Selective anti-markovnikov cyclization and hydrofluorination reaction in superacid HF/SbF5: A tool in the design of nitrogen-containing (fluorinated) polycyclic systems

Article abstract of DOI:10.1021/jo400398y

The selective synthesis of tetrahydroquinolines and fluorinated arylamines was performed in superacid HF/SbF₅ through a superelectrophilic ammonium-carbenium activation process. This anti-Markovnikov oriented reaction was applied to the straightforward synthesis of highly valued (fluorinated) nitrogen-containing heterocyclic compounds.

Full text of DOI:10.1021/jo400398y

Article
pubs.acs.org/joc
Selective Anti-Markovnikov Cyclization and Hydrofluorination
Reaction in Superacid HF/SbF5: A Tool in the Design of Nitrogen-
Containing (Fluorinated) Polycyclic Systems
Guillaume Compain, Celine Bonneau, Agnes Martin-Mingot, and Sebastien Thibaudeau*
́
̀
́
Superacid group in “Organic Synthesis” team, Universite
Poitiers Cedex, France
́
de Poitiers, CNRS UMR 7285 IC2MP, 4, avenue Michel Brunet, F-86022
S
* Supporting Information
ABSTRACT: The selective synthesis of tetrahydroquinolines
and fluorinated arylamines was performed in superacid HF/
SbF5 through a superelectrophilic ammonium−carbenium
activation process. This anti-Markovnikov oriented reaction
was applied to the straightforward synthesis of highly valued
(fluorinated) nitrogen-containing heterocyclic compounds.
compounds can alter both physical and chemical properties16
and is now routinely used to modify ADME parameters of a
drug.17 Among fluorinated bioactive compounds, recently,
fluorinated arylamines were used in the design of bioactive
drugs, going from compounds showing neuroprotective
properties,18 hepatitis C virus entry inhibitors,19 thrombin
inhibitors,20 selective carbonic anhydrase IX cancer related
isoform inhibitors,21 or potential tools for molecular imaging of
apoptosis related caspaces.22 However, few methodologies
focus on their direct preparation and the classically used
dehydroxyfluorination method23 or aziridine ring-opening24
suffer from rearrangement side product formation.
Taking into account these data, we explored the ability to use
HF/SbF5 superacid chemistry to selectively access either to
tetrahydroquinolines or fluorinated arylamines. Then, the use
of this divergent method to the synthesis of novel polycyclic
and fluorinated heterocycles has been explored.
1. INTRODUCTION
Nitrogen heterocycles are widespread molecules in the
pharmaceutical and agrochemical industries. In particular, the
tetrahydroquinoline ring is a very common scaffold,1 and
tetrahydroquinolines bearing simple or complex substituents
act as chemotherapeutic and pharmacodynamic agents2 but are
also used as coordinating ligands or dyes.3 Furthermore,
tetrahydroquinoline-containing sulfonamides, acting as car-
bonic anhydrase selective inhibitors,4 have recently been
shown to be targets of choice in the design of new anticancer
agents,5 which may allow further exploration of the list of
tetrahydroquinolines with antitumor activity.2 Because of the
significance of these scaffolds in drug discovery, the develop-
ment of straightforward synthetic methodologies for the
synthesis of tetrahydroquinoline derivatives remains a very
attractive field of research.1 Among the different ways for
constructing tetrahydroquinolines, acid-catalyzed intramolecu-
lar Friedel−Crafts related reactions of N-arylamines is a
commonly used strategy.6 This methodology allows the
formation of the C4−C4a bond of the tetrahydroquinoline
ring and has been previously applied to the synthesis of natural
products.7 N-Arylated allylamines were found to be the
substrate of choice to achieve the synthesis of tetrahydroquino-
lines through this process.8 However, the method suffers from a
lack of efficiency when applied to electronically deactivated
aniline derivatives.9 In due course of our work on the study of
unsaturated nitrogen compounds’ behavior in superacid10 HF/
SbF5,11 we recently reported the anti-Markovnikov addition to
N-allylic anilines12 through an ammonium−carbenium super-
electrophilic activation process.13 Starting from N-allylic aniline,
after intramolecular reaction, depending on the nature of the
aromatic substitution, indolines and tetrahydroquinolines were
formed. In addition, fluorinated amines were formed as side
products after hydrofluorination reaction.
2. RESULTS AND DISCUSSION
As mentioned above, when studying the anti-Markovnikov-
oriented reaction of N-arylated allylic amines, β- and γ-
fluorinated amines were found to be side products of the
reaction. As a consequence, to evaluate the ability to selectively
access to tetrahydroquinolines or to fluorinated aromatic
amines, the influence of the reaction conditions (acidity,
temperature, ...) on the selectivity of the process were explored
(Scheme 1, Table 1).
First, substrate 1a was submitted to superacid at −20 °C, and
a mixture of β-fluorinated amine 2a, tetrahydroquinoline 4a,
and indoline 5a was formed (Table 1, entry 1). Then the effect
of the temperature on the reaction course was evaluated.
Increasing temperature led to an increase of cyclic products
formation, and working at −50 °C allowed us to selectively
Fluorinated nitrogen containing compounds are regarded as
relevant tools in medicinal chemistry.14 Due to its unique
properties,15 the insertion of fluorine atom(s) in nitrogen
Received: March 5, 2013
Published: April 24, 2013
© 2013 American Chemical Society
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Then, to evaluate the scope of these reactions and the
influence of the nucleophilic character of the aromatic ring on
the selectivity of the reaction, a variety of differently substituted
substrates were submitted to the reaction (Scheme 2, Table 2).
As expected, in hydrofluorination conditions, in all cases the β-
fluorinated anilines could be formed in good yields. No effect of
aromatic ring substitution on this reaction could be observed.
Unfortunately, γ-fluorinated products could not be obtained in
these conditions, except from substrate 1i after reaction at 0 °C
in more acidic conditions (Table 2, entry 18).
Under cyclization conditions, in all cases the tetrahydroqui-
noline products were formed.25 Starting from the activated
aniline 1b, as from the aniline 1a, tetrahydroquinolines were
formed beside the indoline products (Table 2, entries 2 and 4).
Increasing the electronic density on the aromatic ring (σp Me =
−0.15)26 led to an increase of indoline product formation.
However, decreasing the electronic density on the aromatic ring
by introducing a trifluoromethyl group (σp CF3 = 0.54) gave
the tetrahydroquinoline 4c as the major product.27 A similar
effect observed after substitution of the aromatic ring with an
amido or a methoxy group could be attributed to the
protonation of these functions under the superacid conditions.
The protonated functions, in equilibrium with their neutral
forms, could act in these conditions as strong electron-
withdrawing substituents.28 Increasing the withdrawing effects
on the aromatic ring led to the exclusive formation of the
tetrahydroquinoline products (Table 2, entries 16, 19, 21, and
23). When the aromatic ring was too deactivated, only
deallylation occurred (Table 2, entry 25).
Scheme 1. Reactivity of N-Allylaniline 1a in Superacid HF/
SbF5
a
a
Reaction conditions: substrate (1 mmol), HF/SbF5 (4 mL), 10 min.
The starting material was observed in all cases (less than 10%).
Table 1. Competition between Intramolecular Friedel−
Crafts and Hydrofluorination Reactions of Substrate 1a
b
product
a
entry
SbF5 (mol %)
T (°C)
2a
3a
4a
5a
1
2
3
4
3.8
3.8
3.8
0
−20
0
23
2
c
c
45
50
3
28
41
1
−50
−20
20
86
d
c
d
d
c
d
d
e
5
0
d
d
d
6
12.1
12.1
21.6
21.6
−20
−20
−20
0
3
46
46
51
36
43
43
33
57
f
7
3
c
8
9
3
c
c
c
a
HF/SbF5 media composition defined by SbF5 molar percentage.
b
1
Relative abundances determined by analysis of the H NMR spectra
c
of the crude reaction. Only traces of the product could be detected by
d
e
1H NMR in the crude mixture. No reaction. Concentrated neat
f
H2SO4 is used as media for 3 days at room temperature HF/SbF5 (6
These data allowed us to postulate the following mechanism
mL).
(Scheme 3).
By conducting mechanistic investigations using in situ NMR
experiments, DFT calculations, and labeled substrates reactions,
two mechanistic pathways were postulated. Protonation of the
N-allylated aniline leads to the formation of the ammonium ion
A. Then, the superacidity of the media allows a second
protonation and either the formation of a μ-hydrido-bridged
carbocation containing ammonium−carbenium superelectro-
phile B after protonation of the double bond or after
protonation of the aromatic ring to the formation of the
ammonium−arenium dicationic superelectrophile C.12 With
activated substrates, the dicationic ammonium−arenium super-
electrophile of type C is favored, leading to the formation of a
mixture of both cyclic products. With deactivated substrates,
the (poly)protonation leads to the superelectrophilic inter-
mediate B formation. The aromatic ring, despite its electronic
deactivation by the proximal ammonium ion can trap the cation
in an intramolecular way to give the dication E, precursor of the
tetrahydroquinoline products 4. The formation of a five-
membered ring analogue of dication E from B, precursor of
indolines 5 has been shown to be energetically less favorable
than the formation of intermediate E by more than 4 kcal/
mol.12 It has to be noted that when submitting the cyclic
products (for instance for compounds 4a and 5a) to cyclization
conditions (conditions B), no reaction occurred, confirming the
access to fluorinated compound 2a (Table 1, entries 2 and 3).
These observations led to the hypothesis that cyclic products
could be considered the thermodynamic products of the
reaction. To test whether superacid HF/SbF5 is essential for
fluorination and cyclization processes, the reaction was tested in
pure HF and in the presence of concentrated sulfuric acid
(Table 1, entries 4 and 5). The absence of reaction in these
conditions confirmed that the formation of the products is
strongly dependent on the acidity of the media, confirming a
superlectrophilic activation process through (poly)protonation.
However, whatever the tested conditions, only traces of γ-
fluorinated product 3a could be obtained. We next screened
various experimental conditions to optimize the formation of
the cyclic products. By increasing the acidity of the media, that
means increasing SbF5 concentration, the hydrofluorination
process could be decreased in favor of cyclization, with no
significant effect of dilution (Table 1, entries 6−8).10,11
Exclusive formation of the cyclic compounds occurred under
optimized conditions (Table 1, entry 9). Thus, starting from N-
allylic aniline, tetrahydroquinoline and indoline or β-fluorinated
aniline could be selectively obtained in optimized conditions:
Hydrofluorination SbF5 (3.8 mol %), −50 °C (conditions A);
Friedel−Crafts intramolecular cyclization SbF5 (21.6 mol %), 0
°C, 10 min (conditions B).
Scheme 2. Reactivity of Substituted N-Allylaniline 1 in Superacid HF/SbF5
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Table 2. Selective Hydrofluorination and Friedel−Crafts Reactions of N-Allylic Anilines
a
b
c
entry
substrates
method
products (yield, %)
1
1a
1b
1c
1d
1e
1f
R1 = H
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
B
A
2a (50)
2b (82)
2c (92)
2d (87)
2e (85)
2f (52)
2g (87)
2h (66)
3a (d)
3b (d)
3c (d)
3d (d)
3e (d)
2
R3 = H
4a (22)
4b (14)
4c (39)
4d (72)
4e (32)
5a (39)
3
R1 = Me
R3 = H
4
5b (46)
5c (5)
5d (17)
5e(d)
5
R1 = CF3
R3 = H
6
7
R1 = NHAc
R3 = H
8
9
R1 = OMe
R3 = H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
R1 = N(Me)2
R3 = H
3f (d)
e
1g
1h
1i
R1 = COOEt
R3 = H
3g (d)
e
R1 = SO2NH2
R3 = H
3h (d)
4h (92)
4i (85)
R1 = NO2
2i (95)
2i (79)
3i (d)
3i (6)
f
A
R3 = H
B
f
1j
1k
1l
R1 = H
A
2j (97)
2k (95)
2l (48)
3j (d)
3k (d)
g
R3 = H
B
A
B
A
B
4j (66)
4k (84)
R1 = NO2
R3 = Me
R1 = NO2
R3 = NO2
3l (d)
h
a
b
For substrate 1j R2 = NO2, and for all substrates R2 = H. Reaction conditions: method A, substrate (1 mmol), HF/SbF5 (4 mL), 10 min, SbF5 (3.8
mol %), −50 °C; method B, substrate (1 mmol), HF/SbF5 (4 mL), SbF5 (21.6 mol %), 0 °C. The starting material was observed in all cases (less
c
d
e
f
g
than 10%). After column chromatography. Only traces were detected in the crude mixture. Complex mixture. SbF5 12.5 (mol %), 0 °C. 5-Nitro-
h
1,2,3,4-tetrahydroquinoline 4j′ was also formed in 10% yield. Only deallylation occured.
Scheme 3. Postulated Mechanism for Hydrofluorination and Cyclization Reactions
Scheme 4. Postulated Reaction Equilibriums in Fluorinated Products Formation
irreversibility of the cyclization reactions. Then, we investigated
whether the fluorinated derivative could be considered as an
intermediate in the cyclization process. Starting from the
fluorinated derivative 2a, after reaction under cyclization
conditions, the tetrahydroquinoline and indoline derivatives
4a and 5a were exclusively formed, a result that confirmed the
postulated reaction equilibriums (Scheme 4).
However, to discuss the displacement of equilibrium (I)
toward the formation of the ammonium−carbenium ion B in
cyclization conditions, the composition of the media has to be
analyzed. The following conclusions were proposed and largely
accepted from extensive reported studies of ionic composition
in HF/SbF5 solutions.29 For SbF5 concentration lower than 10
mol %, SbF6− is practically the only anionic species present and
+
H3F2 the predominant cationic species. From 10 to 22 mol %
−
−
of SbF5 in HF, the anions are essentially SbF6 and Sb2F11 in
slow equilibrium and only H2F+ is observed. Taking into
account these conclusions, we can consider that the
nucleophilicity of fluoride ion source strongly decreases as
the SbF5 concentration increases, and it has now largely been
shown that increasing the amount of SbF5 increases the acidity
strength of the media. In cyclization conditions, the fluorinated
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a
Scheme 5. Synthesis of Nitrogen-Containing Polycyclic (Fluorinated) Compounds
a
Conditions: (a) NaH, allyl bromide, DMF; (b) HF/SbF5 (SbF5, 21.6 mol %); (c) NaH, AcCl, CH2Cl2; (d) SnCl2, EtOH; (e) (Boc)2O, THF; (f)
TFA, CH2Cl2; (g) HF/SbF5 (SbF5, 3.8 mol %).
intermediate D, after protonation and HF elimination, could
give B, which could be trapped by the more nucleophilic
species (aromatic ring) to give the dication E, precursor of the
tetrahydroquinoline after hydrolysis. Elimination from the
dication B could also give the unsaturated ammonium ion A
under these conditions (Scheme 3).
widespread molecules in medicinal chemistry research, and
among tetrahydroquinolines containing bioactive compounds,
two families retain our attention. First, julolidine derivatives
have found numerous interests as photoconductive materials,
chemoluminescence substances, and dyes intermediates and
also in biological systems as fluorescent probes.33 However,
even if elegant methods have been developed to synthesize
julolidines,34 accessing to the electronically deactivated
analogues is rather limited, and methods existing to prepare
these products suffer from safety concern, poor selectivity, and
oxidation.35 The second family that interested us is the
diazaoctahydroanthracene one. In the quest for molecules
with helical structure, exhibiting optical and electronic proper-
ties,36 the development of methods to synthesize new
constrained functionalized nitrogen-containing polycyclic sys-
tems is of great interest.37 In this context, the previously
described method could be applied to the synthesis of novel
diazaoctahydroanthracene.
Thus, we explored the divergent synthesis of the 9-
nitrojulolidine and 1,5-diazaoctahydroanthracene derivatives.
To access to both compounds in a divergent way, the employed
synthetic strategy was based on the same crucial intermediate 6-
nitro-1,2,3,4-tetrahydroquinoline 4i (Scheme 5), synthesized in
85% yield after anti-Markovnikov Friedel−Crafts superacid-
catalyzed reaction (Table 2). After allylation, in the presence of
allylbromide, N-allylated compound 6 was synthesized in 98%
yield. Then, the cyclization in superacid HF/SbF5 allowed us to
access to the 9-nitrojulolidine 7 in good yield. The key
intermediate 4i was also engaged in the multistep synthesis of
novel nitrogen-containing heterocycles. After acetylation of the
amino function, the reduction of the nitro group to its amino
derivative analogue was performed in the presence of SnCl2. A
subsequent protection of the formed amine in its carbamate
analogue, followed by allylation in the presence of allyl
bromide, led to the synthesis of product 11. When product
11 was submitted to cyclization in superacid, only a complex
mixture of compounds could be obtained. Thus, compound 11
was deprotected to give amine 12. Gratifyingly, the cyclization
of compound 12 under superacid conditions led to the
synthesis of two tricyclic compounds 1338 and 14 in 36 and
21% yields, respectively. At this stage, the selective hydro-
fluorination of the same substrate could also be achieved in
good yield to give the β-fluorinated bicyclic compound 15.
The formation of the β-fluorinated products was largely
favored, and thus despite a possible superelectrophilic charge−
charge repulsive effect30 in the μ-hydrido-bridged carbocation-
containing ammonium−carbenium superelectrophile B
(Scheme 3). In this case, no repulsive effect predominates, as
the three-center two-electron bond intermediate has been
shown by DFT calculations to correspond to a symmetrically μ-
hydrido-bridged species (μ-H---C distances: 1.33 Å, activated
CC bond length: 1.39 Å).12 However, an equilibrated
distribution between the β-fluoro and the γ-fluoro derivatives
could have been expected. The favored formation of the β-
fluorinated product in this reaction could be attributed to a
displacement of the equilibriums I and II between fluorinated
ammonium precursors D, D′, and ion B. After protonation (or
activation),31 HF elimination could be postulated (equilibriums
I and II). When submitting substrate 3i in superacid, a mixture
of β-fluoro product 2i and γ-fluoro product 3i were obtained
beside unsaturated aniline 1i (1i/2i/3i ratio = 3/87/7).
Analogously, when substrate 2i was submitted to superacid, a
similar mixture of compound was formed (1i/2i/3i ratio = 3/
88/6). These results confirm the thermodynamic stability of
intermediate D under superacid conditions. Through electro-
static interactions between the fluorine atom and the
ammonium ion,32 a stabilization of the intermediate could be
postulated. However, the strong electronic withdrawing effect
of the fluorine atom should destabilize the ammonium ion
(with a stronger effect in intermediate D). Another aspect
should be appreciated: The elimination of hydrogen fluoride
could be more favorable from D′, than from D. All these
parameters must influence the displacement of the equilibrium
toward the formation of the precursors of the β-fluorinated
products.
Having in hand a straightforward and selective method to
synthesize electronically deactivated tetrahydroquinolines and/
or β-fluorinated aniline derivatives, we decided to further
explore its potential in accessing structurally more complex
structures. As previously mentioned, tetrahydroquinolines are
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(IES+, ACN): m/z 154 [M + H]+. HRMS (ESI, CH3OH): calcd for
C9H12FN [M + Na]+ 176.08515, found 176.0852.
Starting from N-allylic-4-nitroaniline, these multistep strategies,
including two reactions in superacid, allowed the synthesis of
the targeted cyclic products 13 and 14 in 22% overall yield, the
synthesis of the original fluorinated product 15 in 32% yield,
and the synthesis of 9-nitrojulolidine 7 in 65% yield, making
these synthetic routes good alternatives to existing methods.
N-(2-Fluoropropyl)-4-methylaniline (2b). This compound was
obtained from the substrate 1b (147 mg, 1 mmol) following the
general procedure. The reaction crude was purified with the eluent
petroleum ether/ethyl acetate 99/1, thereby obtaining compound 2b
1
(137 mg, 82%) as a brown oil. H NMR (CDCl3, 400 MHz, ppm) δ:
1.43 (dd, CH3, J = 23.8 Hz, J = 6.3 Hz, H3′), 2.27 (s, CH3), 3.29 (m,
CH2, H1′), 3.68 (broad s, NH), 4.90 (dm, CHF, J = 49.5 Hz, H2′), 6.59
(d, 2CH, J = 8.4 Hz, H2 and H6), 7.03 (d, 2CH, J = 8.5 Hz, H3 and
H5). 13C NMR (CDCl3, 100 MHz, ppm) δ: 18.8 (d, CH3, J = 22 Hz,
C3′), 20.5 (CH3), 50.0 (d, CH2, J = 21 Hz, C1′), 89.6 (d, CHF, J = 167
Hz, C2′), 113.4 (2CH, C2 and C6), 127.3 (C4), 129.9 (2CH, C3 and
C5), 145.6 (C1). 19F{1H} NMR (CDCl3, 376 MHz, ppm) δ: −179.9.
MS (IES+, ACN): m/z 168 [M + H]+. HRMS (ESI, CH3OH): calcd
for C10H14FN [M + Na]+ 190.1008, found 190.1008.
3. CONCLUSION
To conclude, a new selective method to access either β-
fluorinated anilines or electronically deactivated tetrahydroqui-
nolines was developed. This original method is based on a
superacid HF/SbF5 activation through the formation of an
original μ-hydrido-bridged carbocation containing an ammo-
nium−carbenium superelectrophile. This anti-Markovnikov-
oriented reaction was also applied to the straightforward
synthesis of highly valued (fluorinated) nitrogen-containing
heterocyclic compounds showing the synthetic potential of the
developed method.
N-(2-Fluoropropyl)-4-(trifluoromethyl)aniline (2c). This com-
pound was obtained from the substrate 1c (196 mg, 1 mmol)
following the general procedure. The reaction crude was purified with
the eluent pentane/ethyl acetate 95/5, thereby obtaining compound
1
2c (196 mg, 92%) as a light yellow oil. H NMR (CDCl3, 400 MHz,
ppm) δ: 1.43 (dd, CH3, J = 23.8 Hz, J = 6.3 Hz, H3′), 3.34 (m, CH2,
H1′), 4.31 (broad s, NH), 4.88 (dm, CHF, J = 49.3 Hz, H2′), 6.63 (d,
2CH, J = 8.5 Hz, H2 and H6), 7.42 (d, 2CH, J = 8.4 Hz, H3 and H5).
13C NMR (CDCl3, 100 MHz, ppm) δ: 18.7 (d, CH3, J = 22 Hz, C3′),
48.9 (d, CH2, J = 21 Hz, C1′), 89.4 (d, CHF, J = 168 Hz, C2′), 112.2
(2CH, C2 and C6), 119.5 (q, J = 33 Hz, C4), 125.1 (q, J = 270 Hz,
CF3), 126.8 (q, 2CH, J = 4 Hz, C3 and C5), 150.4 (C1). 19F{1H} NMR
(CDCl3, 376 MHz, ppm) δ: −179.92 (CF), −61.07 (CF3). MS (IES+,
ACN): m/z 202 [M − HF + H]+. HRMS (ESI, CH3OH): calcd for
C10H11F4N [M + H]+ 222.09059, found 222.0907.
N-(4-(2-Fluoropropylamino)phenyl)acetamide (2d). This com-
pound was obtained from the substrate 1d (189 mg, 1 mmol)
following the general procedure. The compound 2d was obtained
without purification (183 mg, 87%) as an orange solid. Mp: 90−93 °C.
1H NMR (MeOD, 400 MHz, ppm) δ: 1.34 (dd, CH3, J = 23.6 Hz, J =
6.3 Hz, H3′), 2.06 (s, CH3), 3.22 (m, CH2, H1′), 4.78 (dm, CHF, J =
49.4 Hz, H2′), 6.61 (d, 2CH, J = 8.9 Hz, H2 and H6), 7.25 (d, 2CH, J =
8.9 Hz, H3 and H5). 13C NMR (MeOD, 100 MHz, ppm) δ: 18.9 (d,
CH3, J = 22 Hz, C3′), 23.5 (CH3), 50.6 (d, CH2, J = 22 Hz, C1′), 90.5
(d, CHF, J = 167 Hz, C2′), 114.0 (2CH, C3 and C5), 123.3 (2CH, C2
and C6), 129.7 (C1), 147.0 (C4), 171.2 (CO). 19F{1H} NMR (MeOD,
376 MHz, ppm) δ: −179.52. MS (IES+, ACN): m/z 211 [M + H]+.
HRMS (ESI, CH3OH): calcd for C11H15FN2O [M + Na]+ 233.10661,
found 233.1065.
4. EXPERIMENTAL SECTION
4.1. General Methods. We draw the reader’s attention to the
dangerous features of superacidic chemistry. Handling of hydrogen
fluoride and antimony pentafluoride must be done by experienced
chemists with all the necessary safety arrangements in place.
Reactions performed in superacid were carried out in a sealed
Teflon flask with a magnetic stirrer. No further precautions have to be
taken to prevent mixture from moisture (test reaction worked out in
anhydrous conditions leads to the same results as expected). Yields
1
refer to isolated pure products. H, 13C, and 19F NMR were recorded
on a 400 MHz Bruker Advance DPX spectrometer using CDCl3,
CD3COCD3, or CD3OD as solvent. COSY 1H−1H and 1H−13C
experiments were used to confirm the NMR peaks assignments.
Melting points were determined in a capillary tube with a device
melting point appartus and were uncorrected. Mass Spectra (MS)
were performed with coupled gas chromatography (electronic impact).
All separations were done under flash chromatography conditions on
silica gel (15−40 μm). High-resolution mass spectrometry (HRMS)
spectra were performed with a quadrupole mass analyzer.
Preparation of HF/SbF5 Mixture. After liquid condensation of the
desired quantity of hydrogen fluoride in a Teflon reactor at −30 °C,
antimony pentafluoride was slowly added to the reactor at the same
temperature and the reactor was then sealed and maintained at
reaction temperature. Under these conditions, the SbF5 molar
percentage was determined accordingly: For example, 1 mL of SbF5
(13.8 × 10−3 mol) was added to 7 mL of anhydrous liquid HF (0.35
mol) to give a HF/SbF5 solution with a SbF5 molar percentage of 3.8
mol %.
N-(2-Fluoropropyl)-4-methoxyaniline (2e). This compound was
obtained from the substrate 1e (165 mg, 1 mmol) following the
general procedure. The reaction crude was purified with the eluent
pentane/ethyl acetate 99/1 to 96/4, thereby obtaining compound 2e
1
(158 mg, 85%) as a brown solid. Mp: 34−35 °C. H NMR (CDCl3,
400 MHz, ppm) δ: 1.42 (dd, CH3, J = 23.8 Hz, J = 6.3 Hz, H3′), 3.75
(m, NH), 3.25 (m, CH2, H1′), 4.89 (dm, 1H, J = 49.5 Hz, H2′), 3.77 (s,
CH3, OMe), 6.63 (d, 2CH, J = 9.0 Hz, H2 and H6), 6.82 (d, 2CH, J =
9.0 Hz, H3 and H5). 13C NMR (CDCl3, 100 MHz, ppm) δ: 18.7 (d,
CH3, J = 22 Hz, C3′), 50.6 (d, CH2, J = 21 Hz, C1′), 55.8 (CH3, OMe),
89.6 (d, CHF, J = 166 Hz, C2′), 114.6 (2CH, C2 and C6), 115.0 (2CH,
C3 and C5), 142.0 (C1), 152.5 (C4). 19F{1H} NMR (CDCl3, 376 MHz,
ppm) δ: −179.9. MS (IES+, ACN): m/z 184 [M + H]+. HRMS (ESI,
solvent): calcd for C10H14FNO [M + Na]+ 206.09571, found
206.0957.
4.2. Hydrofluorination Reactions. Optimized Procedure in
Superacidic Media. To a mixture of HF/SbF5 (4 mL, SbF5 3.8 mol %)
maintained at −50 °C was added nitrogen derivative. The mixture was
magnetically stirred at the same temperature during 10 min. The
reaction mixture was then neutralized with water−ice−Na2CO3 and
extracted with dichloromethane (×3). The combined organic phases
were dried (MgSO4) and concentrated in vacuo. Products were
isolated by column chromatography over silica gel.
N-(2-Fluoropropyl)aniline (2a). This compound was obtained from
substrate 1a (133 mg, 1 mmol) following the general procedure. The
reaction crude was purified with the eluent petroleum ether/ethyl
acetate 99/1, thereby obtaining compound 2a (76 mg, 50%) as brown
oil. 1H NMR (CDCl3, 400 MHz, ppm) δ: 1.42 (dd, CH3, J = 23.8 Hz,
J = 6.3 Hz, H3′), 3.28 (m, CH2, H1′), 3.98 (broad s, NH, H1). 4.89
(dm, CH, J = 49.4 Hz, H2′), 6.64 (dd, 2CH, J = 8.5 Hz, J = 0.9 Hz, H2,
H6), 6.74 (t, CH, J = 7.3 Hz, H4), 7.19 (dd, 2CH, J = 8.4 Hz, J = 7.4
Hz, H3, H5). 13C NMR (CDCl3, 100 MHz, ppm) δ: 18.8 (d, CH3, J =
22 Hz, C3′), 49.6 (d, CH2, J = 21 Hz, C1′), 89.6 (d, CH, J = 167 Hz,
C2′), 113.1 (2CH, C2, C6), 118.1 (1CH, C4), 129.4 (2CH, C5, C3),
147.9 (C7). 19F{1H} NMR (CDCl3, 376 MHz, ppm) δ: −180.0. MS
N1-(2-Fluoropropyl)-N4,N4-dimethylbenzene-1,4-diamine (2f).
This compound was obtained from the substrate 1f (140 mg, 0.66
mmol) following the general procedure (with 2.7 mL of the mixture
HF/SbF5). The reaction crude was purified with the eluent petroleum
ether/ethyl acetate 85/15, thereby obtaining compound 2f (79 mg,
1
52%) as a black oil. H NMR (CDCl3, 400 MHz, ppm) δ: 1.41 (dd,
CH3, J = 23.8 Hz, J = 6.3 Hz, H3′), 2.85 (m, 2CH3, N(CH3)2), 3.23
(m, CH2, H1′), 3.56 (broad s, NH), 4.89 (dm, CHF, J = 49.5 Hz, H2′),
6.65 (m, 2CHar), 6.76 (m, 2CHar). 13C NMR (CDCl3, 100 MHz,
ppm) δ: 18.8 (d, CH3, J = 22 Hz, C3′), 42.3 (broad s, 2CH3,
4467
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N(CH3)2), 50.8 (broad s, CH2, C1′), 89.7 (broad d, CH, J = 161 Hz,
C2′), 114.9 (2CHar), 116.0 (2CHar), 140.4 (broad s, CIVar), 144.2
(CIVar). 19F{1H} NMR (CDCl3, 376 MHz, ppm) δ: −179.75. MS (IES
+, ACN): m/z 197 [M + H]+. HRMS (ESI, CH3OH): calcd for
C11H17FN2 [M + H]+ 197.1454, found 197.1452.
N-(2-fluoropropyl)-3-nitroaniline (2j). This compound was ob-
tained from the substrate 1j (178 mg, 1 mmol) following the general
procedure. The compound 2j was obtained without purification (192
1
mg, 97%) as an orange solid. Mp: 59−61 °C. H NMR (CDCl3, 400
MHz, ppm) δ: 1.44 (dd, CH3, J = 23.8 Hz, J = 6.3 Hz, H3′), 3.36 (m,
CH2, H1′), 4.42 (broad s, NH), 4.90 (dd, CHF, J = 49.4 Hz, J = 1.7 Hz,
H2′), 6.91 (ddd, CH, J = 8.2 Hz, J = 2.4 Hz, J = 0.7 Hz, H6), 7.28 (t,
CH, J = 8.1 Hz, H5), 7.40 (t, CH, J = 2.3 Hz, H2), 7.53 (ddd, CH, J =
8.1 Hz, J = 2.1 Hz, J = 0.8 Hz, H4). 13C NMR (CDCl3, 100 MHz,
ppm) δ: 18.6 (d, CH3, J = 22 Hz, C3′), 49.0 (d, CH2, J = 21 Hz, C1′),
89.3 (d, CHF, J = 168 Hz, C2′), 106.4 (C2), 112.4 (CH, C4), 119.3
(CH, C6), 129.9 (CH, C5), 148.7 (C1), 149.4 (C3). 19F{1H} NMR
(MeOD, 376 MHz, ppm) δ: −179.24. MS (IES+, ACN): m/z 199 [M
+ H]+. HRMS (ESI, CH3OH): calcd for C9H11FN2O2 [M + Na]+
221.07023, found 221.0701.
Ethyl 4-(2-Fluoropropylamino)benzoate (2g). This compound was
obtained from the substrate 1g (205 mg, 1 mmol) following the
general procedure. The reaction crude was purified with the eluent
petroleum ether/ethyl acetate 95/5, thereby obtaining compound 2g
(194 mg, 87%) as a light pink solid. Mp: 76−77 °C. 1H NMR (CDCl3,
400 MHz, ppm) δ: 1.22 (t, CH3, J = 7.1 Hz, H2″), 1.23 (dd, CH3, J =
23.7 Hz, J = 6.3 Hz, H3′), 3.28 (m, CH2, H1′), 4.29 (q, CH2, J = 7.1 Hz,
H1″), 4.65 (broad s, NH), 4.81 (dm, CHF, J = 49.3 Hz, H2′), 6.55 (d,
2CH, J = 8.8 Hz, H3 and H5), 7.86 (d, 2CH, J = 8.8 Hz, H2 and H6).
13C NMR (CDCl3, 100 MHz, ppm) δ: 14.3 (CH3, C2″), 18.4 (d, CH3,
J = 22 Hz, C3′), 48.4 (d, CH2, J = 22 Hz, C1′), 60.1 (CH2, C1″), 89.1
(d, CHF, J = 168 Hz, C2′), 111.5 (2CH, C3 and C5), 118.8 (C1), 131.4
(2CH, C2 and C6), 151.6 (C4), 166.8 (CO). 19F{1H} NMR (CDCl3,
376 MHz, ppm) δ: −179.9. MS (IES+, ACN): m/z 227 [M + H +1 ]+.
HRMS (ESI, CH3OH): calcd for C12H16FNO2 [M + Na]+ 248.10628,
found 248.1064.
4-(2-Fluoropropylamino)benzenesulfonamide (2h). This com-
pound was obtained from the substrate 1h (296 mg, 1.39 mmol)
following the general procedure (extracted with ethylacetate). The
reaction crude was purified with a combi-flash with the eluent
pentane/ethyl acetate 60/40, thereby obtaining compound 2h (216
mg, 66%) as a white solid. Mp: 110 °C. 1H NMR (MeOD, 400 MHz,
ppm) δ: 1.40 (dd, CH3, J = 23.6 Hz, J = 6.3 Hz, H3′), 3.37 (m, CH2,
H1′), 4.85 (dm, CHF, J = 49.1 Hz, H2′), 6.73 (d, 2CH, J = 8.9 Hz, H3
and H5), 7.67 (d, 2CH, J = 8.9 Hz, H2 and H6). 13C NMR (MeOD,
100 MHz, ppm) δ: 18.8 (d, CH3, J = 22 Hz, C3′), 49.2 (d, CH2, J = 22
Hz, C1′), 90.4 (d, CHF, J = 168 Hz, C2′), 112.4 (s, 2CH, C3 and C5),
128.9 (s, 2CH, C2 and C6), 130.8 (C1), 153.3 (C4). 19F{1H} NMR
(MeOD, 376 MHz, ppm) δ: −179.18. MS (IES+, ACN): m/z 255 [M
+ Na]+. HRMS (ESI, CH3OH): calcd for C9H13FN2O2S [M + Na]+
255.05795, found 255.0578.
N-(2-Fluoropropyl)-2-methyl-4-nitroaniline (2k). This compound
was obtained from the substrate 1k (96 mg, 0.5 mmol) following the
general procedure (with 2 mL of the mixture HF/SbF5). The
compound 2k was obtained without purification (183 mg, 95%) as an
1
orange solid. Mp: 75−76 °C. H NMR (CDCl3, 400 MHz, ppm) δ:
1.43 (dd, CH3, J = 23.8 Hz, J = 6.3 Hz, H3′), 2.17 (s, CH3), 3.43 (m,
CH2, H1′), 4.64 (broad s, NH), 4.91 (dm, CHF, J = 49.4 Hz, H2′), 6.52
(d, CH, J = 9.0 Hz, H6), 7.93 (dd, CH, J = 2.6 Hz, J = 0.7 Hz, H3),
8.00 (dd, CH, J = 9.0 Hz, J = 2.7 Hz, H5). 13C NMR (CDCl3, 100
MHz, ppm) δ: 17.2 (CH3), 18.6 (d, CH3, J = 22 Hz, C3′), 48.7(d,
CH2, J = 21 Hz, C1′), 89.1 (d, CHF, J = 168 Hz, C2′), 107.9 (CH, C6),
121.62 (C2), 124.5 (CH, C3 or C5), 126.10 (CH, C3 or C5), 137.8
(C4), 151.4 (C1). 19F{1H} NMR (CDCl3, 376 MHz, ppm) δ: −179.75.
MS (IES+, ACN): m/z 213.17 [M + H]+. HRMS (ESI, CH3OH):
calcd for C10H13FN2O2 [M + Na]+ 235.08588, found 235.0858.
4.3. Cyclization Reactions. Optimized Procedure in Superacidic
Media. To a mixture of HF/SbF5 (4 mL, SbF5 21.6 mol %)
maintained at 0 °C was added nitrogen derivative. The mixture was
magnetically stirred at the same temperature for the entire reaction
time. The reaction mixture was then neutralized with water−ice−
Na2CO3 and extracted with ethyl acetate (×3). The combined organic
phases were dried (MgSO4) and concentrated in vacuo. Products were
isolated by column chromatography over silica gel.
N-(2-Fluoropropyl)-4-nitroaniline (2i). This compound was
obtained from the substrate 1i (178 mg, 1 mmol) following the
general procedure. The reaction crude was purified with the eluent
petroleum ether/ethyl acetate 95/5 up to 80/20, thereby obtaining
Formation of Compounds 4a and 5a. These compounds were
obtained from substrate 1a (126 mg, 0.95 mmol) following the general
procedure (reaction time: 10 min). The reaction crude was purified
with the eluent pentane/ethyl acetate 99/1, compound 5a (49 mg,
39%, brown oil) first eluted followed by compound 4a (28 mg, 22%,
brown oil).
1
compound 2i (188 mg, 95%) as a yellow solid. Mp: 62−63 °C. H
NMR (CDCl3, 400 MHz, ppm) δ: 1.40 (dd, CH3, J = 23.8 Hz, J = 6.3
Hz, H3′), 3.38 (m, CH2, H1′), 4.86 (dm, CHF, J = 49.2 Hz, H2′), 5.06
(broad s, NH), 6.55 (d, 2CH, J = 9.2 Hz, H2 and H6), 8.03 (d, 2CH, J
= 9.2 Hz, H3 and H5). 13C NMR (CDCl3, 100 MHz, ppm) δ: 18.4 (d,
CH3, J = 22 Hz, C3′), 48.4 (d, CH2, J = 21 Hz, C1′), 89.2 (d, CHF, J =
168 Hz, C2′), 111.3 (2CH, C2 and C6), 126.4 (2CH, C3 and C5), 138.0
(C4), 153.4 (C1). 19F{1H} NMR (CDCl3, 376 MHz, ppm) δ: −179.2.
MS (IES+, ACN): m/z 199 [M + H]+. HRMS (ESI, CH3OH/CH2Cl2:
90/10): calcd for C9H11FN2O2 [M + Na]+ 221.07023, found
221.0704.
1,2,3,4-Tetrahydroquinoline (4a). 1H NMR (CDCl3, 400 MHz,
ppm) δ: 1.96 (m, CH2, H3), 2.78 (t, CH2, J = 6.4 Hz, H4), 3.31 (t,
CH2, J = 5.4 Hz, H2), 3.56 (broad s, NH, H1), 6.49 (d, CH, J = 7.9 Hz,
H8), 6.63, (dt, CH, J = 7.4 Hz, J = 1.1 Hz, H6), 6.98 (m, 2CH, H5, H7).
13C NMR (CDCl3, 100 MHz, ppm) δ: 22.3 (CH2, C3), 27.1 (CH2,
C4), 42.1 (CH2, C2), 114.4 (CH, C8), 117.1 (CH, C6), 121.6 (C10),
126.8 (CH, C7), 129.6 (CH, C5), 144.8 (C9). MS (IES+, ACN): m/z
134 [M + H]+. Already described in ref 39.
N-(3-Fluoropropyl)-4-nitroaniline (3i). To a mixture of HF/SbF5
(3 mL, SbF5 12.5 mol %) maintained at 0 °C was added 173 mg of N-
allylaniline 1i (0.97 mmol). The mixture was magnetically stirred at
the same temperature during 10 min. The reaction mixture was then
neutralized with water−ice−Na2CO3 and extracted with ethyl acetate
(×3). The combined organic phases were dried (MgSO4) and
concentrated in vacuo. The reaction crude was purified with the eluent
pentane/ethyl acetate 75/25, thereby obtaining compound 2i (151
mg, 79%) and 3i as a yellow solid (11 mg, 6%) as a yellow solid. Mp:
42−43 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ: 2.05 (dm, CH2, J =
28.3 Hz, H2′), 3.42 (dt, CH2, J = 6.6 Hz, J = 5.8 Hz, H1′), 4.61 (dt,
CH2, J = 41.7 Hz, J = 5.4 Hz, H3′), 4.65 (broad s, NH), 6.55 (d, 2CH, J
= 9.2 Hz, H2 and H6), 8.09 (d, 2CH, J = 9.2 Hz, H3 and H5). 13C
NMR (CDCl3, 100 MHz, ppm) δ: 30.0 (d, CH2, J = 20 Hz, C2′), 40.4
(d, CH2, J = 4 Hz, C1′), 82.2 (d, CH2F, J = 173 Hz, C3′), 111.2 (2CH,
C2 and C6), 126.6 (2CH, C3 and C5), 138.4 (C4), 153.2 (C1). 19F{1H}
NMR (MeOD, 376 MHz, ppm) δ: −219.9. MS (IES+, ACN): m/z
199 [M + H]+. HRMS (ESI, CH3OH): calcd for C9H11FN2O2 [M +
Na]+ 221.07023, found 221.0703.
1
3-Methylindoline (5a). H NMR (CDCl3, 400 MHz, ppm) δ: 1.34
(d, CH3, J = 6.8 Hz), 3.12 (t, 1H, J = 8.6 Hz, H2), 3.38 (m, CH, H3),
3.51 (broad s, NH, H1), 3.71 (t, 1H, J = 8.6 Hz, H2), 6.66 (d, CH, J =
7.8 Hz, H7), 6.75 (td, CH, J = 7.4 Hz, J = 1.0 Hz, H5), 7.04 (tm, CH, J
= 7.7 Hz, H6), 7.10 (d, CH, J = 7.3 Hz, H4). 13C NMR (CDCl3, 100
MHz, ppm) δ: 18.7 (CH3), 36.8 (CH, C3), 55.6 (CH2, C2), 109.6
(CH, C7), 118.8 (CH, C5), 123.5 (CH, C4), 128.2 (CH, C6), 134.5
(C9), 151.3 (C8). MS (IES+, ACN): m/z 134 [M + Na]+. Already
described in ref 39.
Formation of Compounds 4b and 5b. These compounds were
obtained from substrate 1b (137 mg, 0.93 mmol) following the general
procedure (reaction time 10 min). The reaction crude was purified
with the eluent petroleum ether/ethyl acetate 98/2, compound 5b (63
mg, 46%, brown oil) first eluted followed by compound 4b (19 mg,
14%, brown oil).
6-Methyl-1,2,3,4-tetrahydroquinoline (4b). 1H NMR (CDCl3, 400
MHz, ppm) δ: 1.97 (m, CH2, H3), 2.25 (s, CH3, H1′), 2.78 (t, CH2, J =
6.3 Hz, H4), 3.31 (m, CH2, H2), 3.59 (m, NH, H1), 6.45 (d, CH, J =
4468
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8.6 Hz, H8), 6.83 (m, 2CH, H5, H7). 13C NMR (CDCl3, 100 MHz,
ppm) δ: 20.5 (CH3, C1′), 22.5 (CH2, C3), 27.0 (CH2, C4), 42.3 (CH2,
C2), 114.6 (CH, C8), 121.7 (C10), 126.3 (C6), 127.3 (CH, C7), 130.2
(CH, C5), 142.5 (C9). MS (IES+, ACN): m/z 148 [M + H]+. Already
described in ref 40.
with the eluent pentane/ethyl acetate 98/1, thereby obtaining
compound 4e (52 mg, 32%) as a brown solid. Mp: 35−38 °C. H
1
NMR (CDCl3, 400 MHz, ppm) δ: 1.94 (m, CH2, H3), 2.77 (t, CH2, J
= 6.5 Hz, H4), 3.26 (t, CH2, J = 5.4 Hz, H2), 3.56 (broad s, NH, H1),
3.74 (s, CH3, H1′), 6.46 (d, CH, J = 8.5 Hz, H8), 6.58 (d, CH, J = 2.7
Hz, H5), 6.62 (dd, CH, J = 8.5 Hz, J = 2.9 Hz, H7). 13C NMR (CDCl3,
100 MHz, ppm) δ: 22.5 (CH2, C3), 27.2 (CH2, C4), 42.4 (CH2, C2),
55.9 (CH3, C1′), 112.9 (CH, C7), 114.9 (CH, C5), 115.6 (CH, C8),
122.9 (C10), 138.9 (C9), 151.9 (C6). MS (IES+, ACN): m/z 164 [M +
H]+. Already described in ref 42.
1
3,5-Dimethylindoline (5b). H NMR (CDCl3, 400 MHz, ppm) δ:
1.36 (d, CH3, J = 6.8 Hz, H1′), 2.33 (s, CH3, H1″), 3.13 (t, CH, J = 8.6
Hz, H3), 3.38 (m, 1H, H2), 3.55 (s, NH, H1), 3.72 (t, 1H, J = 8.6 Hz,
H2), 6.61 (d, CH, J = 7.8 Hz, H7), 6.89 (d, CH, J = 7.8 Hz, H6), 6.97
(s, CH, H4). 13C NMR (CDCl3, 100 MHz, ppm) δ: 18.6 (CH3, C1′),
20.9 (CH3, C1″), 36.8 (CH, C3), 55.8 (CH2, C2), 109.6 (CH, C7),
124.2 (CH, C6), 127.7 (CH, C4), 128.2 (C5), 134.8 (C9), 148.9 (C8).
MS (IES+, ACN): m/z 148 [M + H]+, m/z 189 [M + Na]+. HRMS
(ESI, CH3OH): calcd for C10H13N [M + H]+ 148.11262, found
148.1126.
Formation of Compounds 4c and 5c. These compounds were
obtained from substrate 1c (212 mg, 1.05 mmol) following the general
procedure (reaction time 30 min). The reaction crude was purified
with the eluent pentane/dichloromethane 92/8, compound 5c (11 mg,
5%, brown oil) first eluted followed by compound 4c (82 mg, 39%,
brown oil).
1,2,3,4-Tetrahydroquinoline-6-sulfonamide (4h). This compound
was obtained from substrate 1h (107 mg, 0.5 mmol) following the
general procedure (2 mL of HF/SbF5 mixture, reaction time 60 min).
The reaction crude was purified with the eluent petroleum ether/ethyl
acetate 25/75, thereby obtaining compound 4h (98 mg, 92%) as a
white solid. Mp: 141−143 °C. 1H NMR (CD3OD, 400 MHz, ppm) δ:
1.88 (m, CH2, H3), 2.74 (t, CH2, J = 6.3 Hz, H4), 3.30 (m, CH2, H2),
6.47 (d, CH, J = 9.1 Hz, H8), 7.39 (m, 2CH, H5, H7). 13C NMR
(CD3OD, 100 MHz, ppm) δ: 22.3 (CH2, C3), 28.2 (CH2, C4), 42.2
(CH2, C2), 113.4 (CH, C8), 121.0 (C10), 126.5 (CH, C7), 128.5 (CH,
C5), 129.5 (C6), 150.2 (C9). MS (IES+, ACN): m/z 235 [M + Na]+,
235 [M + Na]+. HRMS (ESI, CH3OH): calcd for C9H12N2SO2 [M +
Na]+ 235.05172, found 235.0516.
6-(Trifluoromethyl)-1,2,3,4-tetrahydroquinoline (4c). 1H NMR
(CDCl3, 400 MHz, ppm) δ: 1.94 (m, CH2, H3), 2.78 (t, CH2, J =
6.3 Hz, H4), 3.34 (t, CH2, J = 5.4 Hz, H2), 4.15 (broad s, NH, H1),
6.44 (d, CH, J = 9.0 Hz, H8), 7.19 (m, 2CH, H7, H5). 13C NMR
(CDCl3, 100 MHz, ppm) δ: 21.5 (CH2, C3), 27.1 (CH2, C4), 41.8
(CH2, C2), 113.1 (CH, C8), 118.1 (q, J = 32 Hz, C6), 120.7 (C10),
124.1 (q, CH, J = 4 Hz, C7), 125.3 (q, J = 270 Hz, CF3), 126.6 (q, CH,
J = 4 Hz, C5), 147.5 (C9). 19F{1H} NMR (CDCl3, 376 MHz, ppm) δ:
−60.80 (CF3). MS (IES+, ACN): m/z 202 [M + H]+. HRMS (ESI,
CH3OH): calcd for C10H10NF3 [M + H]+ 202.08436, found 202.0846.
6-Nitro-1,2,3,4-tetrahydroquinoline (4i). This compound was
obtained from substrate 1i (155 mg, 0.87 mmol) following the
general procedure (reaction time 24 h). The reaction crude was
purified with the eluent pentane/ethyl acetate: 85/15, thereby
obtaining compound 4i (139 mg, 85%) as a yellow solid. Mp: 160−
1
162 °C. H NMR (CDCl3, 400 MHz, ppm) δ: 1.95 (m, CH2, H3),
2.79 (t, CH2, J = 6.3 Hz, H4), 3.41 (m, CH2, H2), 4.72 (broad s, NH,
H1), 6.36 (d, CH, J = 9.5 Hz, H8), 7.88 (m, 2CH, H7, H5). 13C NMR
(CDCl3, 100 MHz, ppm) δ: 20.9 (CH2, C3), 27.0 (CH2, C4), 41.9
(CH2, C2), 112.3 (CH, C8), 120.0 (C10), 124.4 (CH, C7), 126.1 (CH,
C5), 137.4 (C6), 150.5 (C9). MS (IES+, ACN): m/z 179 [M + H]+,
201 [M + Na]+. Already described in ref 35b.
1
3-Methyl-5-(trifluoromethyl)indoline (5c). H NMR (CDCl3, 400
MHz, ppm) δ: 1.34 (d, CH3, J = 6.8 Hz), 3.20 (t, 1H, J = 8.5 Hz, H2),
3.39 (m, CH, H3), 3.78 (t, 1H, J = 8.8 Hz, H2), 3.95 (broad s, NH,
H1), 6.60 (d, CH, J = 8.7 Hz, H7), 7.27 (m, 2CH, J = 6.1 Hz, H4, H6).
13C NMR (CDCl3, 100 MHz, ppm) δ: 18.9 (CH3), 36.3 (CH, C3),
55.5 (CH2, C2), 108.1 (CH, C7), 120.3 (q, J = 32 Hz, C5), 120.6 (q,
2CH, J = 4 Hz, C4 or C6), 125.3 (q, J = 271 Hz, CF3), 125.4 (q, 2CH, J
= 4 Hz, C4 or C6), 134.5 (C9), 154.2 (C8). 19F{1H} NMR (CDCl3,
376 MHz, ppm) δ: −60.67 (CF3). MS (IES+, ACN): m/z 202 [M +
H]+. HRMS (ESI, CH3OH): calcd for C10H10NF3 [M + H]+
202.08436, found 202.0846.
Formation of Compounds 4j and 4j′. These compounds were
obtained from substrate 1i (178 mg, 1 mmol) following the general
procedure (reaction time 24 h). The reaction crude was purified with
the eluent pentane/CH2Cl2 70/30 up to 60/40, thereby obtaining
compound 4j (116 mg, 66%, orange solid, mp 62−64 °C) followed by
4j′ (20 mg, 10%, orange solid, mp 80−82 °C).
7-Nitro-1,2,3,4-tetrahydroquinoline (4j). 1H NMR (CDCl3, 400
MHz, ppm) δ: 1.93 (td, CH2, J = 6.4 Hz, J = 11.6 Hz, H3), 2.79 (t,
CH2, J = 6.4 Hz, H4), 3.33 (t, CH2, J = 5.6 Hz, H2), 4.21 (broad s, NH,
1), 7.00 (d, CH, J = 8.2 Hz, H5), 7.25 (d, CH, J = 2.3 Hz, H8), 7.37
(dd, CH, J = 2.3 Hz, J = 8.2 Hz, H6).13C NMR (CDCl3, 100 MHz,
ppm) δ: 21.1 (CH2, C3), 27.3 (CH2, C4), 41.6 (CH2, C2), 107.8 (CH,
C8), 111.3 (CH, C6), 128.4 (C10), 129.8 (CH, C5), 145.3 (C9), 147.3
(C7). MS (IES+, ACN): m/z 179.08 [M + H]+. Already described in
ref 35b.
Formation of Compounds 4d and 5d. These compounds were
obtained from substrate 1d (189 mg, 1 mmol) following the general
procedure (reaction time 10 min). The reaction crude was purified
with the eluent petroleum ether/ethyl acetate: 50/50, compound 5d
(33 mg, 17%) first eluted followed by compound 4d (135 mg, 72%).
N-(1,2,3,4-Tetrahydroquinolin-6-yl)acetamide (4d). 1H NMR
(CD3OD, 400 MHz, ppm) δ: 1.84 (m, CH2, H3′), 2.04 (s, CH3,
H2), 2.66 (t, CH2, J = 6.4 Hz, H4′), 3.16 (m, CH2, H2′), 6.43 (d, CH, J
= 8.4 Hz, H8′), 7.01 (dd, CH, J = 8.5 Hz, J = 2.2 Hz, H7′), 7.03 (m,
CH, H5′). 13C NMR (CD3OD, 100 MHz, ppm) δ: 23.2 (CH2, C3),
23.5 (CH3, C3′), 28.0 (CH2, C4), 42.8 (CH2, C2), 115.7 (CH, C8),
121.0 (CH, C7), 122.9 (C10), 123.3 (CH, C5), 129.4 (C6), 143.5 (C9),
171.1 (C2′). MS (IES+, ACN): m/z 191 [M + H]+, 213 [M + Na]+.
Already described in ref 41.
5-Nitro-1,2,3,4-tetrahydroquinoline (4j). 1H NMR (CDCl3, 400
MHz, ppm) δ: 1.92 (m, CH2, H3), 2.93 (t, CH2, J = 6.5 Hz, H4), 3.32
(t, CH2, J = 5.6 Hz, H2), 6.66 (dd, CH, J = 1.1 Hz, J = 8.0 Hz, H8),
7.03 (t, CH, J = 8.0 Hz, H7), 7.13 (dd, CH, J = 1.2 Hz, J = 8.0 Hz, H6).
13C NMR (CDCl3, 100 MHz, ppm) δ: 21.2 (CH2, C3), 24.1 (CH2,
C4), 41.2 (CH2, C2), 112.7 (CH, C6), 115.5 (C6), 118.3 (CH, C8),
126.8 (CH, C7), 146.0 (C9), 150.7 (C5). MS (IES+, ACN): m/z
179.24 [M + H]+. Already described in ref 35b.
8-Methyl-6-nitro-1,2,3,4-tetrahydroquinoline (4k). This com-
pound was obtained from substrate 1k (96 mg, 0.5 mmol) following
the general procedure (2 mL of HF/SbF5 mixture, reaction time 8 h).
The reaction crude was purified with the eluent petroleum ether/ethyl
acetate 83/17, thereby obtaining compound 4k (81 mg, 84%) as an
orange solid. Mp: 143−145 °C. 1H NMR (CDCl3, 400 MHz, ppm) δ:
1.95 (m, CH2, H3), 2.11 (s, CH3, H1′), 2.81 (t, CH2, J = 6.3 Hz, H4),
3.48 (m, CH2, H2), 4.53 (broad s, NH, H1), 7.78 (d, CH, J = 2.1 Hz,
H5), 7.81 (d, CH, J = 2.1 Hz, H7). 13C NMR (CDCl3, 100 MHz, ppm)
δ: 17.1 (CH3, C1′), 21.0 (CH2, C3), 27.3 (CH2, C4), 42.2 (CH2, C2),
119.4 (C10 or C8), 119.6 (C10 or C8), 124.1 (CH, C5), 124.6 (CH, C7),
136.6 (C6), 148.7 (C9). MS (IES+, ACN): m/z 193 [M + H]+. HRMS
1
N-(3-Methylindolin-5-yl)acetamide (5d). H NMR (CD3OD, 400
MHz, ppm) δ: 1.29 (d, CH3, J = 6.8 Hz, H1″), 2.08 (s, CH3, H2), 3.02
(t, 1H, J = 8.7 Hz, H2′), 3.30 (m, CH, H3′), 3.61 (t, 1H, J = 8.7 Hz,
H2′), 6.62 (d, CH, J = 8.3 Hz, H7′), 7.08 (ddd, CH, J = 8.3 Hz, J = 2.1
Hz, J = 0.7 Hz, H6′), 7.27 (dd, CH, J = 1.7 Hz, J = 1.1 Hz, H4′). 13C
NMR (CD3OD, 100 MHz, ppm) δ: 18.9 (CH3, C1″), 23.5 (CH3, C2),
38.2 (CH, C3′), 56.4 (CH2, C2′), 111.3 (CH, C7′), 118.0 (CH, C4′),
121.4 (CH, C6′), 131.9 (C5′), 136.8 (C9′), 149.4 (C8′), 171.3 (C1). MS
(IES+, ACN): m/z 191 [M + H]+, 213 [M + Na]+. HRMS (ESI,
CH3OH): calcd for C11H14N2O [M + H]+ 191.11844, found
191.1183.
6-Methoxy-1,2,3,4-tetrahydroquinoline (4e). This compound was
obtained from substrate 1e (165 mg, 1 mmol) following the general
procedure (reaction time 30 min). The reaction crude was purified
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(ESI, CH3OH): calcd for C10H12N2O2 [M + Na]+ 215.07965, found
215.0799.
pressure. The reaction crude was purified by using automatic flash
chromatography with dichloromethane/methanol 97/3 as eluant to
1
4.4. Nitrojulolidine Synthesis. 1-Allyl-1,2,3,4-tetrahydro-6-
nitroquinoline (6). Twelve mg of sodium hydride were introduced
into a mixture of 59 mg of the compound 4i dissolved with 3 mL of
DMF at 0 °C. After 15 min, 70 μL of the allyl bromide was added.
After 3 days, 20 mL of ethanol was introduced. The solvent was then
evaporated under reduced pressure. The residue was taken up in water,
and the solution was extracted three times with ethyl acetate. The
organic layers were combined and dried with anhydrous magnesium
sulfate, and the solvent was evaporated. The reaction crude was
purified by flash chromatography using the eluent petroleum ether/
ethyl acetate 92/8, obtaining the compound 6 (73 mg, 98%) as an
afford compound 9 (450 mg, 79%) as a yellow oil. H NMR (CDCl3,
400 MHz, ppm) δ: 1.88 (m, CH2, H3), 2.14 (broad s, CH3), 2.56
(broad s, CH2, H4), 3.64 (broad s, NH2), 3.74 (broad s, CH2, H2),
6.48 (m, 2CH, H5 and H7), 6.83 (d, CH, J = 7.1 Hz, 85% H8), 7.59
(broad s, CH, 15% H8). 13C NMR (CDCl3, 100 MHz, ppm) δ: 22.9
(CH3), 24.1 (CH2, C3), 26.9 (CH2, C4), 42.5 (CH2, C2), 112.7 (CH,
C7), 114.4 (CH, C5), 125.5 (CH, C8), 130.8 (C8 ou C10), 135.2 (C8 ou
C10), 144.2 (C6), 170.2 (CO). MS (IES+, ACN): m/z 191 [M + H]+.
HRMS (ESI, CH3OH): calcd for C11H14N2O M + Na]+ 213.10038,
found 213.1004.
tert-Butyl 1-Acetyl-1,2,3,4-tetrahydroquinolin-6-ylcarbamate
(10). Compound 9 (250 mg, 1.32 mmol), 288 mg of tert-butyl
dicarbonate, and 16 mg of DMAP were dissolved with 6 mL of THF.
After 3 days at room temperature, the solvent was evaporated under
reduced pressure. The reaction crude was purified with the eluent
dichloromethane/MeOH/NH3 98.5/1.5, thereby obtaining compound
10 (283 mg, 74%) as a solid. Mp: 126−129 °C. There was a splitting
of the signals for carbons number 5 and 7 and the carbonyl carbon of
the tert-butylcarbamate and acetyl group in 13C NMR spectrum,
characteristic of the presence of two conformers. In addition, some
1
orange solid. Mp: 47−48 °C. H NMR (CDCl3, 400 MHz, ppm) δ:
1.97 (m, CH2, H3), 2.78 (t, CH2, J = 6.0 Hz, H4), 3.40 (m, CH2, H2),
3.96 (m, CH2, J = 1.7 Hz, J = 4.5 Hz, H1′), 5.13 (d, 1H, J = 17.1 Hz,
H3′), 5.20 (d, 1H, J = 10.4 Hz, H3′), 5.80 (m, CH, H2′), 6.42 (dm, CH,
J = 9.2 Hz, H8), 7.83 (s, CH, H5), 7.91 (dm, 1H, J = 9.2 Hz, H7). 13
C
NMR (CDCl3, 100 MHz, ppm) δ: 21.5 (CH2, C3), 28.0 (CH2, C4),
49.6 (CH2, C2), 53.7 (CH2, C1′), 109.3 (CH, C8), 116.7 (CH2, C3′),
121.5 (C10), 124.7, 125.0 (2CH, C5 and C7), 131.3 (CH, C2′), 136.5
(C6), 150.6 (C9). MS (IES+, ACN): m/z 219 [M + H]+. HRMS (ESI,
CH3OH): calcd for C12H14N2O2 [M + H]+ 219.1134, found 219.1131.
9-Nitrojulolidine (7). To a mixture of HF/SbF5 (1 mL, SbF5 21.6
mol %) maintained at 0 °C was added 60 mg of compound 6 (0.275
mmol). The solution was then kept at 0 °C for 24 h. The reaction
mixture was then neutralized with water−ice−Na2CO3 and extracted
with ethyl acetate (×3). The combined organic phases were dried
(MgSO4) and concentrated in vacuo. The reaction crude was purified
by flash chromatography using the eluent dichloromethane/methanol:
90/10, obtaining the compound 7 (47 mg, 78%) as an orange solid.
1
signals were output as broad singlet. H NMR (CDCl3, 400 MHz,
ppm) δ: 1.49 (s, 3CH3, Boc), 1.90 (m, CH2, H3), 2.18 (s, CH3, Ac),
2.66 (m, CH2, H4), 3.74 (m, CH2, H2), 6.79 (broad s, CH and NH),
6.97 (broad s, CH, H8), 7.08 (broad s, CH, H7), 7.31 (broad s, CH,
H5). 13C NMR (CDCl3, 100 MHz, ppm) δ: 23.1 (CH3, Ac), 24.0
(CH2, C3), 27.1 (CH2, C4), 28.4 (3CH3, Boc), 42.7 (CH2, C2), 80.6
(CIV, Boc), 116.3, 116.4 (CH, C7), 118.3, 118.4 (CH, C5), 125.0, (CH,
C8), 134.5 (broad s, CIV), 135.8 (broad s, CIV), 152.9, 153.0 (CO,
Boc), 170.2 (CO, Ac). MS (IES+, ACN): m/z 313 [M + Na]+. HRMS
(ESI, CH3OH): calcd for C16H22N2O3 [M + Na]+ 313.15281, found
313.1528.
1
Mp: 141−143 °C. H NMR (CDCl3, 400 MHz, ppm) δ: 1.95 (tt,
2CH2, J = 6.1 Hz, J = 6.1 Hz, H2 and H6), 2.74 (t, 2CH2, J = 6.3 Hz,
H1 and H7), 3.31 (t, 2CH2, J = 6.0 Hz, H3 and H5), 7.69 (s, 2CH, H8
and H10). 13C NMR (CDCl3, 100 MHz, ppm) δ: 21.1 (2CH2, C2 and
C6), 27.8 (2CH2, C1 and C7), 50.2 (2CH2, C3 and C5), 120.0 (C11 and
C13), 123.7 (2CH, C8 and C10), 135.3 (C9), 148.1 (C12). MS (IES+,
ACN): m/z 219 [M + H]+. HRMS (ESI, CH3OH): calcd for
C12H14N2O2 [M + H]+ 219.1134, found 219.1132.
tert-Butyl 1-Acetyl-1,2,3,4-tetrahydroquinolin-6-ylallylcarbamate
(11). 15 mg of sodium hydride (60% in oil, 0.368 mmol) was
introduced slowly into a solution of 89 mg of compound 10 (1.2 equiv,
0.307 mmol) dissolved in 4 mL of THF. Then, 40 μL of allyl bromide
(1.5 equiv, 0.461 mmol) was added. The reaction mixture with
magnetic stirring was then heated to 40 °C for 24 h. This was
hydrolyzed with a saturated aqueous solution of ammonium chloride.
The solution was extracted three times with ethyl acetate. The organic
phases were combined and dried with anhydrous magnesium sulfate,
and the solvent was evaporated under reduced pressure. The reaction
crude was purified with the eluent petroleum ether/ethyl acetate 60/
4.5. N-Acetyl-1,5-diazaoctahydroanthracene and N-Acetyl-
4,5-diazaoctahydroanthracene. 1-(1,2,3,4-Tetrahydro-6-
nitroquinolinyl)ethanone (8). Sodium hydride (60% in oil, 175 mg,
3.38 mmol) was added slowly into a solution of 600 mg of the
compound 4i (3.38 mmol) dissolved in 70 mL of dichloromethane
under nitrogen atmosphere. After 30 min under magnetic stirring, 310
μL of acetyl chloride (1.3 equiv, 4.38 mmol) was added. The reaction
mixture was then heated to 30 °C. After 2 days at the same
temperature, the reaction mixture was hydrolyzed with a saturated
solution of ammonium chloride. The solution was extracted three
times with dichloromethane. The organic phases were combined and
dried with anhydrous magnesium sulfate, and the solvent was
evaporated under reduced pressure. The reaction crude was purified
by flash chromatography using petroleum ether/ethyl acetate 70/30 as
eluent, obtaining the compound 8 (678 mg, 91%) as a yellow solid.
1
40, thereby obtaining compound 11 (96 mg, 95%) as a yellow oil. H
NMR (CDCl3, 400 MHz, ppm) δ: 1.44 (3CH3, Boc), 1.92 (m, CH2,
H3), 2.20 (s, CH3, Ac), 2.68 (t, CH2, J = 5.7 Hz, H4), 3.75 (t, CH2, J =
5.7 Hz, H2), 4.17 (d, CH2, J = 5.1 Hz, H1′), 5.13 (s, 1H, J = 9.3 Hz,
H3′), 5.14 (d, 1H, J = 18.1 Hz, H3′), 5.89 (ddt, CH, J = 15.9 Hz, J =
10.6 Hz, J = 5.4 Hz, H2′), 7.03 (broad s, 3CH, H5, H7 and H8). 13C
NMR (CDCl3, 100 MHz, ppm) δ: 23.3 (CH3, Ac), 23.9 (CH2, H3),
27.1 (CH2, H4), 28.4 (3CH3, Boc), 42.9 (broad s, CH2, H2), 53.0
(CH2, H1′), 80.6 (CIV, Boc), 116.4 (CH2, H3′), 123.9 (CHar), 124.7
(CHar), 126.1 (s CHar), 133.7 (broad s, Car), 134.4 (CH2, H2), 136.8
(broad s, Car), 139.8 (broad s, Car), 154.6 (CO, Boc), 170.1 (CO, Ac).
MS (IES+, ACN): m/z 353 [M + Na]+. HRMS (ESI, CH3OH): calcd
for C19H26N2O3 [M + Na]+ 353.18411, found 353.1841.
1
Mp: 66−68 °C. H NMR (CDCl3, 400 MHz, ppm) δ: 2.02 (m, CH2,
H3), 2.31 (s, CH3), 2.85 (dd, CH2, J = 6.6 Hz, J = 6.6 Hz, H4), 3.80 (t,
CH2, J = 6.3 Hz, H2), 7.64 (d, CH, J = 6.9 Hz, H8), 8.04 (m, 2CH, H5
and H7). 13C NMR (CDCl3, 100 MHz, ppm) δ: 23.5 (CH2, H3), 23.9
(CH3), 27.5 (CH2, H4), 45.1 (CH2, H2), 121.8 (CH, C7), 124.1 (CH,
C5), 124.8 (CH, C8), 132.5 (C10), 143.9 (C6 or C9), 144.6 (C6 or C9),
170.4 (CO). MS (IES+, ACN): m/z 221 [M + H]+. Already described
in ref 35b.
1-(6-(Allylamino)-1,2,3,4-tetrahydroquinolin-yl)ethanone (12). 4
mL of trifluoroacetic acid was introduced into a solution of 184 mg of
compound 11 (0.558 mmol) dissolved with 4 mL of dichloromethane.
After 1 h under magnetic stirring at room temperature, the reaction
mixture was hydrolyzed with a mixture of water and sodium carbonate.
The solution was extracted three times with ethyl acetate. The organic
phases were combined and dried with anhydrous magnesium sulfate,
and the solvent was evaporated under reduced pressure. The reaction
crude was purified with the eluent pentane/dichloromethane 98.5/1.5,
thereby obtaining compound 12 (115 mg, 90%) as an orange oil.
There were two signals for hydrogen number 8 in the 1H NMR
1-(6-Amino-1,2,3,4-tetrahydroquinolin)ethanone (9). Compound
8 (656 mg, 2.98 mmol) followed by 3.36 g of stannyl chloride (5
equiv, 14.9 mmol) were dissolved in 86 mL of ethanol. After being
stirred and heated (70 °C) for 22 h, the crude mixture was cooled to
room temperature. Then, 170 mL of aqueous NaHCO3 (5 mol %) was
added, and the solution was extracted three times with ethyl acetate.
The organic phases were combined and dried with anhydrous
magnesium sulfate, and the solvent was evaporated under reduced
1
spectrum, characteristic of the presence of two conformers. H NMR
(CDCl3, 400 MHz, ppm) δ: 1.88 (m, CH2, H3), 2.15 (s, CH3, Ac),
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2.58 (m, CH2, H4), 3.74 (d, CH2, J = 5.1 Hz, H1′ and CH2, H2), 3.86
(broad s, NH), 5.15 (d, 1H, J = 10.2 Hz, H3′), 5.26 (d, 1H, J = 17.2
Hz, H3′), 5.93 (ddt, 1H, J = 16.7 Hz, J = 10.4 Hz, J = 5.3 Hz, H2′), 6.40
(s, CH, H5), 6.43 (dd, CH, J = 8.5 Hz, J = 2.6 Hz, H7), 6.86 (d, CH, J
= 7.5 Hz, 0.89 H, H8), 7.63 (s, CH, 0.11 H, H8). 13C NMR (CDCl3,
100 MHz, ppm) δ: 23.0 (CH3, Ac), 24.2 (CH2, C3), 27.2 (CH2, C4),
42.5 (CH2, C2), 46.9 (CH2, C1′), 110.8 (CH, C7), 112.3 (CH, C5),
116.6 (CH2, C3′), 125.5 (CH, C8), 130.2 (C10), 135.3 (CH, C2′), 145.8
(C6), 170.2 (CO). MS (IES+, ACN): m/z 231 [M + H]+. HRMS
(ESI, CH3OH): calcd for C14H18N2O [M + Na]+ 253.13168, found
253.1316.
ASSOCIATED CONTENT
■
S
* Supporting Information
1
Copies of H and 13C NMR spectra. This material is available
free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: sebastien.thibaudeau@univ-poitiers.fr. Tel: (+) 33-
549454588. Fax: (+) 33-549453501.
■
Notes
Formation of Compounds 13 and 14. To a mixture of HF/SbF5
(4 mL, SbF5 21.6 mol %) maintained at −50 °C was added 59 mg of
compound 12 (0.256 mmol). The solution was then kept at 0 °C for
10 min. The reaction mixture was then neutralized with water−ice−
Na2CO3 and extracted with ethyl acetate (×3). The combined organic
phases were dried (MgSO4) and concentrated in vacuo. The reaction
crude was purified with the eluent pentane/dichloromethane: 99/1,
compound 13 (21 mg, 36%, light oil) first eluted followed by
compound 14 (12 mg, 21%, light oil).
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the CNRS, the University of Poitiers,
and the Region Poitou-Charentes is gratefully acknowledged.
■
REFERENCES
■
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N-Acetyl-1.5-diazaoctahydroanthracene (13). H NMR (CDCl3,
400 MHz, ppm) δ: 1.89 (m, CH2, H3), 1.95 (m, CH2, H3′), 2.19 (s,
CH3, Ac), 2.55 (broad s, CH2, H4), 2.74 (t, CH2, J = 6.3 Hz, H4′), 3.30
(t, CH2, J = 5.4 Hz, H2′), 3.73 (broad s, CH2, H2), 6.33 (s, CH, H5),
6.67 (broad s, CH2, H8). 13C NMR (CDCl3, 100 MHz, ppm) δ: 22.3
(CH2, C3′), 23.0 (CH3, Ac), 24.2 (CH2, C3), 26.7 (CH2, C4), 26.9
(CH2, C4′), 42.1 (CH2, C2′), 42.6 (CH2, C2), 113.4 (CH, C5), 119.5
(C7), 125.6 (CH, C8), 129.9 (C9), 132.9 (C10), 142.4 (C6), 170.2
(CO). MS (IES+, ACN): m/z 231 [M + H]+. HRMS (ESI, CH3OH):
calcd for C14H18N2O [M + Na]+ 253.13168, found 253.1315.
N-Acetyl-4.5-diazaoctahydrophenanthrene (14). 1H NMR
(CDCl3, 400 MHz, ppm) δ: 1.93 (m, CH2, H9), 2.00 (m, CH2, H2),
2.17 (s, CH3, Ac), 2.56 (t, CH2, J = 6.7 Hz, H10), 2.62 (t, CH2, J = 6.1
Hz, H1), 3.27 (t, CH2, J = 4.6 Hz, H3), 3.76 (broad s, CH2, H8), 6.43
(d, CH, J = 7.7 Hz, H5), 6.74 (s, CH, H6). 13C NMR (CDCl3, 100
MHz, ppm) δ: 22.1 (CH2, C2), 23.1 (CH3, Ac), 23.6 (CH2, C10), 23.7
(CH2, C1), 23.9 (CH2, C9), 41.6 (CH2, C3), 42.1 (CH2, C8), 113.1
(CH, C5), 120.6 (C11), 123.4 (CH, C6), 127.5 (CH, C6), 131.3 (C14),
142.5 (C12), 170.2 (CO). MS (IES+, ACN): m/z 231 [M + H]+.
HRMS (ESI, CH3OH): calcd for C14H18N2O [M + Na]+ 253.13168,
found 253.1318.
́ ́
14, 1851−1862. (c) Urbina, J. M.; Cortes, J. C. G.; Palma, A.; Lopez, S.
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X.; You, S.-L. Synthesis 2009, 12, 2076−2082. (c) Yamashita, K.;
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Hallas, G.; Towns, A. D. Dyes Pigm 2000, 47, 33−43.
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1-(6-(2-Fluoropropylamino)-1,2,3,4-tetrahydroquinolin-yl)-
ethanone (15). To a mixture of HF/SbF5 (4 mL, SbF5 3.8 mol %)
maintained at −50 °C, was added 58 mg of compound 12 (0.252
mmol). The mixture was magnetically stirred at the same temperature
for 10 min. The reaction mixture was then neutralized with water−
ice−Na2CO3, extracted with ethyl acetate (×3). The combined organic
phases were dried (MgSO4) and concentrated in vacuo. Products were
isolated by column chromatography over silica gel. The reaction crude
was purified with the eluent pentane/dichloromethane 98.5/1.5,
thereby obtaining compound 15 (53 mg, 84%) as an orange oil. There
1
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were two signals for hydrogen number 8 in the H NMR spectrum,
1
characteristic of the presence of two conformers. H NMR (CDCl3,
400 MHz, ppm) δ: 1.39 (dd, CH3, J = 23.8 Hz, J = 6.2 Hz, H3′), 1.89
(m, CH2, H3), 2.15 (s, CH3, Ac), 2.59 (m, CH2, H4), 3.25 (m, CH2,
H2′), 3.74 (m, CH2, H2), 4.02 (broad s, NH), 4.86 (dm, CH, J = 49.4
Hz, H2′), 6.41 (broad s, CH, H5), 6.44 (dd, CH, J = 8.6 Hz, J = 2.5 Hz,
H7), 6.87 (d, CH, J = 5.9 Hz, 0.85 H, H8), 7.66 (s, CH, 0.15 H, H8).
13C NMR (CDCl3, 100 MHz, ppm) δ: 18.7 (d, CH3, J = 22 Hz, C3′),
22.9 (CH3, Ac), 24.1 (CH2, C3), 27.1 (CH2, C4), 42.5 (CH2, C2), 49.6
(d, CH2, J = 21 Hz, C1′), 89.4 (d, CHF, J = 167 Hz, C1′), 110.7 (CH,
C7), 112.2 (CH, C5), 125.5 (CH, C8), 130.4 (C9), 135.2 (C10), 145.6
(C6), 170.1 (CO, Ac). 19F{1H} NMR (CDCl3, 376 MHz, ppm) δ:
−179.79. MS (IES+, ACN): m/z 251 [M + H]+, 273 [M + Na]+.
HRMS (ESI, CH3OH): calcd for C14H19FN2O [M + H]+ 251.15597,
found 251.1562.
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