[21] However, these synthetic methods,
although elegant, require the use of the potentially explosive
hypervalent iodine(III) reagents (under certain conditions,
especially when used in large scale synthesis) and/or expensive
reagents (Togni’s reagent, $99.90/g; CF3SO2Cl, $65.60/5 g).[27–29]
Toward the goal of developing cost-effective and efficient
approaches for the synthesis of the trifluoromethylated hydra-
zones, we now report the trifluoromethylation of the aldehyde
hydrazones under mild reaction conditions, using the inex-
pensive, nontoxic, and bench stable Langlois reagent in the
presence of Cu(II) salts as the free-radical initiators.
α-Trifluoromethylated amines and imines have important
applications in the drug design and medicinal chemistry as
isosteric and isopolar bioisosteres of the amide or peptide
moieties.[1–7] Furthermore, the relatively higher electronegativity
of the trifluoromethyl group diminishes the basicity of the
adjacent amino moiety, thereby modulating the pharmacoki-
netics of the drug candidates.
Nucleophilic trifluoromethylation of N-alkylimines using
Ruppert-Prakash reagent (CF3SiMe3) under relatively strong
acidic conditions gives the corresponding α-trifluorometh-
ylamines.[8–10] Nucleophilic trifluoromethylation of chiral N-tert-
butanesulfinylimines, which are activated to the nucleophilic
additions by the adjacent sulfinyl moiety, using Ruppert-
Prakash reagent gives the corresponding trifluoromethylated
products with high diastereoselectivities and yields under mild
conditions.[11–15] Catalytic enantioselective trifluoromethylation
of the azomethine imines gives high yields of the correspond-
ing α-trifluoromethylated amines.[16] We have recently devel-
oped the nucleophilic trifluoromethylation of N-(p-toluenesul-
fonyl)aldimines under nonacidic conditions, using N-
heterocyclic carbene (NHC) catalysts.[17]
Unlike α-trifluoromethylated amines, α-trifluoromethylated
hydrazones are relatively less explored as substrates in the drug
design, presumably owing to the synthetic challenges involved
in the preparation of these compounds. The α-trifluoromethyl
hydrazones can be hydrogenated to give the corresponding
hydrazines, which are useful substrates in the preparation of
the pharmaceutically interesting compounds,[18] or hydrolyzed
to give the trifluoromethyl ketones, which are used as serine
protease inhibitors in the drug design.[19,20] Aldehyde or ketone
[a] Dr. J. Mehta, P. Aryal, Prof. Dr. V. Prakash Reddy
Department of Chemistry
Missouri University of Science and Technology
Rolla, MO 65409, USA
E-mail: preddy@mst.edu
Results and Discussion
https://people.mst.edu/faculty/preddy/index.html
We have explored Langlois reagent as the source of the
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202100205
.
trifluoromethyl (CF3 ) radicals and Cu(II) salts as the radical
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Scheme 1. State-of-the-art synthetic methods for the trifluoromethylation of the aldehyde hydrazones.
initiators for the C(sp2À H)-trifluoromethylation of aldehyde
hydrazones, toward the development of the efficient and cost-
effective synthetic methods. We have initially investigated the
radical trifluoromethylation of aldehyde N-aminomorpholine
hydrazones, using benzaldehyde hydrazone 1 as a model
substrate. Use of various other hydrazones, such as N,N-dimeth-
ylhydrazones, under these conditions gave lower yields of the
trifluoromethylated products.
The reaction of compound 1 with the Langlois reagent
(sodium trifluoromethanesulfinate), under various conditions,
gave the C(sp2)-trifluoromethyl hydrazone 2, in high yields of
up to 94% (Table 1). Typically, the trifluoromethylation reac-
tions of the hydrazones were performed using Langlois reagent
in the presence of potassium persulfate, as a stoichiometric
oxidant, a Cu(II) salt, as a catalyst, and 4 Å molecular sieves,
under N2 atmosphere in acetonitrile solvent, at 80 C for 24 h
°
during the optimization of the reaction conditions, with few
exceptions as noted in Table 1. Use of the catalytic amounts of
MnO2 and K2S2O8 in DMF solvent (Table 1; entry 18) and di-tert-
butyl peroxide (DTBP), in the absence of any catalyst, in DMSO
solvent (Table 1; entry 17) gave only trace amounts of the
trifluoromethylated product (by 19F NMR). No reaction was
observed when Mn(OAc)2.5H2O was used as an oxidant, in the
absence of the Cu(II) catalyst, in acetone as a solvent (Table ;
entry 16). When ethyl acetate was used as a solvent instead of
acetonitrile, the yields were drastically reduced to 7–12%
Table 1. Optimization of the Reaction Conditions.[a]
Entry
Catalyst (equiv)
Oxidant (equiv)
Solvent
Yield [%][b]
1
Cu(OAc)2 (0.25)
Cu(OAc)2 (0.25)
Cu(OAc)2 (0.25)
CuSO4.5H2O (0.25)
CuSO4.5H2O (0.5)
CuSO4.5H2O (0.5)
Cu(OTf)2 (0.25)
CuCl2 (0.25)
Cu(OAc)2 (0.25)
CuSO4.5H2O (0.5)
CuSO4.5H2O (0.5)
CuSO4.5H2O (0.5)
CuSO4.5H2O (0.5)
CuSO4.5H2O (0.5)
None
K2S2O8 (2)
K2S2O8 (3)
K2S2O8 (2)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
K2S2O8 (3)
Mn(OAc)2.4H2O (0.2)
DTBP (0.2)
K2S2O8 (0.12)
ACN
ACN
ACN
ACN
ACN
DCE
ACN
ACN
EtOAc
EtOAc
DMPU
ACN
ACN
ACN
65
91
71
48
94
12
83
NR
12
7
NR
55
81
9
58
NR
2
3[c]
4
5
6
7
8
9
10
11
12[d]
13[e]
14[f]
15
16[f]
17[g]
18[g]
ACN
None
None
MnO2 (0.12)
Acetone
DMSO
DMF
trace by 19F NMR
trace by 19F NMR
[a] Unless otherwise specified, all reactions were carried out using the hydrazone 1 (0.1 mmol) and CF3SO2Na (2 mol equiv) in 2 mL of solvent, under N2
atmosphere, at 80 C for 21–24 h. [b] Yields estimated by GC-MS. [c] 3 mol equiv. of CF3SO2Na was used. d Reaction was carried out in the absence of the N2
atmosphere. [e] Reaction was carried out in the absence of the molecular sieves. [f] Reactions were carried out at room temperature. [g] Reactions were
°
°
performed at 60 C; NR=No reaction.
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(Table 1; entries 9 and 10). Similarly, poor yields (12%) were
hydrazone 1j, under the optimized reaction conditions, gave
the corresponding C(sp2)-trifluoromethyl hydrazone 2j in 46%
yield after 6 h of reaction time. In the latter case, extending the
reaction time to more than 6 h resulted in the formation of the
undesirable byproducts. Trifluoromethylation of the aliphatic
aldehyde hydrazones, however, were not successful in these
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obtained when the reaction was carried out in dichloromethane
as a solvent (Table 1; entry 6) and the reaction did not proceed
in the DMPU solvent (entry 11). When the reaction was
performed using Cu(OAc)2 (0.25 mol equiv) and K2S2O8 (2 mol
equiv), the C(sp2)-trifluoromethyl hydrazone 2a was obtained in
48% yield (Table 1; entry 1). Further increase in the amount of
K2S2O8 (3 mol equiv) dramatically improved the product yield by
up to 91% (Table 1; entry 2) and increasing the amount of
Langlois reagent (3 mol equiv) resulted in the lowering of the
product yield to 71% (Table 1; entry 3). We also investigated
the effect of various other Cu(II) salts as catalysts in this
reaction. When Cu(II) triflate (Cu(OTf)2; Cu(OSO2CF3)2) was used
as a catalyst, the C(sp2)-trifluoromethyl hydrazone 2a was
obtained in 83% yield (Table 1; entry 7) and there was no
reaction when Cu(II)Cl2 was used as the catalyst (Table 1;
entry 8). Although Cu(OAc)2 and Cu(OTf)2 gave satisfactory
yields, we have investigated CuSO4.5H2O as a catalyst because
Cu(OAc)2 and Cu(OTf)2 are relatively expensive reagents (Cu-
(OAc)2: $160 per 100 g; Cu(OTf)2: $96 per 25 g). On the other
hand, CuSO4.5H2O is a cost-effective reagent ($36 per 100 g),
and gratifyingly, the trifluoromethylated product 2 was formed
in high yield (94%) using CuSO4.5H2O (Table 1; entry 5) as the
catalyst. We have also investigated various other reaction
conditions, using CuSO4 as the catalyst, in order to fine tune the
reaction conditions; for example, at room temperature (Table 1;
entry 14), in the absence of the molecular sieves (Table 1;
entry 13), and in the absence of the nitrogen atmosphere
(Table 1; entry 12). In all these cases, low yields of the C(sp2)-
trifluoromethyl hydrazone 2a were observed. Although use of
0.5 equiv. of CuSO4 is optimal for high yields of the
trifluoromethylated product, use of 0.25 equiv. of Cu(OAc)2 or
Cu(OTf)2 also gives similarly high yields (Table 1, entries 2 and
7). We have not further optimized to lower the concentration of
the Cu(II) catalysts, and used the CuSO4.5H2O, as a cost-effective
catalyst, for the trifluoromethylation reactions. With the opti- Conclusion
mized reaction conditions in hand, we then explored the scope
of reaction for aromatic substrates with electron-withdrawing
as well as electron-releasing substituents and aliphatic aldehyde
hydrazones, and the results are summarized in Scheme 2.
As shown in Scheme 2, N-aminomorpholine hydrazones
derived from their corresponding aromatic aldehydes with
electron-withdrawing groups, irrespective of the position of the
group on aromatic ring, gave the C(sp2)-trifluoromethyl hydra-
zones (2b, 2c, 2d, 2f, 2g) in high yields (87%–96%) in 24 h.
However, in case of the N-aminomorpholine hydrazones
derived from the aromatic aldehydes bearing electron-releasing
substituents, longer reaction times of 30–46 h were required to
afford the corresponding C(sp2)-trifluoromethyl hydrazones (2e,
2h, and 2n) in good yields (55%–77%). The trifluorometh-
ylation reaction of heteroaromatic aldehyde hydrazones also
trifluoromethylation
reactions.
The
initially
formed
trifluoromethyl hydrazone 2m apparently degraded under
these conditions. The trifluoromethylation N-aminomorpholine
hydrazones derived from the aromatic aldehydes bearing
hydroxy substituents, such as 1i, similarly, was not successful
and resulted in the formation of the undesirable products, and
the expected product 2i was not observed.
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Based on the mechanisms suggested earlier for the related
Cu-catalyzed free-radical trifluoromethylation of hydrazones
using the Togni’s reagent,[22] we propose the following mecha-
nism for the Cu-catalyzed trifluoromethylation reactions
(Scheme 3). The Langlois reagent is initially oxidized by the
.
Cu(II) to give the CF3 radical and the stoichiometric oxidant
K2S2O8 regenerates the Cu(II) from the Cu(I) formed in the latter
step. The latter trifluoromethyl radical may also be generated
by the direct oxidation of the Langlois reagent by K2S2O8,[30,31]
although relatively poor yields of the trifluoromethylated
products were obtained in the absence of the Cu(II) catalysis
.
(Table 1, entry 15). The CF3 radical addition to the hydrazone 1
.
then gives the aminyl radical (1-CF3 ), which is further oxidized
by the Cu(II) to give the nitrenium cation 1-CF3+, stabilized by
resonance from the morpholine moiety. Deprotonation of the
latter nitrenium cation by a mild base, such as KHSO4 would
then give the trifluoromethylated hydrazone 2. The involve-
ment of aminyl radicals and nitrenium cations in the free-radical
additions to hydrazones is well documented in the
literature.[24,25,32]
In summary, the Cu-catalyzed trifluoromethylation of aromatic
aldehyde N-aminomorpholine hydrazones in the presence of
the Langlois reagent, and K2S2O8 as a stoichiometric oxidant,
gave the corresponding C(sp2)-trifluoromethyl hydrazones in
moderate to high yields. The reaction tolerates a wide variety of
electron-withdrawing and electron-donating substituents, such
as Cl, Br, OMe, NO2, on the aromatic ring and heterocyclic
aromatic rings such as furan. The reaction also obviates the use
of expensive and/or relatively potentially hazardous hypervalent
iodine reagents,[27–29,33] and thus affords an efficient and cost-
effective synthetic method for the synthesis of the C(sp2)-
trifluoromethyl hydrazones.
proceeds readily under these conditions, although relatively Experimental Section
longer reaction times were required for optimal yields; thus, the
radical trifluoromethylation of 2-furfural N-aminomorpholinehy-
drazone after a reaction time of 30 h gave the corresponding
C(sp2)-trifluoromethyl hydrazone 2k in 80% yield. The
trifluoromethylation of 1-naphthaldehde N-aminomorpholine-
Synthesis of hydrazones (1a–1n)
The aldehyde hydrazones (1a–n) were synthesized according to
literature procedures with minor modifications, as follows.[23,25,34,35]
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Scheme 2. Substrate Scope for Trifluoromethylation of Aldehyde N-Aminomorpholine Hydrazones.[a,b] [a] Unless otherwise specified, all reactions were carried
°
out using 1 (0.5 mmol), CF3SO2Na (2 mol equiv), K2S2O8 (3 mol equiv), and ACN (10 mL) at 80 C for 24 h under N2 (balloon) atmosphere. [b] Yields were
estimated by GC-MS (values in parenthesis are for the isolated yields); the yields for the compounds 2h–2n were estimated by GC-MS; ND=yields not
determined; [c] Reaction was terminated after 6 h because of the formation of the undesired products after longer reaction time.
General Procedure: To a solution of aldehyde (10 mmol) in 10 mL
of dichloromethane, was added 4-aminomorpholine (2.04 g,
20 mmol) and anhydrous MgSO4 (240 mg, 20 mmol). The resulting
solution was stirred at room temperature for 12 h. After completion
(E)-N-morpholino-1-phenylmethanimine (1a).[26,34] The compound 1a
was prepared according to the general procedure using benzalde-
hyde (1 g, 9.3 mmol) and 4-aminomorpholine (1.9 g, 18.6 mmol).
Yield: 956 mg (5 mmol; 54%); 1H NMR (400 MHz, DMSO- d6) δ1H
7.68 (s, 1H, CH=N), 7.62–7.58 (m, 2H, m-ArH), 7.34–7.31 (m, 2H, C2-
ArH), 7.27–7. 23 (m, 1H, C4-ArH), 3.87- 3.85 (apparent t, 4H, CH2O),
3.16-3.14 (apparent t, 4H, CH2N); 13C NMR (100 MHz, CDCl3) δ13C
136.8, 136.4, 129, 128.8, 126.7, 67.0, 52.4.
1
of the reaction as monitored by H NMR. MgSO4 was filtered off,
and the solvent was evaporated under reduced pressure. The
hydrazones were purified either by recrystallization from absolute
ethanol (in case of solid products) or by flash chromatography
using silica gel stationary phase and dichloromethane as an eluent
(in case of liquid products). The 1H and 13C NMR spectra of the
compounds are in agreement with the literature data.
(E)-N-morpholino-1-(4-nitrophenyl)methanimine (1b).[26] The com-
pound 1b was prepared according to general procedure using 4-
nitrobenzaldehyde (360 mg, 2.38 mmol) and 4-aminomorpholine
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Scheme 3. Proposed Mechanism for the trifluoromethylation of hydrazones.
(486 mg, 4.76 mmol). Yield: 426 mg (1.8 mmol; 76%); 1H NMR
(400 MHz, CDCl3) δ1H 8.18–8.16 (m, 2H, C3-ArH), 7.69–7.67 (m, 2H,
C2-ArH), 7.51 (s, 1H, CH=N), 3.89-3.86 (apparent t, 4H, CH2O), 3.26–
3.23, (apparent t, 4H, CH2N); 13C NMR (100 MHz, CDCl3) δ13C 147.1,
142.6, 131.8, 126.4, 124.2, 66.4, 51.4.
line (113 mg, 1.10 mmol). Yield: 82 mg (0.36 mmolo; 66%); H NMR
1
(400 MHz, CDCl3) δ1H 7.52 (s, 1H, CH=N), 7.50–7.49 (m, 2H, ArH),
7.30–7.27 (m, 2H, ArH), 3.87-3.85 (apparent t, 4H, CH2O), 3.13-3.11,
(apparent t, 4H, CH2O); 13C NMR (100 MHz, CDCl3) δ13C 134.7, 134.1,
128.9, 127.5, 66.6, 51.9.
(E)-1-(4-bromophenyl)-N-morpholinomethanimine (1c).[25,26] The com-
pound 1c was prepared according to general procedure using 4-
bromobenzaldehyde (213 mg, 1.15 mmol) and 4-aminomorpholine
(235 mg, 2.3 mmol). Yield: 202 mg (0.75 mmol; 65%); 1H NMR
(400 MHz, CDCl3) δ1H 7.48 (s, 1H, CH=N), 7.44 (apparent s, 4H, ArH),
3.87–3.85, (apparent t, 4H, CH2O) 3.16–3.14 (apparent t, 4H, CH2N);
13C NMR (100 MHz, CDCl3) δ13C 135.2, 134.7, 131.8, 127.8, 122.3,
66.6, 51.9.
(E)-1-(3-bromophenyl)-N-morpholinomethanimine (1g).[32] The com-
pound 1g was prepared according to the general procedure using
3-bromobenzaldehyde (498 mg, 2.69 mmol) and 4-aminomorpho-
1
line (550 mg, 5.39 mmol). Yield: 370 mg (1.37 mmol; 51%); H NMR
(400 MHz, CDCl3) δ1H 7.76–7.75 (m, 1H, ArH), 7.45 (s, 1H, CH=N),
7.38–7.36 (m, 2H, ArH), 7.20–7.16 (m, 1H, ArH), 3.87–3.85 (apparent
t, 4H, CH2O), 3.17–3.15 (apparent t, 4H, CH2N); 13C NMR (400 MHz,
CDCl3) δ13C 138.3, 134, 131.2, 130.2, 128.9, 125, 123, 66.6, 51.8.
(E)-N-morpholino-1-(2-nitrophenyl)methanimine (1d).[26] The com-
pound 1d was prepared according to general procedure using 2-
nitrobenzaldehyde (186 mg, 1.23 mmol) and 4-aminomorpholine
(252 mg, 2.47 mmol). Yield: 250 mg (1.06 mmol; 86%); 1H NMR
(400 MHz, CDCl3) δ1H 8.05-8.09 (m, 2H, ArH), 7.92-7.94 (m, 1H, ArH),
7.56 (s, 1H, CH=N), 7.52–7.54 (m, 1H, ArH), 3.86- 3.88 (apparent t,
4H, CH2O), 3.23–3.25, (apparent t, 4H, CH2N); 13C NMR (100 MHz,
CDCl3) δ13C (ppm) 147.6, 133.2, 131.2, 130.2, 128.3, 127.7, 124.8,
66.5, 51.6.
(E)-1-(4-methoxyphenyl)-N-morpholinomethanimine (1h).[25] The com-
pound 1h was prepared according to the general procedure using
p-anisaldehyde (1.09 g, 8.05 mmol) and 4-aminomorpholine
(1.644 g, 16.1 mmol). Yield: (94 mg (0.43 mmol; 53%); 1H NMR
(400 MHz, CDCl3) δ1H 7.57 (s, 1H, CH=N), 7.50–7.47 (m, 2H, ArH),
7.30–7.27 (m, 2H, ArH), 3.87 (s, 3H, OCH3), 3.86–3.80 (apparent t, 4H,
CH2O), 3.13–3.11, (apparent t, 4H, CH2N); 13C NMR (100 MHz, CDCl3)
δ13C 160.1, 136.9, 127.7, 114.2, 66.7, 55.5, 52.3.
(E)-4-((morpholinoimino)methyl)phenol (1i).[36] The compound 1i was
prepared according to the general procedure using 4-hydroxyben-
zaldehyde (179 mg, 1.46 mmol) and 4-aminomorpholine (300 mg,
2.93 mmol). Yield: 109 mg (0.53 mmol; 36%); 1H NMR (400 MHz,
CDCl3) δ1H 7.56 (s, 1H, CH=N), 7.48–7.46 (m, 2H, ArH), 6.79–6.77
(apparent t, 2H, ArH), 3.87–3.85 (apparent t, 4H, CH2O), 3.13–3.10,
(m, 4H, CH2N); 13C NMR (100 MHz, CDCl3) δ13C 156.4, 137.3, 128.8,
128.0, 115.7, 66.7, 52.3.
(E)-N-morpholino-1-(p-tolyl)methanimine (1e).[25,26] The compound
1e was prepared according to general procedure using p-
tolualdehyde (245 mg, 2.05 mmol) and 4-aminomorpholine
(418 mg, 4.09 mmol). Yield: 208 mg (1.02 mmol; 50%); 1H NMR
(400 MHz, CDCl3) δ1H 7.66 (s, 1H, CH=N), 7.58-7.56 (m, 2H, ArH),
7.33–7.23 (m, 2H, ArH), 3.95–3.94 (apparent t, 4H, CH2O), 3.24-3.22,
(apparent t, 4H, CH2O), 2.42 (s, 3H, CH3); 13C NMR (100 MHz, CDCl3)
δ13C 138.5, 136.9, 133.4, 129.4, 126.4, 66.7, 52.2, 21.5.
(E)-N-morpholino-1-(naphthalen-2-yl)methanimine (1j).[36] The com-
pound 1j was prepared according to the general procedure using
1-naphthaldehyde (428 mg, 2.72 mmol) and 4-aminomorpholine
(556 mg, 5.45 mmol). Yield: 380 mg (1.58 mmol; 58%); 1H NMR
(E)-1-(4-chlorophenyl)-N-morpholinomethanimine (1f).[26] The com-
pound 1f was prepared according to the general procedure using
4-chlorobenzaldehyde (77.7 mg, 0.55 mmol) and 4-aminomorpho-
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(400 MHz, CDCl3) δ1H 8.51–8.54 (m, 1H, ArH), 8.27a (s, 1H, CH=N),
(376 MHz, CDCl3 ) δ19F À 66.7 (s, 3F); GC-MS (m/z (relative %)): tR =
2.3 min; m/z 258 (100, M.+), 199 (36), 131 (50), 104 (49), 86 (38), 77
(51).
1
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3
4
5
6
7
8
9
7.50–7.86 (m, 3H, ArH), 7.44–7.49 (m, 3H, ArH), 3.91–3.94 (apparent
t, 4H, CH2O), 3.27–3.29, (apparent t, 4H, CH2O); 13C NMR (400 MHz,
CDCl3) δ13C 135.5, 134.1, 131.6, 130.9, 129, 128.9, 126.6, 125.9, 125.7,
125.5, 124, 66.7, 52.2.
(E)-2,2,2-trifluoro-N-morpholino-1-(4-nitrophenyl)ethan-1-imine
(2b).[25,26,37] The compound 2b was prepared according to general
procedure using 1b (116 mg, 0.5 mmol) and the crude product was
purified by column chromatography to afford 2b as a yellow solid.
(E)-1-(furan-2-yl)-N-morpholinomethanimine (1k).[25] The title com-
pound was prepared according to the general procedure 1 using 2-
furfural (353 mg, 1.96 mmol) and 4-aminomorpholine (401 mg,
3.92 mmol). Yield: 230 mg (1.28 mmol; 65%); 1H NMR (400 MHz,
CDCl3) δ1H 7.44 (s, 1H, CH=N), 7.40 (s, 1H, ArH), 6.39–6.45 (apparent
t, 2H, ArH), 3.84–3.86 (apparent t, 4H, CH2O), 3.12–3.14, (apparent t,
4H, CH2O); 13C NMR (100 MHz, CDCl3) δ13C 151.4, 143, 126.9, 111.6,
109.4, 66.5, 51.9.
1
Yield: 105 mg (0.35 mmol; 70%); H NMR (400 MHz, CDCl3) δ1H 8.25
(d, 2H, J=8 Hz), 7.6 (d, 2H, J=8 Hz), 3.6-3.63 (apparent t, 4H, CH2O),
2.98–3.01 (apparent t, 4H, CH2N); 13C NMR (100 MHz, CDCl3) δ13C
1
148.6, 138.3, 132.6 (q, 2JC-F =34 Hz), 130, 124.2, 122.5 (q, JC-F
=
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
271 Hz), 66.1, 54.6 ; 19F NMR (376 MHz, CDCl3 ) δ19F À 66.1(s, 3F); GC-
MS (m/z (relative %)): tR =4.2 min; m/z 303 (M.+), 288 (13), 244 (21),
198 (35), 176 (31), 103 (38), 85 (36), 56 (100).
(E)-1-(2,6-dichlorophenyl)-N-morpholinomethanimine (1l).[26] The
compound 1l was prepared according to the general procedure
using 2,6-dichlorobenzaldehyde (417 mg, 1.61 mmol) and 4-amino-
morpholine (329 mg, 3.22 mmol). Yield: 351 mg (1.36 mmol; 84%);
1H NMR (400 MHz, CDCl3) δ1H 7.61 (s, 1H, CH=N), 7.31–7.29 (m, 2H,
ArH), 7.11 (m, 1H, ArH), 3.90–3.88 (apparent t, 4H, CH2O), 3.23–3.21,
(apparent t, 4H, CH2N); 13C NMR (100 MHz, CDCl3) δ13C 134.7, 132.4,
131.3, 129, 128.9, 128, 66.4, 54.4, 51.6.
(E)-1-(4-bromophenyl)-2,2,2-trifluoro-N-morpholinoethan-1-imine
(2c).[21,25,26,37] The compound 2c was prepared according to general
procedure 2 using 1c (135 mg, 0.5 mmol) and the crude product
was purified by column chromatography to afford 2c as a yellow
1
oil. Yield: 121 mg (0.36 mmo; 72%); H NMR (400 MHz, CDCl3) δ1H
7.47 (d, 2H, J=8 Hz), 7.21 (d, 2H, J=8 Hz), 3.53-3.55 (apparent t, 4H,
CH2O), 2.9–2.92 (apparent t, 4H, CH2N); 13C NMR (100 MHz, CDCl3)
2
1
δ13C 135.4 (q, JC-F =34 Hz), 132.3, 130.5, 130.2, 124.4, 122.5 (q, JC-F
=270 Hz), 66.2, 54.4; 19F NMR (376 MHz, CDCl3) δ19F-66.6 (s, 3F); GC-
MS (m/z (relative %)): tR =3.5 min; m/z 338 (M+ +1), 279 (23), 199
(29), 157 (23), 102 (22), 86 (57), 56 (100).
(E)-N-morpholinoheptan-1-imine (1m).[25] The compound 1m was
prepared according to the general procedure using heptanal
(498 mg, 4.36 mmol) and 4-aminomorpholine (891 mg, 8.72 mmol).
1
Yield: 450 mg (2.27 mmol; 52%); H NMR (400 MHz, CDCl3) δ1H 6.93
(s, 1H, CH=N), 3.78–3.77 (apparent t, 4H, CH2O) 2.90–2.92, (apparent
t, 4H, CH2N), 2.20–2.19 (m, 2H, CH2) 1.43–1.25 (m, 8H, 4CH2) 0.84–
0.83 (m, 3H, CH3); 13C NMR (100 MHz, CDCl3) δ13C 142.6, 66.5, 52.6,
33.1, 31.7, 28.9, 27.4, 22.6, 14.1.
(E)-2,2,2-trifluoro-N-morpholino-1-(2-nitrophenyl)ethan-1-imine
(2d).[26] The compound 2d was prepared according to the general
procedure using 1d (133 mg, 0.5 mmol) and the crude product was
purified by column chromatography to afford 2d as a yellow oil.
1
Yield: 108 mg (0.36 mmol; 72%); H NMR (400 MHz, CDCl3) δ1H 8.14
(E)-N-morpholino-1-(3,4,5-trimethoxyphenyl)methanimine (1n)[26] The
compound 1n was prepared according to the general procedure
using 3,4,5- trimethoxybenzaldehyde (521 mg, 2.66 mmol) and 4-
aminomorpholine (542 mg, 5.3 mmol). Yield: 551 mg (1.96 mmol;
(d, 1H, J=8 Hz), 7.68 (d, 1H, J=8 Hz), 7.65–7.7 (m, 1H), 7.62–7.65
(M, 1H), 3.57–3.59 (apparent t, 4H, CH2O), 2.97–2.99 (apparent t, 4H,
2
CH2N); 13C NMR (100 MHz, CDCl3) δ13C 148.2, 134.1, 132.1(q, JC-F
=
33 Hz), 131.7, 127.6, 125.5, 122.6 (q, 1JC-F =280 Hz), 66.6, 54.2; 19F
NMR (376 MHz, CDCl3 ) δ19F À 66.5 (s, 3F); GC-MS (m/z (relative %)):
tR =3.9 min; 303 (4, M+), 203 (6), 123 (38), 43 (100).
1
74%); H NMR (400 MHz, CDCl3) δ1H 7.49 (s, 1H, CH=N), 6.83 (s, 2H,
ArH), 3.88 (s, 9H, 3CH3), 3.88–3.83 (apparent t, 4H, CH2O), 3.16–3.13
(apparent t, 4H, CH2N); 13C NMR (100 MHz, CDCl3) δ13C 153.6, 138.7,
136.3, 131.8, 103.4, 66.6, 61.1, 56.3, 52.1.
(E)-2,2,2-trifluoro-N-morpholino-1-(p-tolyl)ethan-1-imine (2e).[25,26] The
compound 2e was prepared according to general procedure using
1e (110 mg, 0.5 mmol) and the crude product was purified by
column chromatography (3:1 hexane: ethyl acetate) to afford 2e as
a yellow oil. Yield: 92 mg (0.34 mmol; 68%); 1H NMR (400 MHz,
CDCl3); δ1H 7.29 (d, 2H, J=8 Hz), 7.2 (d, 2H, J=8 Hz), 3.59–3.61
(apparent t, 4H, CH2O), 2.95–2.97 (apparent t, 4H, CH2N), 2.36 (s,
3H); 13C NMR (100 MHz, CDCl3) δ13C 130.4, 128.8, 66.6, 54.7 21.9; 19F
NMR (376 MHz, CDCl3 ); δ19F -66.8 (s, 3F); GC-MS (m/z (relative %)):
tR =2.7 min; 272 (100, M.+), 215 (35), 145(40), 118 (42), 86 (47), 56
(71).
Trifluoromethylation of hydrazones
General Procedure (for compounds 2a–2n). An oven-dried round-
bottom flask (25 mL), equipped with a magnetic stir bar, powdered
4 Å mol. sieves, and a N2 balloon, was added Compound 1
(1 mmol), CF3SO2Na (2 mmol), K2S2O8 (3 mmol), and CuSO4.5H2O
(0.5 mmol) at room temperature. A 10 mL portion of acetonitrile
was added to the contents with a syringe under N2. The resulting
°
solution was stirred at 80 C, and the progress of the reaction was
monitored by GC-MS. After the reaction was complete, the reaction
mixture was filtered to remove the molecular sieves, the solvent
was removed in vavuo, and the resulting product was subjected to
column chromatography on silica gel (eluent: 10% ethyl acetate in
hexane) to afford the products 2a–2g. The products were
(E)-1-(4-chlorophenyl)-2,2,2-trifluoro-N-morpholinoethan-1-imine
(2f).[21,26] The compound was prepared according to general
procedure using 1f (24 mg, 0.107 mmol) and the crude product
was purified by column chromatography to afford 2f as a yellow
oil. Yield: 22 mg (0.0752 mmol; 70%); 1H NMR (400 MHz, CDCl3); δ1H
7.38 (m, 4H,ArH), 3.6–3.62 (apparent t, 4H, 2CH2), 2.96–2.99
1
characterized by H NMR, 13C NMR, 19F NMR, and GC-MS, and are in
2
(apparent t, 4H, 2CH2); 13C NMR (100 MHz, CDCl3) δ13C 136.7 (q, JC-F
accordance with literature data. The yields for compounds 2h–2n
were estimated by GC-MS.
1
=36 Hz), 130.4, 129.7, 122.9 (q, JC-F =272 Hz), 66.5, 54.7; 19F NMR
(376 MHz, CDCl3 ) δ19F À 66.8 (s, 3F); GC-MS (m/z (relative %)): tR =
(E)-2,2,2-trifluoro-N-morpholino-1-phenylethan-1-imine
(2a).[21,26,32]
3.0 min; 292 (86, M+.), 235 (32), 165 (37), 138 (44), 86 (55), 56 (100).
The compound 2a was prepared according to general procedure
using 1a (191 mg, 1.0 mmol) and the crude product was purified
by column chromatography to afford 2a as a yellow oil. Yield:
195 mg (0.75 mmol; 75%); 1H NMR (400 MHz, CDCl3) δ1H 7.4 (m, 5H,
ArH), 3.58-3.61 (apparent t, 4H, CH2O), 2.95–2.97 (apparent t, 4H,
(E)-1-(3-bromophenyl)-2,2,2-trifluoro-N-morpholinoethan-1-imine
(2g).[32] The compound 2g was prepared according to general
procedure using 1g (130 mg, 0.48 mmol) and the crude product
was purified by column chromatography to afford 2g as a yellow
2
CH2O); 13C NMR (100 MHz, CDCl3) δ13C 136.6 (q, JC-F =33 Hz), 131.8,
1
oil. Yield: 118 mg (0.35 mmol; 72%); H NMR (400 MHz, CDCl3) δ1H
130, 129, 128.6, 122.7 (q, 1JC-F =280 Hz), 66.5, 54.5; 19F NMR
7.53–7.57 (m, 2H, ArH), 7.28–7.33 (m, 2H, ArH), 3.61-3.63 (apparent t,
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4H, CH2O), 2.98-3.0 (apparent t, 4H, CH2N); 13C NMR (100 MHz,
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6
7
8
9
2
CDCl3) δ13C 134.4 (q, JC-F =33 Hz), 133.7, 133.2, 131.6, 130.5, 127.4,
123.1, 122.6 (q, 1JC-F =275 Hz), 66.2, 54.5; 19F NMR (376 MHz) δ19F
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+
1), 279 (18), 199 (47), 184 (9), 102 (23), 56 (100).
Conflict of Interest
The authors declare no conflict of interest.
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Keywords: Catalysis
Trifluoromethylation
·
Hydrazones
·
Langlois reagent
·
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Manuscript received: February 19, 2021
Revised manuscript received: March 9, 2021
Accepted manuscript online: March 12, 2021
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© 2021 Wiley-VCH GmbH