Hydroxyl-directed trifluoromethylation of hydrazones

Article abstract of DOI:10.1016/j.mencom.2009.05.009

The trifluoromethylation of hydrazones derived from salicyl aldehydes and N-aminopiperidine and N-aminomorpholine through the generation of chelate difluoroboron complexes, which subsequently interact with Me₃SiCF₃ in the presence of

Full text of DOI:10.1016/j.mencom.2009.05.009

Mendeleev
Communications
Mendeleev Commun., 2009, 19, 141–143
Hydroxyl-directed trifluoromethylation of hydrazones
Alexander D. Dilman,*a Vitalii V. Levin,a Pavel A. Belyakov,a
Alexander A. Korlyukov,b Marina I. Struchkovaa and Vladimir A. Tartakovskya
a N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 119991 Moscow, Russian Federation.
Fax: +7 499 135 5328; e-mail: dilman@ioc.ac.ru
b A. N. Nesmeyanov Institute of Organoelement Compounds, Russian Academy of Sciences, 119991 Moscow,
Russian Federation
DOI: 10.1016/j.mencom.2009.05.009
The trifluoromethylation of hydrazones derived from salicyl aldehydes and N-aminopiperidine and N-aminomorpholine through
the generation of chelate difluoroboron complexes, which subsequently interact with Me3SiCF3 in the presence of sodium acetate,
has been developed.
Nucleophilic trifluoromethylation reactions using the Ruppert–
Y
Y
F2
B
Prakash reagent (Me3SiCF3) have become the subject of intense
investigations in recent years.1 As electrophilic substrates,
carbonyl compounds have been studied comprehensively, and
methods for the addition of CF3 carbanion to aldehydes, ketones
and esters are very well developed.1,2 At the same time, the
scope of nucleophilic trifluoromethylation of the C=N bond is
narrow, which is associated with low reactivity of azomethine
fragment.2(b),3,4 Importantly, the latter process leads to amines
bearing the CF3 group at the α-position, and such compounds
have gained considerable attention due to potential pharmaceutical
applications.5 In this regard, besides nucleophilic trifluoro-
methylation, several approaches have been reported for the
synthesis of these substances from CF3 substituted imines by
nucleophilic addition6–8 and 1,3-proton shift reactions.9
Hydrazones constitute a class of readily available compounds,
which are quite stable and, at the same time, poorly electro-
philic substrates.10 Recently, we introduced an approach for
the activation of C=N bond by means of intramolecular com-
plexation with Lewis acidic difluoroboryl group.11 Concerning
the hydrazone functionality, two modes of chelating activation
can be proposed (Scheme 1). In path A, the acidic activator is
provided from the side of hydrazine moiety, and the validity
of this mode was demonstrated for the trifluoromethylation of
N-benzoylhydrazones.12 Here, we report the trifluoromethyla-
tion of hydrazones activated according to path B, where the
delivery of Lewis acidic group occurs from the side of the
azomethine fragment.
N
N
OH
N
O
N
BF3·OEt2
SiMe3
R1
R2
R1
R2
dichloroethane
Δ, 10 min
1
2
Y
N
OH HN
Me3SiCF3, AcONa
DMF, 50–52 °C, 2 h
R1
CF3
R2
3
Scheme 2
Table 1 Trifluoromethylation of hydrazones.
Compound
R1
R2
Y
Isolated yield of 3 (%)
1a
1b
1c
1d
1e
H
MeO
H
H
H
H
H
O
O
CH2
CH2
O
91%
82%
82%
82%
97%
MeO
benzo
type (hydrazones 1) were readily prepared from salicyl aldehydes
and N-aminopiperidine and N-aminomorpholine.†
Treatment of hydrazones 1 with boron trifluoride etherate in
the presence of allyltrimethylsilane in dichloroethane12 results
To implement this approach, the starting hydrazone should
contain a functional group capable of generating the chelating
Lewis acid. Thus, N,N-dialkylhydrazones bearing adjacent
hydroxyl substituent were considered, and compounds of this
†
All reactions were performed under argon. Dichloroethane was distilled
from CaH2 before use. DMF was distilled in a vacuum from P2O5 and
stored over MS 4 Å. Starting compounds were obtained from commercially
available aldehydes and hydrazines in methanol. Compounds 1a,e13 and
1c14 have been described.
2-Methoxy-6-[(E)-(morpholin-4-ylimino)methyl]phenol 1b: mp 110–
112 °C. 1H NMR (200 MHz, CDCl3) d: 2.98–3.20 (m, 4H, 2CH2N),
3.73–3.95 (m, 7H, MeO + 2CH2O), 6.67–6.93 (m, 3H, 2CHAr), 7.66 (s,
1H, CH=N), 11.72 (s, 1H, OH). 13C NMR (75 MHz, CDCl3) d: 51.4, 55.8,
65.8, 111.8, 118.4, 118.7, 121.3, 140.4, 147.0, 147.9. Found (%): C, 60.87;
H, 6.77; N, 11.74. Calc. for C12H16N2O3 (%): C, 61.00; H, 6.83; N, 11.86.
2-Methoxy-6-[(E)-(piperidin-1-ylimino)methyl]phenol 1d: mp 60–61 °C.
1H NMR (200 MHz, CDCl3) d: 1.37–1.89 [m, 6H, (CH2)3], 2.90–3.26 (m,
4H, 2CH2N), 3.86 (s, 3H, MeO), 6.61–6.93 (m, 3H, 2CHAr), 7.61 (s, 1H,
CH=N), 12.06 (s, 1H, OH). 13C NMR (75 MHz, CDCl3) d: 23.6, 24.5, 51.8,
55.8, 111.3, 118.3, 119.3, 121.1, 138.9, 147.0, 147.9. Found (%): C, 66.60;
H, 7.88; N, 11.88. Calc. for C13H18N2O2 (%): C, 66.64; H, 7.74; N, 11.96.
R2
O
LA
N
path A
path B
N
N
R2
R2
N
R1
N
R2
R2
N
R1
LA
R2
O
R1
LA = Lewis acid
Scheme 1
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© 2009 Mendeleev Communications. All rights reserved.

Mendeleev Commun., 2009, 19, 141–143
in the formation of chelate difluoroboron complexes 2 (Scheme 2).
O(2)
Then, the solvent was exchanged from dichloroethane to dimethyl-
formamide followed by addition of Me3SiCF3 and sodium acetate.
The trifluoromethylation reaction was effected by heating at
50–52 °C for 2 h with subsequent work-up with aqueous sodium
carbonate. Under these conditions, substrates 1a–e were trifluoro-
methylated affording CF3-substituted hydrazines 3a–e in high
yields (Table 1).‡
To provide the support for the formation of chelate boron
complexes as key reaction intermediates complex 2e derived
from naphthalene substrate 1e (R1 + R2 = benzo) was isolated in
C(14)
C(15)
N(1)
C(13)
C(12)
F(2)
C(10)
C(9)
C(1)
N(2)
C(11)
C(2)
B(1)
C(8)
F(1)
C(6)
C(5)
C(3)
C(4)
O(1)
C(7)
Figure 1 Molecular structure of 2e presented by thermal ellipsoids with
50% probability. The hydrogen atoms are omitted for clarity. Selected
bond lengths (Å) and angles (°): N(1)–C(1) 1.303(2), N(1)–B(1) 1.600(3),
N(1)–N(2) 1.403(2), O(1)–B(1) 1.448(3); C(1)–N(1)–N(2) 122.45(16),
N(1)–C(1)–C(2) 121.52(17), C(1)–N(1)–B(1) 119.28(16), O(1)–B(1)–N(1)
108.14(15).
‡
General procedure for the synthesis of 3a–e. To the flask containing
hydrazone 1 (1.0 mmol) were successively added dichloroethane (2 ml),
allyltrimethylsilane (238 μl, 1.5 mmol) and BF3·OEt2 (190 μl, 1.5 mmol),
and the mixture was heated under gentle reflux for 10 min. The solvent
was evaporated under vacuum, DMF (2 ml) was added, and the mixture was
stirred for 2 h at 50–52 °C. The reaction mixture was cooled to room
temperature, quenched by the addition of saturated aqueous Na2CO3
(0.5 ml), the mixture was stirred for 2 min, diluted with water (7 ml) and
extracted with diethyl ether (3×7 ml). The combined organic phase was
filtered through Na2SO4, concentrated under vacuum, and the crude
product was chromatographed on silica gel.
2-[2,2,2-Trifluoro-1-(morpholin-4-ylamino)ethyl]phenol 3a: Rf 0.36
(hexanes–EtOAc, 1:1), mp 92–94 °C. 1H NMR (200 MHz, CDCl3) d:
2.65–2.95 (m, 4H, 2CH2N), 3.22 (br. s, 1H, NH, Δn1/2 11.9 Hz), 3.62–3.78
(m, 4H, 2CH2O), 4.59 (q, 1H, CHN, J 8.2 Hz), 6.82–6.96 (m, 2H,
2CHAr), 7.05–7.15 (m, 1H, CHAr), 7.22–7.34 (m, 1H, CHAr), 9.58 (br. s,
1H, OH, Δn1/2 12.6 Hz). 13C NMR (75 MHz, CDCl3) d: 56.0, 63.0 (q,
J 28.4 Hz), 66.5, 116.8, 117.4, 119.6, 124.6 (q, J 282.0 Hz), 130.5, 130.6,
157.2. 19F NMR (282 MHz, CDCl3) d: –73.13 (d, J 8.2 Hz). Found (%):
C, 52.24; H, 5.44; N, 10.07. Calc. for C12H15F3N2O2 (%): C, 52.17;
H, 5.47; N, 10.14.
individual form.§ This substance was purified by recrystallization
from dichloroethane, and its structure was proved by 1H, 19F and
11B NMR spectroscopy and X-ray diffraction analysis (Figure 1).¶
In summary, we demonstrated that N,N-dialkylhydrazones
bearing adjacent hydroxyl group can be smoothly trifluoro-
methylated with the Ruppert–Prakash reagent. The Lewis acidic
activation of the hydrazone C=N double bond is achieved through
the intramolecular complexation with difluoroboryl group.
This work was supported by the Ministry of Education and
Science, the Russian Academy of Sciences, the Russian Science
Support Foundation and the Russian Foundation for Basic
Research (project no. 08-03-00428). We are grateful to E. Kremer
for experimental contribution.
2-Methoxy-6-[2,2,2-trifluoro-1-(morpholin-4-ylamino)ethyl]phenol 3b:
Rf 0.53 (hexanes–EtOAc, 1:1), mp 100–101 °C. 1H NMR (200 MHz,
CDCl3) d: 2.64–2.77 (m, 4H, 2CH2N), 3.04 (br. s, 1H, NH, Δn1/2 60.0 Hz),
3.64–3.73 (m, 4H, 2CH2O), 3.88 (s, 3H, OMe), 4.89 (q, 1H, CHN,
J 7.6 Hz), 6.82–7.00 (m, 4H, 3CHAr + OH). 13C NMR (75 MHz, CDCl3)
d: 55.9, 57.0, 58.7 (q, J 28.8 Hz), 66.8, 111.1, 119.5, 119.6, 120.9 (q,
J 1.2 Hz), 125.2 (q, J 282.1 Hz), 144.6, 146.9. 19F NMR (282 MHz,
CDCl3) d: –73.79 (d, J 7.6 Hz). Found (%): C, 51.11; H, 5.61; N, 9.14.
Calc. for C13H17F3N2O3 (%): C, 50.98; H, 5.59; N, 9.15.
References
1 (a) G. K. S. Prakash and A. K. Yudin, Chem. Rev., 1997, 97, 757;
(b) G. K. S. Prakash and M. Mandal, J. Fluorine Chem., 2001, 112,
123; (c) R. P. Singh and J. M. Shreeve, Tetrahedron, 2000, 56, 7613;
(d) J.-A. Ma and D. Cahard, J. Fluorine Chem., 2007, 128, 975;
(e) N. Shibata, S. Mizuta and H. Kawai, Tetrahedron: Asymmetry, 2008,
19, 2633.
§
2-[2,2,2-Trifluoro-1-(piperidin-1-ylamino)ethyl]phenol 3c: Rf 0.15
Complex 2e. Allyltrimethylsilane (83 μl, 0.52 mmol) and BF3·OEt2
1
(hexanes–EtOAc, 10:1), mp 50–52 °C. H NMR (200 MHz, CDCl3) d:
(66 μl, 0.52 mmol) were successively added to a solution of hydrazone
1e (89 mg, 0.35 mmol) in dichloroethane (1.5 ml), and the mixture was
heated under gentle reflux for 10 min. The solution was allowed to cool
slowly and kept overnight at 5 °C. The solvent was decanted, the crystals
were washed with cold dichloroethane and hexane, and dried in a vacuum
1.33–1.50 and 1.55–1.75 [m, 2H and 4H, (CH2)3], 2.56–2.96 (m, 4H,
2CH2N), 3.15 (br. s, 1H, NH, Δn1/2 11.3 Hz), 4.55 (q, 1H, CHN, J 8.3 Hz),
6.80–7.01 (m, 2H, 2CHAr), 7.07–7.18 (m, 1H, CHAr), 7.21–7.33 (m, 1H,
CHAr), 10.59 (br. s, 1H, OH, Δn1/2 15.1 Hz). 13C NMR (75 MHz, CDCl3)
d: 23.2, 25.5, 57.0, 63.3 (q, J 28.2 Hz), 117.7, 117.9 (q, J 1.1 Hz), 119.3,
124.8 (q, J 282.1 Hz), 130.2, 130.3, 157.6. 19F NMR (282 MHz, CDCl3)
d: –72.57 (d, J 8.3 Hz). Found (%): C, 57.09; H, 6.34; N, 10.47. Calc.
for C13H17F3N2O (%): C, 56.93; H, 6.25; N, 10.21.
2-Methoxy-6-[2,2,2-trifluoro-1-(piperidin-1-ylamino)ethyl]phenol 3d:
Rf 0.36 (hexanes–EtOAc, 3:1), mp 97–100 °C. 1H NMR (200 MHz, CDCl3)
d: 1.27–1.43 and 1.52–1.69 [m, 2H and 4H, (CH2)3], 2.57–2.77 (m, 4H,
2CH2N), 2.94 (br. s, 1H, NH, Δn1/2 11.3 Hz), 3.87 (s, 3H, OMe), 4.76
(q, 1H, CHN, J 8.2 Hz), 6.76–6.93 (m, 3H, 3CHAr), 8.48 (br. s, 1H,
OH, Δn1/2 18.7 Hz). 13C NMR (75 MHz, CDCl3) d: 23.3, 25.6, 55.8,
57.3, 60.3 (q, J 28.4 Hz), 111.3, 119.2, 119.5, 121.1 (q, J 1.1 Hz),
125.1 (q, J 282.0 Hz), 145.7, 147.7. 19F NMR (282 MHz, CDCl3) d:
–73.29 (d, J 8.2 Hz). Found (%): C, 55.05; H, 6.36; N, 9.02. Calc. for
C14H19F3N2O2 (%): C, 55.26; H, 6.29; N, 9.21.
1-[2,2,2-Trifluoro-1-(morpholin-4-ylamino)ethyl]-2-naphthol 3e: Rf 0.24
(hexanes–EtOAc, 2:1), mp 101–103 °C. 1H NMR (200 MHz, CDCl3) d:
2.67–3.02 (m, 4H, 2CH2N), 3.25 (br. s, 1H, NH, Δn1/2 130 Hz), 3.57–3.76
(m, 4H, 2CH2O), 5.56 (q, 1H, CHN, J 8.0 Hz), 7.18 (d, 1H, CHAr, J 8.9 Hz),
7.31–7.44 (m, 1H, CHAr), 7.53 (t, 1H, CHAr, J 7.5 Hz), 7.75–7.90 (m,
3H, 3CHAr), 10.65 (br. s, 1H, OH, Δn1/2 130 Hz). 13C NMR (75 MHz,
CDCl3) d: 55.7, 57.9 (q, J 28.5 Hz), 66.4, 106.0, 119.9, 120.8, 122.9,
125.0 (q, J 283.8 Hz), 127.1, 128.7, 129.0, 131.5, 133.5, 157.3. 19F NMR
(282 MHz, CDCl3) d: –72.16 (d, J 8.0 Hz). Found (%): C, 58.94; H, 5.18;
N, 8.62. Calc. for C16H17F3N2O2 (%): C, 58.89; H, 5.25; N, 8.58.
1
to give 62 mg of 2e as pale yellow crystals; mp 187–188 °C. H NMR
(300 MHz, CD2Cl2) d: 3.33–3.41 (m, 4H, 2CH2O), 3.86–3.93 (m, 4H,
2CH2N), 7.26 (d, 1H, CHAr, J 9.2 Hz), 7.48–7.55 (m, 1H, CHAr), 7.65–7.73
(m, 1H, CHAr), 7.88 (d, 1H, CHAr, J 8.1 Hz), 8.04–8.12 (m, 2H, 2CHAr),
9.18 (br. s, 1H, CH=N, Δn1/2 11 Hz). 19F NMR (282 MHz, CD2Cl2) d:
–134.97 (q, JF–B 15.5 Hz). 11B NMR (160 MHz, CD2Cl2) d: –0.09 (t,
JF–B 15.5 Hz).
¶
Crystallographic data for 2e: crystals of C15H15BF2N2O2 are ortho-
rhombic, space group Pbca, a = 13.425(2), b = 8.4912(15) and c =
= 24.387(4) Å, V = 2780.0(8) Å3, Z = 8, M = 304.10, dcalc = 1.453 g cm–3,
m(MoKα) = 1.14 mm–1, F(000) = 1264. Intensities of 17786 reflections
were measured with a Smart APEX II diffractometer at 100 K [l(MoKα) =
= 0.71072 Å, w-scans, 2q < 55.74°] and 3316 independent reflections
(Rint = 0.0913) were used in further refinement. The structure was solved
by direct method and refined by the full-matrix least-squares technique
against F2 in the anisotropic–isotropic approximation. Hydrogen atoms
were calculated and refined in the rigid body approximation with the
U(H) = 1.2Ueq(C). The refinement converged to wR2 = 0.1098 and GOF =
= 0.993 for all independent reflections [R1 = 0.0456 was calculated against
F for 2042 observed reflections with I > 2s(I)].
CCDC 714416 contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
For details, see ‘Notice to Authors’, Mendeleev Commun., Issue 1, 2009.
– 142 –

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Received: 24th December 2008; Com. 08/3256
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