Synthesis of azomethine imines using an intramolecular alkyne hydrohydrazination approach

Article abstract of DOI:10.1021/jo4011409

Azomethine imines can be accessed upon heating appropriate alkynylhydrazide precursors. This simple thermal hydroamination approach allows the formation of five- and six-membered dipoles in modest to excellent yields. The structure of the acyl group is important to minimize side reactions and allow the isolation of the azomethine imines by column chromatography.

Full text of DOI:10.1021/jo4011409

Note
pubs.acs.org/joc
Synthesis of Azomethine Imines Using an Intramolecular Alkyne
Hydrohydrazination Approach
Ashley D. Hunt, Isabelle Dion, Nicolas Das Neves, Sandrine Taing, and Andre M. Beauchemin*
́
Centre for Catalysis Research and Innovation, Department of Chemistry, University of Ottawa, 10 Marie-Curie, Ottawa, ON,
K1N 6N5, Canada
S
* Supporting Information
ABSTRACT: Azomethine imines can be accessed upon heat-
ing appropriate alkynylhydrazide precursors. This simple thermal
hydroamination approach allows the formation of five- and six-
membered dipoles in modest to excellent yields. The structure
of the acyl group is important to minimize side reactions
and allow the isolation of the azomethine imines by column
chromatography.
zomethine imines are valuable intermediates in synthetic
organic chemistry.1 In addition to being useful 1,3-dipoles
associated with this metal-free reactivity.11a In addition, we
speculated that the bis(trifluoromethyl)benzoyl group would
stabilize the negative charge of the dipole sufficiently to allow
isolation of azomethine imines from appropriate precursors.
Satisfyingly, initial results showed the desired reactivity after
some reaction optimization. As expected, the bis(trifluoromethyl)-
benzoyl group proved crucial to allow somewhat milder reac-
tion conditions, to isolate the desired dipole, and to minimize
byproduct formation, which is observed with the parent ben-
zhydrazide (see Supporting Information details). The reaction
scope is shown in Table 1.
Gratifyingly, cyclization of the alkynylhydrazides occurred
upon heating at 110−160 °C, providing access to both five- and
six-membered azomethine imines. While heating was typically
performed using microwave irradiation to minimize reaction
time, this reactivity also proceeds well upon heating with a
reflux condensor (entry 1). Terminal (entries 1, 9−12) and
internal alkynes proved competent substrates, with both methyl
(entry 2) and aryl groups (entries 3−8, 13) being well tolerated.
A variety of aryl substituents were compatible with the reaction
(Me, Br, OMe, CO2Me, entries 4−8), and the reaction
provided the desired dipole with both electron-poor (entry 7)
and electron-rich (entries 6, 8) conjugated arylacetylenes.
Improved yields are observed for substrates with substituents
on the carbon bearing the hydrazide functionality (R1, entry 1
vs 9−11).
A
in cycloadditions and rearrangements, azomethine imines are
versatile electrophiles.2 Several stereoselective reactions have
recently emerged, providing access both to enantioenriched
azomethine imines via kinetic resolution and to useful adducts
via asymmetric synthesis.2c,d,3 The synthetic scope of all these
transformations is inherently linked to the methods available to
generate azomethine imines, which can be sensitive to decomposi-
tion or dimerization; the dipoles are thus often generated in
situ.1 Reactions to access these synthetic intermediates include1c
(1) condensation of a carbonyl precursor and a hydrazide;4 (2)
in situ generation upon a 1,2-proton shift from an appropriate
hydrazone;5 (3) deprotonation of suitable hydrazonium salts;6
(4) oxidation of hydrazine derivatives;7 (5) N-alkylation of
hydrazone precursors;8 and (6) aminocarbonylation of
alkenes using hydrazones.9,10 While reliable, these ap-
proaches impose limitations on the types of substrates that
can be accessed. In our efforts toward the development of
metal-free hydroamination reactivity,11 we became attracted
by the opportunity of forming azomethine imines via intra-
molecular alkyne hydrohydrazination reactions.12 Herein, we
report that five- and six-membered azomethine imines are
formed simply upon heating of appropriate alkynylhydra-
zides precursors (eq 1).13
The overall reaction likely proceeds via a Cope-type hydro-
hydrazidation11 (hydroamination) event to provide an ene-
hydrazide intermediate,14 followed by tautomerization to
provide the more stable azomethine imine. Such tautomeriza-
tion has been observed in related intermolecular additions of
hydrazides to dimethyl acetylenedicarboxylate (DMAD), which
also afford azomethine imines.13 In all cases, none of the ene-
hydrazide intermediate was observed by NMR.
In recent work on thermal hydrohydrazinations, we noted the
increased reactivity associated with the use of 3,5-bis(trifluoro-
methyl)benzhydrazides.11b Our current hypothesis is that these
convenient, crystalline precursors facilitate both a concerted
Cope-type hydroamination step and the proton-transfer steps
Received: June 3, 2013
© XXXX American Chemical Society
A
dx.doi.org/10.1021/jo4011409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
a
Table 1. Scope of Hydrohydrazination Route to Azomethine Imines
a
b
Conditions: a solution of hydrazide in PhCF3 (0.05M) was heated for 12−14 h (microwave reactor). Performed on a 5.77 mmol scale in refluxing
c
PhCF3 overnight. Yield after reduction with NaBH4.
microwave reactor, monitoring temperatures with an external sensor.
Product purification was performed using silica gel (40−60 μm) flash
column chromatography. Analytical thin layer chromatography (TLC)
Finally, we explored the reactivity of those azomethine imines
by performing a [3 + 2] dipolar cycloaddition. Encouragingly, the
desired cycloadduct 3a was isolated in a modest yield despite the
hindrance present in azomethine 1a as shown in eq 2. In summary,
was performed on aluminum plates precoated with silica gel 60 F254
.
Visualization was accomplished under UV light followed by staining
with KMnO4 solution and heating.
NMR spectra were recorded at ambient temperature, unless otherwise
indicated. Spectral data was reported in ppm from tetramethylsilane
using solvent as the reference. Data was reported as multiplicity (br,
broad; s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet), integration,
and coupling constant(s) (with * denoting minor conformers). Infrared
spectra were obtained with neat thin films on NaCl disks, recorded on
a FTIR spectrometer. High-resolution mass spectrometry (HRMS)
was performed on a mass spectrometer with a 70ev electron beam.
Materials. Commercial materials were used as purchased. Solvents
were freshly distilled prior use: THF and ether over sodium;
triethylamine and dichloromethane over CaH2; PhCF3 over molecular
sieves.
we have shown that a variety of cyclic azomethine imines can
be obtained upon simple thermolysis of an appropriate alkynyl-
hydrazide precursor. This reactivity further illustrates that
Cope-type hydroaminations are useful for the synthesis of a
variety of nitrogen-containing molecules.
EXPERIMENTAL SECTION
General Procedure for Alkyne Cyclizations (Table 1).
Procedure A. A microwave vial was charged with a stir bar,
capped with a septum, and purged with argon. The hydrazide and
■
General Information. All reactions were performed in oven-dried
glassware under argon. Microwave reactions were run in a Biotage
B
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The Journal of Organic Chemistry
Note
α,α,α-trifluorotoluene ([hydrazide] = 0.05 M) were added. The septum
was removed, and the vial was quickly capped and heated in a
microwave reactor for 12−14 h at 110−160 °C. The reaction was
(s, 2H), 3.91 (s, 2H), 3.79 (s 3H), 2.51 (s, 2H), 2.04−1.99 (m, 2H),
1.85−1.74 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 159.1, 139.4,
130.9 (q, J = 33.3 Hz, 2C), 130.8 (2C), 128.0 (2C), 124.8, 123.6
(q, J = 272.6 Hz, 2C), 123.1, 114.4 (2C), 55.1, 54.5, 39.3, 30.0, 21.7,
17.7;15 IR (film) 2956, 1569, 1514, 1316, 1279, 1132 cm−1; HRMS
(EI-Q-TOF) exact mass calcd for C22H20F6N2O2 458.1429 [M]+,
found 458.14221.
1
cooled, concentrated, and analyzed by H NMR using 1,4-dimeth-
oxybenzene as internal standard. Concentration and purification by
chromatography yielded the product.
(3,5-Bis(trifluoromethyl)benzoyl(6-methyl-2,3,4,5-tetrahy-
dropyridinium-1-yl)amide (2a). Synthesized using 1a (0.250 g,
0.710 mmol; procedure A, 140 °C, 14 h). Chromatographic purifica-
tion (2.5% MeOH/CH2Cl2) afforded a yellow oil (0.169 g, 68% yield).
1H NMR (300 MHz, DMSO-d6) δ 8.46 (s, 2H), 8.14 (s, 1H), 3.75
(t, J = 5.2 Hz, 2H), 2.82 (t, J = 6.0 Hz, 2H), 2.12 (s, 3H), 1.96−1.88
(m, 2H), 1.77−1.69 (m, 2H); 13C NMR (75 MHz, DMSO-d6,
120 °C) δ 170.3, 162.6, 140.7, 129.3 (q, J = 32.9 Hz, 2C), 126.9 (2C),
124.5 (q, J = 273.0 Hz, 2C), 121.3, 53.3, 30.9, 20.8, 20.1, 16.7; IR
(film) 3260, 2937, 1649, 1276, 1132 cm−1; HRMS (EI-Q-TOF) exact
mass calcd for C15H14F6N2O 352.1010 [M]+, found 352.09917.
(3,5-Bis(trifluoromethyl)benzoyl(6-ethyl-2,3,4,5-tetrahydro-
pyridinium-1-yl)amide (2b). Synthesized using 1b (0.0450 g, 0.123
mmol; procedure A, 160 °C, 14 h). Chromatographic purification (4%
MeOH/CH2Cl2) afforded a yellow oil (0.030 g, 67% yield). 1H NMR
(400 MHz, CDCl3) δ 8.50 (s, 2H), 7.87 (s, 1H), 3.94 (s, 2H), 2.73
(s, 2H), 2.65 (s, 2H), 2.04 (s, 2H), 1.94−1.85 (m, 2H), 1.17 (t, J = 7.6
Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 176.1, 165.7, 139.6, 131.0 (q,
J = 33.3 Hz, 2C), 128.0 (2C), 123.5 (q, J = 272.7 Hz, 2C), 123.1, 54.3,
29.6, 27.7, 21.8, 17.9, 9.2; IR (film) 3405, 2360, 1653, 1278, 1132
cm−1; HRMS (EI-Q-TOF) exact mass calcd for C16H16F6N2O
366.1167 [M]+, found 366.1170.
(3,5-Bis(trifluoromethyl)benzoyl(6-(4-methyl benzoate)-
2,3,4,5-tetrahydropyridinium-1-yl)amide (2g). Synthesized
using 1g (0.250 g, 0.510 mmol; procedure A 140 °C, 14 h). Chroma-
tographic purification (2% MeOH/CH2Cl2) afforded a yellow solid
1
(0.132 g, 53% yield). H NMR (300 MHz, CDCl3) δ 8.50 (s, 2H),
8.01 (d, J = 8.4 Hz, 2H), 7.88 (s, 1H), 7.34 (d, J = 8.4 Hz, 2H), 4.00
(s, 4H), 3.90 (s, 3H), 2.47 (s, 2H), 2.07−1.96 (m, 2H), 1.85−1.76 (m,
2H); 13C NMR (75 MHz, CDCl3) δ 166.6, 138.7, 131.1 (q, J = 33.3
Hz, 2C), 130.3 (2C), 129.8 (2C), 129.7, 128.0 (2C), 123.4 (q, J =
272.7 Hz, 2C), 123.3, 54.6, 52.2, 40.2, 30.2, 21.8, 17.9;15 IR (film)
3287, 2954, 2235, 1725, 1679, 1573, 1279, 1133, 904 cm−1; HRMS
(EI-Q-TOF) exact mass calcd for C23H20F6N2O3 486.1378 [M]+,
found 486.13870.
(3,5-Bis(trifluoromethyl)benzoyl(6-(2-thiophene)-2,3,4,5-tet-
rahydropyridinium-1-yl)amide (2h). Synthesized using 1h (0.496 g,
1.14 mmol; procedure A, 120 °C, 14 h). Chromatographic purification
(1.5% MeOH/CH2Cl2) afforded a yellow oil (0.263 g, 53% yield). 1H
NMR (400 MHz, CDCl3) δ 8.52 (s, 2H), 7.88 (s, 1H), 7.25 (dd, J =
1.3, 4.8 Hz, 1H), 7.02−6.94 (m, 2H), 4.10 (s, 2H), 3.95 (s, 2H), 2.57
(s, 2H), 1.99 (s, 2H), 1.88−1.76 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 169.6, 163.1, 134.1, 131.1 (q, J = 33.2 Hz, 2C), 128.2, 127.8
(2C), 127.2, 126.0, 123.4 (q, J = 272.7 Hz, 2C), 54.2, *51.3, 34.4,
*32.5, 29.5, *23.2, 21.7, *20.7, 17.9;15 IR (film) 3237, 2944, 1671,
1626, 1565, 1279, 1133 cm−1; HRMS (EI-Q-TOF) exact mass calcd
for C19H16SF6N2O 434.0888 [M]+, found 434.0912.
(6-Benzyl-2,3,4,5-tetrahydropyridinium-1-yl)(3,5-bis-
(trifluoromethyl)benzoyl)amide (2c). Synthesized using 1c
(0.250 g, 0.584 mmol; procedure A, 140 °C, 14 h). Chromatographic
purification (2% MeOH/CH2Cl2) afforded a yellow oil (0.178 g, 72%
1
yield). H NMR (300 MHz, CDCl3) δ 8.54 (s, 2H), *8.41 (s, 2H),
(3,5-Bis(trifluoromethyl)benzoyl(2,6-dimethyl-2,3,4,5-tetra-
hydropyridinium-1yl)amide (2i). Synthesized using 1i (0.250 g,
0.682 mmol; procedure A, 110 °C, 14 h). Chromatographic puri-
fication (2% MeOH/CH2Cl2) afforded a yellow oil (0.228 g, 91%
*7.97 (s, 1H), 7.87 (s, 1H), 7.36−7.23 (m, 5H), 3.97 (s, 4H), 2.50 (s,
2H), 2.02−1.97 (m, 2H), 1.82−1.24 (m, 2H); 13C NMR (75 MHz,
CDCl3) δ 156.6, 133.4, 131.2 (q, J = 33.4 Hz, 2C), 129.7 (2C), 129.1
(2C), 128.0 (2C), 127.8, 123.4 (q, J = 272.6 Hz, 2C), 123.2, 54.6, 40.2,
30.1, 21.8, 17.8;15 IR (film) 3343, 2940, 2360, 1635, 1094 cm−1;
HRMS (EI-Q-TOF) exact mass calcd for C21H18F6N2O 428.13233
[M]+, found 428.13260.
1
yield). H NMR (300 MHz, CDCl3) δ 8.55−8.06 (m, 3H), *4.45−
4.42 (m, 1H), 4.10−4.03 (m, 1H), 2.83−2.81 (m, 2H), 2.12 (s, 3H),
2.07−1.73 (m, 2H), *1.65 (s, 3H), 1.36 (dd, J = 6.57 Hz, 3H), *1.05
(dd, J = 6.57 Hz, 3H), 1.25−1.23 (m, 2H), *0.86−0.84 (m, 2H); 13C
NMR (75 MHz, CDCl3) δ 163.4 (C), 141.3 (C), 130.1 (q, J = 32.7
Hz, 2C, CCF3), 128.1 (2C), 125.7 (q, J = 272.6 Hz, 2C, CF3), 60.0
(CH), 32.4 (CH2), *30.6 (CH2), 28.1 (CH2), 21.8 (CH3), *21.4
(CH3), *19.4 (CH3), 18.8 (CH3), 14.3 (CH2); IR (film) 1280, 1136,
1082 cm−1;; HRMS (EI-Q-TOF) exact mass calcd for C16H16F6N2O
366.11668 [M]+, found 366.11723.
(3,5-Bis(trifluoromethyl)benzoyl(6-(3,5-dimethylbenzyl)-
2,3,4,5-tetrahydropyridinium-1-yl)amide (2d). Synthesized using
1d (0.250 g, 0.548 mmol; procedure A, 140 °C, 14 h). Chromato-
graphic purification (1−3% MeOH/CH2Cl2) afforded a yellow oil
1
(0.229 g, 92% yield). H NMR (300 MHz, CDCl3) δ 8.56 (s, 2H),
7.89 (s, 1H), 6.93 (s, 1H), 6.86 (s, 2H), 4.00 (t, J = 5.5 Hz, 2H), 3.89
(s, 2H), 2.55 (t, J = 5.7 Hz, 2H), 2.29 (s, 6H), 2.22−1.98 (m, 2H),
1.82−1.73 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 138.7, 133.2 (2C),
131.0 (q, J = 34.3 Hz, 2C), 129.4, 128.1 (2C), 127.6 (2C), 125.3 (q,
J = 272.7 Hz, 2C), 123.2, 54.6, 40.1, 30.2, 21.8, 21.2 (2C), 17.8;15 IR
(film) 3467, 2967, 1660, 1276, 1136 cm−1; HRMS (EI-Q-TOF) exact
mass calcd for C23H22F6N2O 456.1636 [M]+, found 456.16288.
(3,5-Bis(trifluoromethyl)benzoyl(6-(4-bromobenzyl)-2,3,4,5-
tetrahydropyridinium-1-yl)amide (2e). Synthesized using 1e
(0.250 g, 0.490 mmol; procedure A, 140 °C, 14 h). Chromatographic
purification (2% MeOH/CH2Cl2) afforded a red oil (0.18 g, 73%
yield). 1H NMR (300 MHz, CDCl3) δ 8.49 (s, 2H), 7.86 (s, 1H), 7.43
(d, J = 8.3 Hz, 2H), 7.12 (d, J = 8.3 Hz, 2H), 3.95 (s, 2H), 3.88 (s,
2H), 2.45 (s, 2H), 1.98 (s, 2H), 1.82−1.68 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 132.5, 132.1 (2C), 131.4 (2C), 131.0 (q, J = 33.2 Hz,
2C), 127.9, 123.5 (q, J = 272.7 Hz, 2C), 123.2, 121.8, 54.5, 39.6, 30.0,
21.7, 17.8;15 IR (film) 3378, 2943, 1728, 1568, 1276 1132 cm−1;
HRMS (EI-Q-TOF) exact mass calcd for C21H17BrF6N2O 506.0428
[M]+, found 506.04220.
(3,5-Bis(trifluoromethyl)benzoyl(2-butyl-6-methyl-2,3,4,5-
tetrahydropyridinium-1-yl)amide (2j). Synthesized using 1j (0.250 g,
0.610 mmol; procedure A, 120 °C, 14 h). Chromatographic purifica-
tion (1% MeOH/CH2Cl2) afforded a brown oil (0.230 g, 93% yield).
1H NMR (300 MHz, CDCl3) δ 8.51 (s, 2H), 7.84 (s, 1H), 3.95−4.01
(m, 1H), 2.74 (s, 2H), 2.20 (s, 3H), 2.19−1.95 (m, 3H), 1.94−1.77
(m, 2H), 1.75−1.57 (m, 1H), 1.47−1.24 (m, 4H), 0.84 (s, 3H); 13C
NMR (75 MHz, CDCl3) δ 171.3, 165.1, 139.8, 130.8 (q, J = 33.1 Hz,
2C), 128.2 (2C), 123.2 (q, J = 272.3 Hz, 2C), 123.0, 64.6, 32.5, 31.1,
28.4, 24.8, 22.2, 21.9, 14.1, 13.7; IR (film) 2964, 1626, 1576, 1318,
1278, 1131 cm−1; HRMS (EI-Q-TOF) exact mass calcd for
C19H22N2OF6 408.1636 [M]+, found 408.16248.
(3,5-Bis(trifluoromethyl)benzoyl(2-phneyl-6-methyl-2,3,4,5-
tetrahydropyridinium-1-yl)amide (2k). Synthesized using 1k
(0.170 g, 0.397 mmol; procedure A, 120 °C, 12 h). Chromatographic
purification (2% MeOH/CH2Cl2) afforded a yellow solid (0.156 g,
91% yield). 1H NMR (400 MHz, CDCl3) δ 8.31 (s, 2H), 7.79 (s, 1H),
7.37−7.28 (m, 3H), 7.24−7.22 (m, 2H), 5.40 (s, 1H), 2.89 (t, J = 6.4
Hz, 2H), 2.49−241 (m, 1H), 2.37 (s, 3H), 2.21−214 (m, 1H), 1.87−
1.72 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 165.1, 139.4, 137.8,
130.7 (q, J = 33.0 Hz, 2C), 128.6 (2C), 127.9 (2C), 127.1, 126.5 (2C),
123.3 (q, J = 272.7 Hz, 2C), 122.9, 67.7, 32.7, 30.0, 22.2, 18.8, 14.1;15
IR (film) 3279, 2945, 1660, 1569, 1278, 1133, 907 cm−1; HRMS
(3,5-Bis(trifluoromethyl)benzoyl(6-(4-methoxybenzyl)-
2,3,4,5-tetrahydropyridinium-1-yl)amide (2f). Synthesized using
1f (0.250 g, 0.545 mmol; procedure A, 140 °C, 14 h). Chromato-
graphic purification (1−2% MeOH/CH2Cl2) afforded a yellow oil
1
(0.215 g, 86% yield). H NMR (400 MHz, CDCl3) δ 8.54 (s, 2H),
7.88 (s, 1H), 7.17 (d, J = 8.5 Hz, 2H), 6.86 (d, J = 8.6 Hz, 2H), 3.99
C
dx.doi.org/10.1021/jo4011409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
(EI-Q-TOF) exact mass calcd for C21H18F6N2O 428.1323 [M]+, found
428.13142.
(400 MHz, CDCl3) δ 8.21 (s, 2H), 8.01 (s, 1H), 7.37−7.35 (m, 2H),
7.27−7.24 (m, 3H), 3.05 (t, J = 6.7 Hz, 2H), 2.47 (t, J = 6.5 Hz, 2H),
1.80−1.67 (m, 4H); 13C NMR (100 MHz, CDCl3) δ 164.5, 134.7,
132.4 (q, J = 34.0 Hz, 2C), 131.5 (2C), 128.2 (2C), 127.6, 127.3 (2C),
125.4, 123.7, 122.7 (q, J = 273.3 Hz, 2C), 89.5, 81.1, 51.7, 26.9, 26.0,
19.2; IR (film) 3295, 2918, 2878, 1649, 1082 cm−1; HRMS (EI-Q-
TOF) exact mass calcd for C21H18F6N2O 428.1323 [M]+, found
428.13067.
N-(2-Methylpyrrolidin-1-yl)-3,5-bis(trifluoromethyl)-
benzamide [3l (reduction of 2l)]. Synthesized using 1l (0.250 g,
0.739 mmol; procedure A, 140 °C, 14 h). 1H NMR analysis showed a
45% NMR yield. Due to instability, it was reduced for isolation. Dipole 2l
was dissolved in MeOH (7.5 mL), and NaBH4 (0.084 g, 2.22 mmol)
was added. After 2 h, the reaction was quenched (aqueous NH4Cl),
extracted (CH2Cl2), washed (NaHCO3, brine), dried (Na2SO4), and
concentrated. Chromatographic purification (50% Et2O/pentane)
afforded a yellow oil (0.110 g, 44% yield). 1H NMR (300 MHz,
CDCl3) δ 8.37−8.25 (m, 2H), 7.96 (s, 1H), 6.85 (br s, 1H), 3.51−2.63
(m, 3H), 2.10−1.63 (m, 4H), 1.24−1.22 (m, 2H), 0.99−0.97 (m, 1H);
13C NMR (75 MHz, CDCl3) δ 144.6, 131.9 (q, J = 31.6 Hz, 2C),
3,5-Bis(trifluoromethyl)-N′-(6-(3,5-dimethylphenyl)hex-5-
ynyl)benzohydrazide (1d). Synthesized using 6-(3,5-
dimethylphenyl)hex-5-yn-1-ol18 (1.10 g, 5.84 mmol; procedure B).
Chromatographic purification (45% Et2O/pentane) afforded a pink oil
1
(1.48 g, 56% yield). H NMR (300 MHz, CDCl3) δ *8.43 (s, 2H),
8.20 (s, 2H), *8.05 (s, 1H), 8.01 (s, 1H), 7.00 (s, 2H), *6.96 (s, 2H),
6.90 (s, 1H), 3.04 (t, J = 6.8 Hz, 2H), 2.46 (t, J = 6.5 Hz, 2H), 2.25 (s,
6H), *2.23 (s, 6H), 1.79−1.65 (m, 4H); 13C NMR (100 MHz,
CDCl3) δ 164.5, *163.5, 137.7 (2C), 134.8, 132.4 (q, J = 34.0 Hz, 2C),
*131.3, *129.7, 129.5, 129.2 (2C), *129.1, 127.3 (2C), 125.4, 123.3,
*122.9, 122.8 (q, J = 272.9 Hz, 2C), 88.7, *87.4, *82.1, 81.3, *57.4,
51.7, *27.0, 26.1, *25.3, 24.6, 21.0, *20.9, 19.2, *18.9; IR (film) 3465,
2945, 1645, 1280, 1136 cm−1; HRMS (EI-Q-TOF) exact mass calcd
for C23H22F6N2O 456.1636 [M]+, found 456.16519.
129.6, 127.5 (2C), 124.3, 122.9 (q, J = 272.8 Hz, 2C), 62.6, *56.5,
55.6, 30.3, *30.0, 20.5, *19.8, 17.7; IR (film) 3370, 2940, 2890, 1680,
1276, 1128, 1083 cm−1; HRMS (EI-Q-TOF) exact mass calcd for
C14H14F6N2O 340.10103 [M]+, found 340.10162.
(5-Benzyl-3,4-dihydro-2H-pyrrolium-1-yl)(3,5-bis-
(trifluoromethyl)benzoyl)amide (2m). Synthesized using 1m
(0.250 g, 0.603 mmol; procedure A, 150 °C, 14 h). Chromatographic
purification (2% MeOH/CH2Cl2) afforded a yellow oil (0.153 g, 62%
1
yield). H NMR (300 MHz, CDCl3) δ 8.56 (s, 2H), *8.34 (s, 2H),
6-(4-Bromophenyl)hex-5-yn-1-ol (Procedure C). To hex-5-yn-
1-ol (1.00 g, 10.2 mmol) in Et3N (30.0 mL) were added 1-bromo-4-
iodobenzene (3.46 g, 12.2 mmol), CuI (0.040 g, 0.020 mmol), and
PdCl2(PPh3)2 (0.070 g, 0.010 mmol). The reaction was stirred at
room temperature (16 h), quenched (NaHCO3), extracted (EtOAc),
washed (brine), dried (Na2SO4), and concentrated. Chromatographic
purification (30% Et2O/pentane) afforded a brown oil (1.95 g, 76%
*7.99 (s, 1H), 7.89 (s, 1H), 7.38−7.24 (m, 5H), 4.51 (s, 2H), 3.96 (s,
2H), 2.86 (t, J = 7.2 Hz, 2H), 2.28−2.18 (m, 2H); 13C NMR (75
MHz, CDCl3) δ 166.3, 133.0, 131.0 (q, J = 33.3 Hz, 2C), 129.3 (2C),
129.2 (2C), 128.3, 127.9, 127.7, 123.4 (q, J = 272.8 Hz, 2C), 123.4,
60.2, 35.9, 34.4, 17.9;15 IR (film) 3393, 3207, 1668, 1280, 1178, 1132,
908 cm−1; HRMS (EI-Q-TOF) exact mass calcd for C20H16F6N2O
414.1167 [M]+, found 414.1169.
1
yield). H NMR (300 MHz, CDCl3) δ 7.41 (d, J = 8.5 Hz, 2H), 7.24
Dimethyl 1-(3,5-Bis(trifluoromethyl)benzoyl)-3a-methyl-
1,3a,4,5,6,7-hexahydropyrazolo[1,5-a]pyridine-2,3-dicarboxy-
late (3a, eq 2). Synthesized by refluxing 2a (0.090 g, 0.25 mmol) and
dimethylacetylene dicarboxylate (0.044 g, 0.31 mmol) for 48 h in
toluene (0.1 M). Evaporation and then chromatography (20% Et2O/
(d, J = 8.5 Hz, 2H), 3.71 (t, J = 6.2 Hz, 2H), 2.44 (t, J = 6.7 Hz, 2H),
1.64−1.84 (m, 4H), 1.41 (s, 1H); 13C NMR (75 MHz, CDCl3) δ
132.9 (2C), 131.4 (2C), 122.8, 121.6, 91,1, 79.9, 62.4, 31.9, 24.9, 19.2;
IR (film) 3370, 2941, 1486, 1072, 824 cm−1. HRMS (EI-Q-TOF)
exact mass calcd for C12H13BrO 252.0150 [M]+, found 252.01651.
N′-(6-(4-Bromophenyl)hex-5-ynyl)-3,5-bis(trifluoromethyl)-
benzohydrazide (1e). Synthesized using 6-(4-bromophenyl)hex-5-
yn-1-ol (1.95 g, 7.72 mmol; procedure B). Chromatographic
purification (20% Et2O/pentane) afforded a white solid (0.48 g,
18% yield). 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 2H), 8.03 (s, 1H),
7.39 (d, J = 8.1 Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 3.07 (t, J = 6.0 Hz,
2H), 2.46 (t, J = 6.0 Hz, 2H), 1.82−1.61 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 164.5, 134.8, 132.9 (2C), 132.4 (q, J = 33.9 Hz, 2C),
131.4 (2C), 127.3 (2C), 125.4, 121.8 (q, J = 131.0 Hz, 2C), 121.7,
90.8, 80.1, 51.7, 27.0, 25.9, 19.2; IR (film) 3308, 2941, 1654, 1279,
1137 cm−1. HRMS (EI-Q-TOF) exact mass calcd for C21H17BrF6N2O
506.04284 [M]+, found 506.0430.
1
hexane) afforded a yellow oil (0.055 g, 45% yield). H NMR (300
MHz, CDCl3) δ 8.67 (s, 2H), 8.03 (s, 1H), 3.98 (s, 3H), 3.81 (s, 3H),
2.83 (d, J = 10.0 Hz, 1H), 2.67 (d, J = 11.1 Hz, 2H), 1.53−1.76 (m, 6
H), 1.47 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 162.9, 162.4, 161.6,
140.0, 134.0, 131.8, 131.3, 130.1 (2C), 125.5, 124.7, 121.2, 70.3, 53.2,
52.9, 52.1, 30.6, 29.7, 27.4, 23.0, 20.4; IR (film) 1652, 1508, 1330,
1278, 1143, 1095 cm−1; HRMS (EI-Q-TOF) exact mass calcd for
C21H20F6N2O5 494.1276 [M]+, found 494.1270.
Substrate Preparation. The procedure B to form the substrates
has been reported.11b
3,5-Bis(trifluoromethyl)-N′-(hex-5-ynyl)benzohydrazide
(1a). Synthesized using hex-5-yn-1-ol (1.50 g, 15.3 mmol; procedure
B). Chromatographic purification (50% Et2O/pentane) afforded a
pink solid (3.06 g, 57% yield). 1H NMR (300 MHz, CDCl3) δ 8.22 (s,
2H), 8.03 (s, 1H), 3.00 (t, J = 6.9 Hz, 2H), 2.26 (td, J = 6.68, 2.6 Hz,
2H), 1.96 (t, J = 2.6 Hz, 1H), 1.74−1.59 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 164.5, 134.9, 132.4 (q, J = 34.0 Hz, 2C), 127.3 (2C),
125.4, 122.8 (q, J = 273.1 Hz, 2C), 84.1, 68.7, 51.5, 26.7, 25.7, 18.2; IR
(film) 3447, 2922, 2850, 1649, 1539, 1079 cm−1; HRMS (EI-Q-TOF)
exact mass calcd for C15H14F6N2O 352.1010 [M]+, found 352.10145.
3,5-Bis(trifluoromethyl)-N′-(hept-5-ynyl)benzohydrazide
(1b). Synthesized using hept-5-yn-1-ol16 (0.26 g, 2.23 mmol; pro-
cedure B). Chromatographic purification (40% Et2O/pentane) afforded a
3,5-Bis(trifluoromethyl)-N′-(6-(4-methoxyphenyl)hex-5-
ynyl)benzohydrazide (1f). Synthesized using 6-(4-methoxy-phe-
nyl)-hex-5-yn-1-ol19 (2.03 g, 9.91 mmol; procedure B). Chromato-
graphic purification (10% EtOAc/hexanes) afforded a beige solid (1.49
1
g, 33% yield). H NMR (300 MHz, CDCl3) δ 8.17 (s, 2H), 8.00 (s,
1H), 7.28 (d, J = 8.8 Hz, 2H), 6.77 (d, J = 8.8 Hz, 2H), 3.77 (s, 3H),
3.02 (t, J = 6.7 Hz, 2H), 2.45 (t, J = 6.1 Hz, 2H), 1.73−1.68 (m, 4H),
1.61 (br, 2H); 13C NMR (75 MHz, CDCl3) δ 164.5, 159.0, 134.8,
132.7 (2C), 132.2 (q, J = 33.9 Hz, 2C), 127.3 (2C), 125.2 (2C), 122.8
(q, J = 273.0 Hz, 2C), 115.8, 113.8 (2C), 87.9, 80.8, 55.1, 51.6, 27.1,
26.1, 19.2; IR (film) 3272, 2939, 1660, 1288, 1134 cm−1; HRMS (EI-
Q-TOF) exact mass calcd for C22H20F6N2O2 458.1429 [M]+, found
458.14039.
1
white solid (0.33 g, 40% yield). H NMR (300 MHz, CDCl3) δ 8.20
(s, 2H), 8.03 (s, 1H), 7.71 (br, 1H), 4.88 (br, 1H), 2.99 (t, J = 7.1 Hz,
2H), 2.23−2.14 (m, 2H), 1.77 (t, J = 2.5 Hz, 3H), 1.71−1.58 (m, 4H);
13C NMR (100 MHz, CDCl3) δ 164.4, 135.0, 132.3 (q, J = 32.9 Hz,
2C), 127.2 (2C), 125.4, 122.8 (q, J = 274.8 Hz, 2C), 78.7, 67.2, 51.7,
27.0, 26.4, 18.6, 3.4; IR (film) 3211, 2940, 1641, 1277, 1133 cm−1;
HRMS (EI-Q-TOF) exact mass calcd for C16H16F6N2O 366.11668
[M]+, found 366.1195.
4-(6-Hydroxyhex-1-ynyl) Methyl Benzoate. Prepared using
hex-5-yn-1-ol (0.47 g, 4.77 mmol; procedure C) to afford a yellow oil
1
(1.09 g, 99% yield). H NMR (300 MHz, CDCl3) δ 7.94 (d, J = 8.5
Hz, 2H), 7.43 (d, J = 8.4 Hz, 2H), 3.90 (s, 3H), 3.71 (t, J = 6.1 Hz,
2H), 2.48 (t, J = 6.7 Hz, 2H), 1.80−1.65 (m, 4H); 13C NMR (75
MHz, CDCl3) δ 166.6, 131.4 (2C), 129.4 (2C), 128.9, 128.7, 93.3,
80.4, 62.4, 52.1, 31.8, 24.8, 19.7; IR (film) 3383, 2949, 1721, 1276
cm−1; HRMS (EI-Q-TOF) exact mass calcd for C14H16O3 232.1099
[M]+, found 232.11002.
3,5-Bis(trifluoromethyl)-N′-(6-phenylhex-5-ynyl)-
benzohydrazide (1c). Synthesized using 6-phenylhex-5-yn-1-ol17
(1.87 g, 10.7 mmol; procedure B). Chromatographic purification
1
(20% EtOAc/hexanes) afforded a pink solid (quantitative). H NMR
D
dx.doi.org/10.1021/jo4011409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
3,5-Bis(trifluoromethyl)-N′-(6-(4-methyl benzoate)hex-5-
ynyl)benzohydrazide (1g). Synthesized using 6-(4-methyl ben-
zoate)-hex-5-yn-1-ol (2.03 g, 9.91 mmol; procedure B). Chromato-
graphic purification (50% Et2O/hexanes) afforded a white solid
2C), 128.6 (2C), 128.0 (2C), 127.8 (2C), 127.3, 125.2, 122.7 (q,
J = 273.0 Hz, 2C), 83.8, 68.8, 64.7, 33.8, 24.6, 18.2; IR (film) 3302,
2945, 1641, 1277, 1134 cm−1; HRMS (EI-Q-TOF) exact mass calcd
for C21H18F6N2O 428.1323 [M]+, found 428.1298.
1
(1.25 g, 55% yield). H NMR (300 MHz, CDCl3) δ *8.37 (s, 2H),
3,5-Bis(trifluoromethyl)-N′-(pent-4-ynyl)benzohydrazide
(1l). Synthesized using 4-pentyn-1-ol (1.50 g, 17.8 mmol; procedure
B). Chromatographic purification (40% Et2O/pentane) afforded a
pink solid (1.87 g, 31% yield). 1H NMR (300 MHz, CDCl3) δ 8.25 (s,
2H), 8.03 (s, 1H), 3.13 (t, J = 6.9 Hz, 2H), 2.35 (td, J = 7.0, 2.7 Hz,
2H), 1.99 (t, J = 2.6 Hz, 1H), 1.80 (p, J = 7.1 Hz, 2H); 13C NMR (100
MHz, CDCl3) δ 164.4, 134.1, 132.4 (q, J = 34.1 Hz, 2C), 127.6 (2C),
125.7, 122.8 (q, J = 272.8 Hz, 2C), 83.3, 69.4, 50.9, 26.0, 16.0; IR
(film) 3275, 2941, 2890, 1596, 1132 cm−1; HRMS (EI-Q-TOF) exact
mass calcd for C14H12F6N2O 338.0854 [M]+, found 338.08366.
3,5-Bis(trifluoromethyl)-N′-(5-phenylpent-4-ynyl)-
benzohydrazide (1m). Synthesized using 5-phenylpent-4-yn-1-ol23
(1.78 g, 11.9 mmol; procedure B). Chromatographic purification
(40% Et2O/pentane) afforded a pink oil (1.87 g, 38% yield). 1H NMR
(300 MHz, CDCl3) δ 8.21 (s, 2H), 8.02 (s, 1H), 7.40−7.35 (m, 2H),
7.29−7.24 (m, 3H), 3.16 (t, J = 6.9 Hz, 2H), 2.56 (t, J = 6.9 Hz, 2H),
1.87 (p, J = 6.9 Hz, 2H); 13C NMR (100 MHz, CDCl3) δ 164.5, 134.8,
132.4 (q, J = 34.0 Hz, 2C), 131.5 (2C), 128.3 (2C), 127.7, 127.2 (2C),
127.2, 125.4, 123.5, 122.8 (q, J = 273.3 Hz, 2C), 89.1, 81.3, 51.0, 27.0,
17.1; IR (film) 3289, 3098, 2937, 1649, 1284, 1139 cm−1; LRMS m/z
(relative intensity) 323.0617 (37.1%), 241.0068 (100%), 173.1080
(90.5%), 145.0792 (29.6%), 129.0679 (24.9%), 128.0631 (56.7%),
115.0561 (81.9%).
8.19 (s, 2H), *8.07 (s, 1H), 8.02 (s, 1H), 7.93 (d, J = 8.5 Hz, 2H),
*7.89 (d, J = 8.6 Hz, 2H), 7.76 (br s, 1H), 7.42 (d, J = 8.5 Hz, 2H), *
7.36 (d, J = 8.5 Hz, 2H), 4.88 (br s, 1H), 3.91 (s, 3H), 3.04 (t, J =
6.4 Hz, 2H), 2.50 (t, J = 6.5 Hz, 2H), 1.79−1.70 (m, 4H); 13C NMR
(75 MHz, CDCl3) δ 166.7, *166.4, 164.4, *163.7, 134.8, 132.1 (q, J =
33.9 Hz, 2C), 131.3 (2C), *131.3 (2C), 129.3 (2C), *129.2 (2C),
128.8, *128.7, *128.6, 128.5, 127.3 (2C), 125.1, 122.8 (q, J = 273.2
Hz, 2C), *93.2, 93.0, *80.6, 80.5, 57.4, 52.1, *51.6, 27.1, *26.4, *26.0,
25.9, 19.3; IR (film) 3454, 2942, 1721, 1656, 1280, 1139 cm−1; HRMS
(EI-Q-TOF) exact mass calcd for C23H20F6N2O3 486.1378 [M]+,
found 486.13996.
3,5-Bis(trifluoromethyl)-N′-(6-(thiophen-2-yl)hex-5-ynyl)-
benzohydrazide (1h). Synthesized using 6-(thiophen-2-yl)hex-5-yn-
1-ol20 (2.00 g, 11.1 mmol; procedure B). Chromatographic
purification (0.5% MeOH/CH2Cl2) afforded a white solid (1.14 g,
47% yield). 1H NMR (300 MHz, CDCl3) δ 8.20 (s, 2H), 8.02 (s, 1H),
7.77 (s, 1H), 7.16 (dd, J = 1.1, 5.2 Hz, 1H), 7.10 (dd, J = 1.0, 3.6 Hz,
1H), 6.92 (dd, J = 3.6, 5.2 Hz, 1H), 4.89 (s, 1H), 3.03 (t, J = 5.8 Hz,
2H), 2.53−2.46 (m, 2H), 1.77−1.68 (m, 4H); 13C NMR (75 MHz,
CDCl3) δ 164.5, 134.7, 132.1 (q, J = 34.0 Hz, 2C), 130.9, 127.3 (2C),
126.7, 125.9, 125.2, 123.7, 122.8 (q, J = 273.1 Hz, 2C), 93.6, 74.1, 51.5,
27.0, 25.8, 19.4; IR (film) 3219, 2938, 1653, 1380, 1128, 906 cm−1;
HRMS (EI-Q-TOF) exact mass calcd for C19H16SF6N2O 434.0888
[M]+, found 434.08915.
3,5-Bis(trifluoromethyl)-N′-(hept-6-yn-2-yl)benzohydrazide
(1i). Synthesized using hept-6-yn-2-ol21 (10.2 mmol; procedure B).
Chromatographic purification (40% Et2O/pentane) afforded a beige
solid (1.38 g, 37% yield). 1H NMR (300 MHz, CDCl3) δ 8.22 (s, 2H),
8.02 (s, 1H), 3.18−3.08 (m, 1H), 2.25 (s, 2H), 1.95 (s, 1H), 1.75−
1.47 (m, 4H), 1.13 (d, J = 6.3 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ
164.6, 135.0 (C), 132.4 (q, J = 34.0 Hz, 2C), 127.3 (2C), 125.3, 122.8
(q, J = 272.9 Hz, 2C), 84.3 (CH), 68.7 (C), 55.5 (C), 33.3 (CH2),
24.3 (CH2), 18.5 (CH2), 18.4 (CH3); IR (film) 3249, 2953, 1637,
1379, 1276, 1136 cm−1; HRMS (EI-Q-TOF) exact mass calcd for
C16H16F6N2O 352.0932 [M − CH3]+, found 352.09257.
ASSOCIATED CONTENT
■
S
* Supporting Information
Short discussion on the importance of the 3,5-bis-
(trifluoromethyl)benzhydrazide substituent, results for other
hydrazides investigated, and full spectroscopic data for all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: andre.beauchemin@uottawa.
N′-(Dec-9-yn-5-yl)-3,5-bis(trifluoromethyl)benzohydrazide
(1j). Hex-5-yn-1-ol (1.00 g, 10.2 mmol) and Et3N (5.68 mL, 40.8
mmol) were premixed in CH2Cl2 (30.9 mL). SO3·pyridine (4.90 g,
30.6 mmol) in DMSO (30.9 mL) was added at 0 °C. The reaction was
stirred until complete, quenched (aqueous NH4Cl), and extracted
(CH2Cl2). The organic extracts were washed with water and brine,
dried, and concentrated to afford the crude aldehyde. To this aldehyde
were added THF (25.5 mL) and n-BuMgCl (2.0 M in THF, 25.5 mL,
50.9 mmol) at 0 °C. The solution was warmed to room temperature
over 2 h. It was then diluted with Et2O, quenched (aqueous NH4Cl),
extracted (Et2O), washed (brine), dried (Na2SO4), and concentrated.
Due to instability, dec-9-yn-5-ol was used immediately (procedure B).
Chromatographic purification (20% Et2O/pentane) yielded a white
solid (1.64 g, 40% yield). 1H NMR (300 MHz, CDCl3) δ 8.19 (s, 2H),
8.00 (s, 1H), 7.72 (br s, 1H), 4.90 (br s, 1H), 2.97 (t, J = 5.5 Hz, 1H),
2.32−2.27 (m, 2H), 1.95 (t, J = 2.6 Hz, 1H), 1.72−1.27 (m, 12H),
0.91 (t, J = 6.9 Hz, 3H); 13C NMR (75 MHz, CDCl3) δ 164.4, 135.0,
132.4 (q, J = 33.4 Hz, 2C), 127.2 (2C), 125.3, 122.8 (q, J = 279.3 Hz,
2C) 84.6, 68.7, 59.9, 32.0, 30.7, 27.9, 23.8, 22.9, 18.5, 14.0; IR (film)
3212, 2940, 1641, 1274, 1170, 1140 cm−1; HRMS (EI-Q-TOF) exact
mass calcd for C19H22F6N2O 408.1636 [M]+, found 408.16348.
3,5-Bis(trifluoromethyl)-N′-(1-phenylhex-5-ynyl)-
benzohydrazide (1k). Synthesized using 1-phenylhex-5-yn-1-ol22
(0.67 g, 3.82 mmol; procedure B). Chromatographic purification (10%
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the University of Ottawa, the Canadian Foundation
for Innovation, the Ontario Ministry of Research and
Innovation, and NSERC for support. I.D. thanks NSERC and
FQRNT for graduate scholarships. An exchange scholarship
from the Universite
acknowledged.
́
Pierre et Marie Curie (S.T.) is also
REFERENCES
■
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1
EtOAc/hexanes) yielded a white solid (0.47 g, 29% yield). H NMR
(400 MHz, CDCl3) δ 8.35 (br, 1H), 8.00 (s, 2H), 7.98 (s, 1H), 7.37−
7.32 (m, 4H), 7.31−7.28 (m, 1H), 5.21 (br, 1H), 4.11 (dd, J = 5.5, 8.3
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13C NMR (100 MHz, CDCl3) δ 164.6, 140.9, 134.9, 132.2 (q, J = 34.0 Hz,
E
dx.doi.org/10.1021/jo4011409 | J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Note
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́ ́
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