Iron-Catalysed Direct Aromatic Amination with N-Chloroamines

Article abstract of DOI:10.1002/ejoc.201900614

An optimized procedure for the direct intra- and intermolecular amination of aromatic C–H bonds with aminium radicals generated from N-chloroamines under iron catalysis is reported. A range of substituted tetrahydroquinolines could be readily prepared, while extension to the synthesis of benzomorpholines was more limited in scope. A direct one-pot variant was developed, allowing direct formal oxidative N–H/C–H coupling.

Full text of DOI:10.1002/ejoc.201900614

A Journal of
Accepted Article
Title: Iron-Catalysed Direct Aromatic Amination with N-Chloroamines
Authors: Gayle Douglas, Steven Raw, and Stephen Marsden
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900614
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900614
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201900614
FULL PAPER
Iron-Catalysed Direct Aromatic Amination with N-Chloroamines
[a]
[b]
[a]
Gayle E. Douglas, Steven A. Raw, and Stephen P. Marsden*
Abstract: An optimized procedure for the direct intra- and
practical homogeneous media for the amination reactions under
photolytic conditions,[5a,b] which allowed us to (i) explore the
structural and functional group tolerance of the reaction, (ii)
develop a one-pot protocol for the in situ activation and cyclisation
of free secondary amines to tertiary aryl amine products, and (iii)
to develop continuous flow variants capable of delivering gram
intermolecular amination of aromatic C-H bonds with aminium radicals
generated from N-chloroamines under iron catalysis is reported.
A
range of substituted tetrahydroquinolines could be readily prepared,
while extension to the synthesis of benzomorpholines was more
limited in scope. A direct one-pot variant was developed, allowing
direct formal oxidative N-H/C-H coupling.
quantities of products.[5b]
benzenes and benzazoles under photocatalysis using in situ
Direct amination of substituted
[
4b]
generated N-chloroamines has also been reported by Leonori
and respectively. Although the
Xiao[5d]
Introduction
photochemical/photocatalysed reactions deliver excellent results,
the requirement for specialist equipment prompted us to re-
Aryl amines are common motifs in functional organic molecules
including pharmaceuticals, agrochemicals, dyes and polymers.[1]
Amongst the myriad methods for their synthesis, direct amination
of aromatic C-H bonds is an area of growing interest since it offers
synthetic efficiency compared with multi-step approaches from
e.g. nitro- or haloarenes. The use of electrophilic nitrogen-centred
radicals has been prominent amongst these approaches,[2] and
methods are available for the introduction of primary,[
investigate the application of metal-based catalysts as
a
complementary approach, with the aim that the organic media
would also allow for a one-pot direct arylation of secondary
amines. We report herein the outcome of these studies.
Results and Discussion
3]
secondary[4] or tertiary[5] amines, amides,
[6]
imides,
[7]
We began our studies by examining the intramolecular direct C-H
amination using N-chloroamine 1a as the substrate. Our starting
point was the use of an excess of strong organic acids in
dichloromethane (our optimized conditions for the photochemical
variant) in conjunction with 10 mol% of iron additives (Table 1).
The use of iron(II) sulfate heptahydrate in conjunction with TFA
and p-toluenesulfonic acid were unsuccessful (entries 1, 2)
returning only unreacted 1a, but the use of methanesulfonic acid
returned a 73% yield of tetrahydroquinoline 2a (entry 3). The
difference in reactivity between the p-toluenesulfonic and
methanesulfonic acids may be due to the limited solubility of the
former at the reaction concentration used (a heterogeneous
mixture was observed). The importance of both additives was
verified – omission of either acid or iron salt resulted in no
observable reaction (entries 4, 5). A range of iron salts and
complexes were screened (entries 6-11), but no improvement
was seen. Support for the role of the iron salt in mediating radical-
based processes (either through halide atom abstraction or SET)
rather than as a Lewis acid was seen in the differing outcomes
with iron(II) and iron(III) chlorides: the former led to efficient
cyclisation, the latter to unreacted starting material. In the case
of iron(II) acetate and iron(II) triflate, formation of the reduction
product (amine 3a) was the sole observable outcome. A range of
solvents were also screened, but dichloromethane remained
optimum: some cyclisation was seen in toluene (entry 12) but
other solvents also favoured reduction to 3a, possibly arising
through hydride atom abstraction from the solvent itself. With the
combination of iron(II) sulfate and methanesulfonic acid identified
as optimal, an investigation of the effect of the stoichiometry of
both additives was undertaken (see Supporting Information for
[
8]
[7b,9]
phosphonamides and sulfonamides and their derivatives.
These methods generally require the (sometimes multistep)
synthesis of precursors to the nitrogen-centred radical, and
approaches which allow the one-pot formal oxidative coupling of
N-H and aryl C-H bonds are synthetically more attractive. This is
most commonly achieved by in situ activation of amine derivatives
bearing electron-withdrawing substituents,[7e,8,9a,c,e,h,i] and
examples facilitating direct transfer of simple aliphatic amines are
scarce: Nicewicz elegantly demonstrated direct photoredox-
catalysed union of primary amines with arenes to generate
secondary aryl amines.[4] The first reports of direct aromatic
amination by aminium radicals were described by Minisci[5e,h] and
Kompa,[5f,g] using N-chloroamines as the radical precursors under
both photochemical and metal-catalysed conditions.
The
reactions were carried out in strongly acidic aqueous media which
have limited scope for organic reactions and, more significantly,
preclude the in situ generation of the N-chloroamine radical
precursors. We recently revisited this chemistry and developed
[a]
Dr Gayle E. Douglas, Professor Stephen P. Marsden
School of Chemistry and Institute of Process Research and
Development
University of Leeds
Leeds LS2 9JT (UK)
E-mail: s.p.marsden@leeds.ac.uk
Homepage: physicalsciences.leeds.ac.uk/staff/190/professor-steve-
marsden
[b]
Dr Steven A. Raw
Pharmaceutical Development
AstraZeneca
Macclesfield SK10 3RN (UK)
Supporting information for this article is given via a link at the end of
the document.
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European Journal of Organic Chemistry
10.1002/ejoc.201900614
FULL PAPER
details), but the use of 10 mol% iron salt with 10 equivalents of
acid were the best performing conditions.
tetrahydroquinolines.[12]
Moderately
electron-donating
substituents such as para-methyl and meta,meta-dimethyl are
also tolerated (2k,l), but as in the photochemical variants,[
more electron-rich arenes such as substituted anisoles are
unsuccessful. The involvement of electrophilic aminating species
was verified by competition experiments between differentially-
substituted 3,3-diarylpropylamine substrates: cyclisation occurs
predominantly (2n) or exclusively (2o) on the more electron-rich
aromatic ring. This outcome matches previous observations in
the photochemically-mediated aminations,[5a,b] and is consistent
with the intermediacy of aminium radicals, potentially generated
by single-electron transfer from iron(II) species. Our previous
DFT work supports amination through a 6-exo addition to the
arene.[5a] Rearomatisation could then be effected either by atom
5a,b]
Table 1. Optimisation of intramolecular amination
Entry
Iron salt
Acid
Solvent
Product/Yield (%)
[
a]
1
2
3
4
5
6
7
8
9
FeSO4.7H
FeSO4.7H
FeSO4.7H
none
2
2
2
O
O
O
CF
3
CO
2
H
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
CH
2
2
2
2
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
2
2
2
2
1a 100[b]
1a 100[b]
2a 73
p-TsOH
MeSO
MeSO
none
3
H
transfer/elimination or SET to generate
intermediate followed by proton loss.
a
Wheland-type
1a 100[b]
1a 100[b]
2a 63
3
H
FeSO4.7H
2
O
FeCl
FeCl
2
3
MeSO
MeSO
MeSO
MeSO
MeSO
MeSO
MeSO
MeSO
MeSO
MeSO
3
H
3
H
3
H
3
H
3
H
3
H
3
H
3
H
3
H
3
H
1a 90
Ferrocene
Fe(acac)
Fe(OAc)
Fe(OTf)
2a 20
2
1a 88
N
N
N
n
Me
C H
4 9
10
11
12
13
14
15
2
3a 88
2
2
a 73%
2b 69%
2c 43%
2
3a 85
n
N
Me
N
C H
5 11
FeSO4.7H
FeSO4.7H
FeSO4.7H
FeSO4.7H
2
O
2
O
2
O
2
O
Toluene
MeOH
2a 45
N
n
Me
Me
C H
6
13
3a 85
d 48%
2e 79%
2f (angustureine) 53%
Cl
2-MeTHF
Dioxane
3a 85
Cl/H
3a 50
Cl
N
N
N
Me
H/Cl Me
Me
1
[
a] Isolated yield. [b] Estimated by H NMR.
2
g 42%
2h/2h' 48% (1.4:1)
2i 0%
Me
Br
N
Me
N
N
Me
Me
Me Me
We then examined the substrate scope of the intramolecular
amination (Scheme 1). Variations in the N-substituent were
tolerated, including the potentially removable[10] allyl-substituent
in 2b. As expected, longer N-alkyl chains gave lower yields (2c,d)
owing to competing Hoffman-Loeffler-Freytag reactions of the
aminium radicals. Substitution in the linking alkyl chain was
2
j 72%
2k 78%
2l 28%
Ph
3-(CF3)C6H4
MeO
N
Me
N
N
Me
Me
Me
tolerated, including
corresponds to the naturally-occurring alkaloid angustereine.
Substituted aromatics also reacted: substrates with chloride
a
2-pentyl substituent in 2f, which
2m 0%
2n 73% (10.4:1)
2o 77%
[
11]
O
O
substituents in the para- and meta-positions cyclized successfully
N
Me
N
Me
(
2
the latter giving a mixture of C6/C8-chlorotetrahydroquinolines
h), but the ortho-derivative failed to deliver 2i. Bromide
Me
Bu
2p 40% (+ 8% Cl)
2q 15%
substitution was also tolerated in 2j, and the availability of 7-
halotetrahydroquinolines is noteworthy in the context of their
potential utility in subsequent metal-catalysed cross-coupling
chemistry along with the regiocomplementarity to products
obtained by electrophilic halogenation of the parent
Scheme 1. Substrate scope of the iron-catalysed direct aryl amination.
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European Journal of Organic Chemistry
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FULL PAPER
Overall, the average yield for the ten substrates which have been
prepared by both the photochemical and iron-catalysed variants
was broadly similar (ca. 6% higher in the former case), supporting
the general interchangeability of the two practically
complementary methods. We were also interested to see if the
chemistry could be extended to other benzo-fused nitrogen
heterocycles. Togo has previously demonstrated the synthesis of
N-sulfonylated benzomorpholine derivatives through radical-
mediated direct amination,[9h,i] and so we attempted the formation
of N-alkyl derivatives from readily-available -aryloxyalkyl N-
chloroamines. The N-methylbenzomorpholine 2p was isolated as
an inseparable mixture 5:1 mixture with a chlorinated derivative in
5
Me
Cl
0.9
2g 42
1
[a] Isolated yield. [b] Estimated by H NMR.
Minisci’s initial work on direct aromatic amination focused on
intermolecular reactions of N-chloroamines with arenes, the latter
usually being present in a large excess,[5e] while Leonori’s recent
work demonstrates efficient photocatalysed couplings are
possible.[ We wished to verify that intermolecular processes
were also possible under our iron-catalysed conditions, and so
investigated the coupling of two substituted piperidine derivatives
4b]
4
8% yield. Such over-chlorination has previously been seen with
electron-rich products.[5a] Disappointingly, however, relatively
minor changes in either N- or aryl substituents resulted in poor
yields (e.g. 15% for the N-butyl analogue 2q) and this series was
discontinued.
6
a,b with two substituted aromatics (tetralin 4 and toluene 5).
Using the arene in excess, moderate yields of aminated products
were observed (Table 3, entries 1, 3, 4 and 6). The reactions with
tetralin produced, in each case, a single regioisomer, with
substitution being observed at the less-hindered 4-position.
Reactions with toluene gave mixtures of ortho-, meta- and para-
substitution, as anticipated by comparison with Minisci’s earlier
Mindful of the success of our own group[5a,b] and others[4b,5d] in
developing one-pot photochemical N-chlorination/amination
procedures, we next investigated the development of a one-pot
variant using iron-catalysis. N-Chlorination of amine 1a was
carried out using a molar equivalent of N-chlorosuccinimide
before addition of methanesulfonic acid and the iron(II) sulfate.
Disappointingly, only a trace of the product 2a was observed
studies.[5e]
Such reaction conditions (large excess of arene)
would be appropriate for decoration of a valuable amine with a
cheap/readily-available arene; however, more generally useful
would be a process using only a modest excess of either reagent.
After some optimization, we found that the use of a small excess
(
Table 2, entry 1). We eliminated the presence of the succinimide
by-product of N-chlorination as the cause of this behavior by
doping a reaction using pre-formed chloroamine with a molar
equivalent of succinimide: an identical 73% yield of 2a to that in
Table 1, entry 3 was obtained. We therefore suspected that N-
chlorosuccinimide was responsible for the issues. Although this
reagent was charged in equimolar amounts to the amine and
should be consumed in chloroamine formation, traces could be
present either through incomplete chloroamine production or
weighing errors. The reaction was therefore repeated with N-
chlorosuccinimide as the limiting reagent (Table 2, entry 2), and a
pleasing 65% yield of 2a was observed. This yield compares well
with the overall 48% yield for the two-step sequential chlorination
(
1.5 equivalents) of N-chloroamine gave reasonable yields of the
aminated products (entries 2 and 5). The use of the N-
chloroamine in larger excess (2-3 equivalents) gave lower
isolated yields and was not pursued.
Table 3. Intermolecular amination
(
66%)/N-arylation (73%).
Three other substrates were
investigated and in each case the yield for the one-pot process
was either comparable or superior to the two-step approach.
Entry
Product
R
Ratio
Product,
Yield
(%)[a]
4
5
or
:6
1
2
COPh
COPh
10:1
7a 33
7a 78
Table 2. One-pot amination
1:1.5
Entry
R1
R2
Equiv. NCS
Product, Yield
(
%)[
a]
3
4
5
6
Ph
10:1
10:1
1:1.5
10:1
7b 28
COPh
COPh
Ph
8a 29b]
8a 28[c]
8b 39[d]
2a <5[b]
1
2
3
4
Me
H
H
H
H
1.0
0.9
0.9
0.9
Me
2a 65
2d 45
2b 57
Allyl
Butyl
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European Journal of Organic Chemistry
10.1002/ejoc.201900614
FULL PAPER
1
-Methyl-1,2,3,4-tetrahydroquinoline (2a): The general procedure was
1
[
[
a] Isolated yield. [b] Mixture of o:m:p isomers in 3.6:7.2:5.5 ratio by H NMR.
followed, using chloroamine 1a (100 mg, 0.54 mmol), MeSO
.40 mmol) and FeSO .7H O (15 mg, 0.050 mmol). Purification by column
chromatography, eluting with 10% EtOAc in hexane afforded 2a (58 mg,
3
H (350 µL,
1
c] Mixture of o:m:p isomers in 3.6:7.2:5.5 ratio by H NMR. [b] Mixture of
5
4
2
1
o:m:p isomers in 3.5:4.7:5.0 ratio by H NMR.
0
.39 mmol, 73%) as a colourless oil. The data was in accordance with the
literature.[ . (ii) One-pot synthesis from amine: the general procedure
5a]
was followed using amine 1a (100 mg, 0.67 mmol), NCS (80 mg, 0.60
H (435 µL, 6.70 mmol) and FeSO .
mmol), MeSO 7H O (19 mg, 0.07
3 4 2
mmol). Purification by column chromatography, eluting with 10% EtOAc in
hexane afforded 2a (57 mg, 0.39 mmol, 65%) as a colourless oil. 1H NMR
(
500 MHz, CDCl
ArCH), 6.65 – 6.62 (2H, m, 2 × ArCH), 3.28 – 3.24 (2H, m, NCH
3H, s, CH ), 2.81 (2H, t, J = 6.4, ArCH ), 2.05 – 2.00 (2H, m, CH
NMR (126 MHz, CDCl
3
): δ = 7.11 (1H, t, J = 7.7, ArCH), 6.99 (1H, d, J = 7.1,
), 2.92
); 13C
2
(
3
2
2
3
): δ = 146.8, 128.8, 127.0, 122.9, 116.2, 110.9, 51.3,
39.1, 27.8, 22.5; IR υmax (neat) / cm- 3075, 3032, 2998, 2931, 2834, 1639,
1
1
Conclusions
+
+
611, 1583; HRMS (ESI ): C10
H
14N [M+H ]: calculated 148.1121, found
1
48.1118.
In conclusion, we have optimized the iron-catalysed direct C-H
amination of arenes from N-chloroamines in organic media, a
development which enables a direct one-pot formal oxidative
coupling to generate tetrahydroquinolines and derivatives. The
yields of this operationally simple process are comparable to our
previously-developed photochemical aminations, and obviate the
need for specialized photochemical reactors. While this work
further demonstrates the utility of electrophilic nitrogen-centred
radicals in organic synthesis, it is important to acknowledge some
limitations: both highly electron-rich and electron-deficient
substrates are problematic using this technique (the latter
1-(Prop-2-en-1-yl)-1,2,3,4-tetrahydroquinoline
(2b):
(i)
From
chloroamine: the general procedure was followed, using chloroamine 2b
100 mg, 0.48 mmol), MeSO H (315 µL, 4.80 mmol) and FeSO .7H O (13
(
3
4
2
mg, 0.05 mmol). Purification by column chromatography, eluting with 10%
EtOAc in hexane afforded 2b (57 mg, 0.33 mmol, 69%) as a colourless oil.
(ii) One-pot synthesis from amine: the general procedure was followed
using amine 3b (100 mg, 0.57 mmol), NCS (68 mg, 0.51 mmol), MeSO
(331 µL, 5.10 mmol) and FeSO .
7H O (14 mg, 0.05 mmol). Purification by
column chromatography, eluting with 10% EtOAc in hexane afforded the
3
H
4
2
2
b (40 mg, 0.23 mmol, 45%) as a colourless oil. The data was in
accordance with the literature. [ 1H NMR (400 MHz, CDCl
5a]
) δ = 7.02 (1H,
3
complication is common to
a nearly all radical-mediated
t, J = 7.8, ArCH), 6.94 (1H, d, J = 7.5, ArCH), 6.58 – 6.54 (2H, m, 2 × ArCH),
.89 – 5.80 (1H, m, CHCH ), 5.24 – 5.10 (2H, m, CHCH ), 3.89 – 3.82 (2H,
m, NCH CH), 3.31 – 3.23 (2H, m, NCH ), 2.76 (2H, t, J = 6.3, ArCH ), 2.02
aminations, as noted and overcome in the specific instance of
primary amine synthesis by Ritter[3a]). Nevertheless, the simplicity,
cost-effectiveness and convenience of (particularly) the one-pot
variant offers attractive alternatives to processes involving more
5
2
2
2
2
2
– 1.90 (2H, m, CH2); 13C NMR (101 MHz, CDCl ) δ = 145.4, 133.6, 129.0,
127.1, 122.4, 115.9, 115.7, 111.0, 53.9, 49.2, 28.2, 22.4; IR υmax (neat) /
3
complex pre-activated nitrogen species for appropriate substrates. cm-1 3065, 3022, 2928, 2841, 1725, 1675, 1642, 1601; HRMS (ESI ):
+
+
C
12
H16N [M + H] : calculated 174.1277, found 174.1272.
Our ongoing work in the applications of aminium radical-mediated
direct C-H aminations will be reported in due course.
1
-Butyl-1,2,3,4-tetrahydroquinoline (2c): (i) From chloroamine: The
general procedure was followed, using chloroamine 1c (100 mg, 0.44
mmol), MeSO H (285 µL, 4.40 mmol) and FeSO .7H O (12 mg, 0.04
3
4
2
Experimental Section
mmol). Purification by column chromatography, eluting with 10% EtOAc in
hexane afforded 2c (36 mg, 0.19 mmol, 43%) as a pale yellow oil. (ii) One-
pot synthesis from amine: the general procedure was followed using amine
3c (100 mg, 0.52 mmol), NCS (63 mg, 0.47 mmol), MeSO
mmol) and FeSO .
General procedure for the Intramolecular N-Arylation using Pre-
Formed N-Chloroamines: To a stirred solution of the N-chloroamine 1
3
H (305 µL, 4.70
7H O (14 mg, 0.05 mmol). Purification by column
(
1.0 eq) in DCM (0.2 M) at 0 oC was added MeSO
FeSO .7H
3
H (10 eq) and
O (10 mol%). The reaction mixture was stirred at 0 oC for 1 h.
4
2
4
2
chromatography, eluting with 10% EtOAc in hexane afforded 2c (51 mg,
The reaction mixture was basified using 2 M NaOH (pH 9). The two phases
were separated and the aqueous phase was extracted three times with
0.27 mmol, 57%) as a colourless oil. The data was in accordance with the
literature.[5a] 1H NMR (300 MHz, CDCl
) δ = 7.08 – 6.98 (1H, m, ArCH),
6.98 – 6.86 (1H, m, ArCH), 6.60 – 6.49 (2H, m, 2 × ArCH), 3.34 – 3.15 (4H,
m, C and C ), 2.80 – 2.68 (2H, m, ArCH ), 2.02 – 1.86 (2H, m, C ),
1.64 – 1.48 (2H, m, C ), 1.42 – 1.26 (2H, m, CH CH ), 0.95 (3H, t, J =
.3, CH ) δ = 145.4, 129.1, 127.0, 122.1, 115.1,
); 13C NMR (75 MHz, CDCl
3
DCM. The organic phases were combined, dried over MgSO
4
and
concentrated in vacuo. Purification by column chromatography yielded the
desired product 2.
H
b 2
c
H
2
2
a 2
H
H
d 2
2
3
7
3
3
-
1
General Procedure for the Direct One-pot N-Arylation of Free Amines:
To a stirred solution of the amine 3 (1.0 eq) in DCM (0.5 M) in the dark was
added NCS (0.9 eq) portionwise over 10 min at RT. The reaction mixture
110.5, 51.2, 49.5, 28.4, 28.2, 22.3, 20.5, 14.1; IR υmax (neat) / cm 3064,
3020, 2954, 2929, 2860, 1676, 1601, 1503; HRMS (ESI ): C13
H] : calculated 190.1590, calculated 190.1593.
+
H
20N [M +
+
was stirred for 1 h at RT then cooled to 0 oC. MeSO
FeSO .
7H
H (10 eq) and
3
o
4
2
O (10 mol%) were added and the mixture was stirred at 0 C for
1-Hexyl-1,2,3,4-tetrahydroquinoline (2d): The general procedure was
followed, using chloroamine 1d (100 mg, 0.39 mmol), MeSO H (255 µL,
3.90 mmol) and FeSO .7H O (11 mg, 0.04 mmol). Purification by column
1
h. The reaction mixture was basified using 2 M NaOH (pH 9). The two
phases were separated and the aqueous phase was extracted three times
with DCM. The organic phases were combined, dried over MgSO and
3
4
2
4
chromatography, eluting with 10% EtOAc in hexane afforded 2d (41 mg,
concentrated in vacuo. Purification by column chromatography yielded the
desired product 2.
0.19 mmol, 48%) as a colourless oil. The data was in accordance with the
literature.[5a] 1H NMR (300 MHz, CDCl
) δ = 7.09-6.99 (1H, m, ArCH), 6.97-
.89 (1H, m, ArCH), 6.63-6.47 (2H, m, includes 2 × ArCH), 3.34-3.15 (4H,
m, includes CH2c and CH2b), 2.75 (2H, t, J = 6.4, ArCH ), 2.02-1.88 (2H,
3
6
2
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European Journal of Organic Chemistry
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FULL PAPER
m, CH2a), 1.66-1.51 (2H, m, CH2d), 1.40-1.24 (6H, m, includes CH2e, CH2f
6.93 (1H, d, J = 2.6, ArCH), 6.50 (1H, d, J = 8.7, ArCH), 3.25 – 3.19 (2H,
and CH
2
CH
3
), 0.98-0.81 (3H, m, CH
3
); 13C NMR (125 MHz, CDCl
3
) δ =
m, CH
CH
), 13C NMR (101 MHz, CDCl
126.6, 124.4, 111.9, 51.1, 39.2, 27.7, 22.2; 1H NMR (400 MHz, CDCl
peaks for 2h’) δ = 7.19 (1H, d, J = 7.8, ArCH), 6.97 (1H, d, J = 7.8), 6.85
(1 H, t, J = 7.8, ArCH), 3.19 – 3.14 (2H, m, CH NMe), 2.91 (3H, s, CH ),
), 1.91 – 1.85 (2H, m, CH
); 13C NMR (101 MHz,
2 3 2
NMe), 2.88 (3H, s, CH ), 2.75 (2H, t, J = 6.5, ArCH ), 1.99 (2H, m,
1
2
1
2
45.5, 129.3, 127.2, 122.3, 115.3, 110.6, 51.7, 49.6, 31.9, 28.4, 27.1, 26.3,
2
3
, peaks for 2h) δ = 145.3, 131.2, 128.4,
-1
2.8, 22.4, 14.2; IR υmax (neat)/cm : 3066, 2925, 2855, 1601, 1574, 1504,
3
,
+
456, 1369; HRMS (ESI): C15
H
24N [M+H] : calculated 218.1903, found
18.1902.
2
3
2
.82 (2H, t, J = 6.7, ArCH
2
2
CDCl
4
3
, peaks for 2h’) δ = 146.0, 128.3, 128.2, 127.5, 122.0, 120.7, 52.0,
1
,2-Dimethyl-1,2,3,4-tetrahydroquinoline (2e): The general procedure
2.8, 27.9, 17.2; IR υmax (neat) / cm- 3040, 2934, 2861, 2841, 1596, 1560,
1
was followed, using chloroamine 1e (100 mg, 0.50 mmol), MeSO
330 µL, 5.10 mmol) and FeSO .7H O (14 mg, 0.051 mmol). Purification
by column chromatography, eluting with 10% EtOAc in hexane afforded
e (65 mg, 0.40 mmol, 79%) as a colourless oil. The NMR data is in
accordance with literature.[5a] 1H NMR (500 MHz, CDCl
) δ = 7.13 (1H, t,
J = 7.7, ArCH), 7.02 (1H, d, J = 7.3, ArCH), 6.64 (1H, t, J = 7.3, ArCH),
3
H
+
35
+
1499, 1463; HRMS (ESI ): C10H13 ClN [M+H] : calculated 182.0731,
(
4
2
found 182.0727.
2
3
7-Bromo-1-methyl-1,2,3,4-tetrahydroquinoline (2j): The general
procedure was followed, using chloroamine 1j (100 mg, 0.38 mmol),
6
2
.60 (1H, d, J = 8.2, ArCH), 3.52 – 3.44 (1H, m, CH), 2.94 (3H, s, NCH
.93 – 2.84 (1H, m, ArCH ), 2.75 – 2.72 (1H, m, ArCH ) 2.07 – 1.99 (1H,
), 1.84 – 1.76 (1H, m, CH ), 1.18 (3H, d, J = 6.5, CH
); 13C NMR
125 MHz, CDCl ) δ = 145.4, 128.5, 127.1, 122.1, 115.4, 110.6, 53.8, 37.0,
3
),
3 4 2
MeSO H (250 µL, 3.80 mmol) and FeSO .7H O (11 mg, 0.038 mmol).
Purification by column chromatography, eluting with 10% EtOAc in hexane
afforded 2j (62 mg, 0.27 mmol, 72%) as a colourless oil. The NMR data is
2
2
m, CH
(
2
2
3
in accordance with literature.[14] 1H NMR (300 MHz, CDCl
) δ = 6.78 (1H,
d, J = 7.7, ArCH), 6.70 – 6.65 (2H, m, 2 × ArCH), 3.26 – 3.18 (2H, m,
CH NMe), 2.86 (3H, s, CH ), 2.68 (2H, t, J = 6.4, ArCH ), 2.00 – 1.88 (2H,
m, CH ) δ = 147.7 (C ), 129.8 (ArCH), 121.5
); 13C NMR (75 MHz, CDCl
), 120.6 (C ), 118.5 (ArCH), 113.2 (ArCH), 50.9 (CH NMe), 38.9 (CH ),
7.4 (ArCH ), 22.1 (CH
); IR υmax (neat) / cm-1 3015, 2928, 2886, 2837,
593, 1557, 1497, 1464; HRMS (ESI+): 1379Br35ClN [M H]+
3
3
-
1
2
1
1
8.1, 23.8, 17.6; IR νmax (neat)/cm : 3068, 3021, 2962, 2925, 2843, 2790,
603, 1575; HRMS (ESI ):C11
62.1273.
+
16N [M + H]+ : calculated 162.1277, found
H
2
3
2
2
3
q
(
C
q
q
2
3
2
1
2
2
1-Methyl-2-hexyl-1,2,3,4-tetrahydroquinoline (angustureine, 2f): The
10
C H
+
general procedure was followed, using chloroamine 1f (100 mg, 0.39
mmol), MeSO H (260 µL, 3.90 mmol) and FeSO .7H O (11 mg, 0.039
calculated 226.1583, found 226.1583.
3
4
2
mmol). Purification by column chromatography, eluting with 10% EtOAc in
hexane afforded 2f (45 mg, 0.21 mmol, 53%) as a colourless oil. The NMR
1,7-Dimethyl-1,2,3,4-tetrahydroquinoline (2k): The general procedure
was followed, using chloroamine 1k (100 mg, 0.51 mmol), MeSO H (335
µL, 5.10 mmol) and FeSO .7H O (14 mg, 0.051 mmol). Purification by
column chromatography, eluting with 10% EtOAc in hexane afforded 2k
(64 mg, 0.40 mmol, 78%) as a colourless oil. 1H NMR (400 MHz, CDCl
δ = 6.76 (1H, d, J = 7.3, ArCH), 6.36 (2H, m, 2 × ArCH), 3.16 – 3.08 (2H,
m, NCH ), 2.80 (3H, s, NCH ), 2.65 (2H, t, J = 6.5, ArCH ), 2.20 (3H, s,
ArCH ), 1.93 – 1.84 (2H, m, CH ) δ = 146.6,
); 13C NMR (101 MHz, CDCl
data is in accordance with literature.[5a] 1H NMR (400 MHz, CDCl
) δ =
.07 (1H, t, J = 7.7, ArCH), 6.96 (1H, d, J = 7.3, ArCH), 6.57 (1H, t, J = 7.3,
ArCH), 6.51 (1H, d, J = 8.2, ArCH), 3.29 – 3.17 (1H, m, CH), 2.92 (3H, s,
CH ), 2.86 – 2.73 (1H, m, ArCH ), 2.71 – 2.58 (1H, m, ArCH ) 1.94 – 1.82
2H, m, CH ), 1.65 – 1.53 (1H, m, C ), 1.44 – 1.19 (7H, m, includes C
, C and C ) 0.98 – 0.81 (3H, m, CH
) ; 13C NMR (100 MHz,
CDCl ) δ = 145.7, 128.8, 127.2, 122.0, 115.3, 110.5, 59.1, 38.1, 32.2, 31.3,
3
3
7
4
2
3
2
2
3
)
(
2
H
a 2
a 2
H ,
C H
b 2
c
H
2
H
d 2
3
2
3
2
3
3
2
3
-
1
2
1
2
5.9, 24.6, 23.7, 22.8, 14.2; IR νmax (neat)/cm : 3020, 2926, 2856, 1602,
575, 1498, 1479, 1455; HRMS (ESI ):C15
18.1903, found 218.1903.
136.6, 128.7, 112.0, 117.0, 111.8, 51.4, 39.2, 27.5, 22.7, 21.6; IR υmax
+
24N [M + H]+ : calculated
-1
H
(neat) / cm 3041, 3022, 2924, 2856, 2839, 2812, 1611, 1575; HRMS
+
+
(ESI ): C11H16N [M + H] : calculated 162.1277, found 162.1280.
7
-Chloro-1-methyl-1,2,3,4-tetrahydroquinoline (2g):
The general
1,6,8-Trimethyl-1,2,3,4-tetrahydroquinoline (2l):
procedure was followed, using chloroamine 1l (100 mg, 0.47 mmol),
MeSO H (305 mL, 4.70 mmol) and FeSO .7H O (13 mg, 0.047 mmol).
The general
procedure was followed, using chloroamine 1g (100 mg, 0.46 mmol),
MeSO H (300 µL, 4.40 mmol) and FeSO .7H O (13 mg, 0.046 mmol).
3
4
2
3
4
2
Purification by column chromatography, eluting with 10% EtOAc in hexane
afforded 2g (37 mg, 0.20 mmol, 42%) as a colourless oil. The data was in
accordance with the literature.[5a] . (ii) One-pot synthesis from amine: the
general procedure was followed using amine 1g (100 mg, 0.54 mmol),
Purification by column chromatography, eluting with 10% EtOAc in hexane
afforded 2l (22 mg, 0.13 mmol, 28%) as a colourless oil. 1H NMR (400
MHz, CDCl
m, NCH ), 2.75 (2H, t, J = 6.7, ArCH
ArCH ), 2.22 (3H, s, ArCH ), 1.88 – 1.78 (2H, m,CH
CDCl
3
) δ = 6.81 (1H, s, ArCH), 6.72 (1H, s, ArCH), 3.14 – 3.06 (2H,
), 2.68 (3H, s, CH ), 2.27 (3H, s,
); 13C NMR (101 MHz,
2
2
3
MeSO
3
H (318 µL, 4.90 mmol) and FeSO .
4
2
7H O (14 mg, 0.05 mmol).
3
3
2
Purification by column chromatography, eluting with 10% EtOAc in hexane
afforded 2g (37 mg, 0.20 mmol, 42%) as a colourless oil. 1H NMR (400
3
) δ = 131.3, 131.1, 130.5, 129.7, 128.8, 127.9, 52.2, 43.0, 27.7, 20.6,
-1
18.4, 16.7; IR υmax (neat) / cm 2997, 2933, 2853, 1722, 1678, 1605, 1479.
+
+
MHz, CDCl
3
) δ = 6.83 (1H, d, J = 7.8, ArCH), 6.56 – 6.49 (2H, m, 2 × ArCH),
.25 – 3.19 (2H, m, NCH CH ), 2.86 (3H, s, CH ), 2.70 (2H, t, J = 6.4,
), 1.99 – 1.90 (2H, m, CH ) δ = 147.5,
); 13C NMR (101 MHz, CDCl
1439; HRMS (ESI ): C12
H
18N [M + H] : calculated 176.1453, found
3
3
2
3
176.1455.
ArCH
2
2
3
1
32.5, 129.5, 121.0, 115.5, 110.5, 50.9, 38.9, 27.3, 22.2; IR υma× (neat) /
1
,7-Dimethyl-4-phenyl-1,2,3,4-tetrahydroquinoline (2n): The general
procedure was followed, using chloroamine 1n (100 mg, 0.37 mmol),
MeSO H (240 µL, 3.70 mmol) and FeSO .7H O (10 mg, 0.037 mmol).
-1
+
cm 3022, 2929, 2890, 2840, 1599, 1564, 1502, 1466; HRMS (ESI ):
C
35
+
10
H
13 ClN [M+H] : calculated 182.0731, found 182.0723.
3
4
2
Purification by column chromatography, eluting with 10% EtOAc in hexane
afforded 1n as an inseperable mixture 10.4:1 mixture with the isomeric
product 1-methyl-4-(4-methylphenyl)-1,2,3,4-tetrahydroquinoline (64 mg,
0.27 mmol, 73%) as a colourless oil. The data is in accordance with the
6
-Chloro-1-methyl-1,2,3,4-tetrahydroquinoline (2h) and 8-chloro-1-
methyl-1,2,3,4-tetrahydroquinoline (2h’): (i) From chloroamine: the
general procedure was followed, using chloroamine 1h (100 mg, 0.46
mmol), MeSO
literature.[5a] 1H NMR (400 MHz, CDCl
3
H (300 µL, 4.60 mmol) and FeSO
4 2
.7H O (13 mg, 0.046
3
) δ = 7.30 – 7.25 (2H, m, 2 × ArCH),
mmol). Purification by column chromatography, eluting with 10% EtOAc in
hexane afforded the regioisomers of 2h/2h’ as an inseparable mixture of
isomers (1.4 : 1, 40 mg, 0.22 mmol, 48%) as a colourless oil. The NMR
data for the 6-chloro product was in accordance with the literature.[13] 1H
7.21 – 7.17 (1H, m, ArCH), 7.12 – 7.09 (2H, m, 2 × ArCH), 6.62 (1H, d, J
= 7.6, ArCH), 6.49 (1H, s, ArCH), 6.39 (1H, d, J = 7.6, ArCH), 4.09 (1H, t,
J = 6.2, CHCH
s, ArCH ), 2.26 – 2.19 (1H, m, CHCH
NMR (101 MHz, CDCl ) δ = 146.8 (2 × C
q
2
), 3.23 – 3.11 (2H, m, NCH
), 2.12 – 2.02 (1H, m, CHCH
), 137.2, 129.8, 128.7, 128.3,
2
), 2.93 (3H, s, NCH
3
), 2.29 (3H,
); 13
C
3
2
2
NMR (400 MHz, CDCl
3
, peaks for 2h) δ = 7.02 (1H, dd, J = 8.7, 2.6, ArCH),
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900614
FULL PAPER
-1
1
26.1, 122.1, 117.1, 111.8, 48.7, 43.2, 39.3, 31.3, 21.7; IR υmax (neat) / cm-
43.6, 29.9, 28.7, 28.6, 23.5, 23.4; IR υmax (neat) / cm 3057, 3013, 2854,
2834, 2801, 1679, 1609, 1597; HRMS (ESI ): C22
calculated 342.1828, found 342.1825.
1
+
+
25NNaO [M + Na]+:
3
076, 3063, 2975, 2950, 1640, 1568, 1452, 1415; HRMS (ESI ): C17
20
H N
H
+
[M + H] : calculated 238.1590, found 238.1585.
1
2
0
-Methyl-4-[3-(trifluoromethyl)phenyl]-1,2,3,4-tetrahydroquinoline
o: The general procedure was followed, using chloroamine 1o (100 mg,
.31 mmol), MeSO H (200 µL, 3.10 mmol) and FeSO .7H O (9 mg, 0.031
Synthesis
of
4-phenyl-1-(5,6,7,8-tetrahydronaphthalen-2-
yl)piperidine 7b: To a stirred solution of the chloroamine 6b (100 mg, 0.51
mmol) in DCM (0.51 mL) at 0 C was added tetralin (695 µL, 5.10 mmol)
o
3
4
2
mmol). Purification by column chromatography, eluting with 10% EtOAc in
hexane afforded 2o (69 mg, 0.24 mmol, 77%) as a colourless oil. The data
MeSO
3
H (330 µL, 5.10 mmol) and FeSO
4
.7H
2
O (14 mg, 0.051). The RM
o
was stirred at 0 C for 1 h. The RM was basified using 2 M NaOH (pH 9).
The two phases were separated and the aqueous phase was extracted
with DCM (3 × 15 mL). The organic phases were combined, dried over
is in accordance with the literature.[5a] 1H NMR (300 MHz, CDCl
–
) δ = 7.50
7.35 (3H, m, 3 × ArCH), 7.25 (1H, d, J = 7.6, ArCH), 7.18 – 7.10 (1H, m,
ArCH), 6.70 – 6.67 (2H, m, 2 × ArCH), 6.57 (1H, td, J =7.3, 1.1, ArCH),
3
MgSO
eluting with DCM in hexane afforded 7b (39 mg, 0.13 mmol, 26%) as a
colourless oil. 1H NMR (400 MHz, CDCl
) δ = 7.38 – 7.15 (5H, m, 5 ×
ArCH), 6.97 (1H, d, J = 8.1, ArCH), 6.78 (1H, d, J = 8.1, ArCH), 6.70 (1H,
s, ArCH), 3.72 (2H, d, J = 11.4, 2 × NCH ), 2.79 – 2.66 (7H, m, includes
CH, 2 × C , 2 CH CH), 1.92 (4 H, s, 2 × CHCH ), 1.77 (4H, s, J = 2.0, 2
× C ) δ = 149.9, 146.3, 137.6, 129.7, 128.7,
); 13C NMR (101 MHz, CDCl
4
and concentrated in vacuo. Purification by column chromatography,
4
2
1
.24 – 4.15 (1H, m, CHCH
.35 – 2.01 (2H, m, CHCH
32.2, 130.7 (q, J = 32.0), 129.8, 128.8, 128.0, 125.3 (q, J = 3.8), 124.3 (q,
2
), 3.31 – 3.07 (2H, m, CH
2
N), 2.94 (3H, s, CH
3
),
); 13C NMR (101 MHz, CDCl
2
3
) δ = 147.5, 146.8,
3
J = 272.3), 123.8, 123.1 (q, J = 3.8), 116.5, 111.3, 48.4, 43.4, 39.2, 31.1;
IR υmax (neat) / cm- 3066, 3026 2945, 2927, 1602, 1503, 1444, 1322;
2
1
H
b 2
2
2
+
+
HRMS (ESI ): C17
H
17
F
3
N [M + H] : calculated 292.1308, found 292.1313.
H
a 2
3
1
28.5, 126.9, 126.3, 117.4, 115.1, 51.3, 42.6, 33.5, 29.9, 28.6, 23.6, 23.4;
IR υma× (neat) / cm- 3058, 3025, 2923, 2852, 2798, 1736, 1681, 1609;
1
3
,4-Dimethyl-3,4-dihydro-2H-benzo[b][1,4]oxazine 2p: The general
procedure was followed, using chloroamine 1p (150 mg, 0.75 mmol),
MeSO H (490 µL, 7.50 mmol) and FeSO .7H O (21 mg, 0.075 mmol).
+
+
LCMS (ESI ): 292.2 [M+H] . Accurate mass data could not be obtained.
3
4
2
Purification by column chromatography, eluting with 10% EtOAc in hexane
afforded 2p (25 mg, 0.15 mmol, 20%) as a colourless oil. The NMR data
is in accordance with the literature.[15] 1H NMR signals for the major product
[1-(Methylphenyl)-4-piperidinyl]phenylmethanone 8a To a stirred
solution of the chloroamine 6a (100 mg, 0.45 mmol) in DCM (0.45 mL) at
o
0 C was added toluene (480 µL, 4.50 mmol) MeSO
3
H (295 µL, 4.50 mmol)
o
reported (300 MHz, CDCl
m, ArCH), 6.69 – 6.61 (2H, m, 2 × ArCH), 4.21 (1H, dd, J = 10.5, 2.6, CH
.04 (1H, dd, J = 10.5, 2.6, CH ), 3.44 – 3.33 (1H, m, CH), 2.89 (3H, s,
NCH ), 1.22 (3H, d, J = 6.5, CH
); 13C NMR signals for the major product
reported (101 MHz, CDCl ) δ = 144.2, 126.6, 121.8, 116.6, 116.4, 111.7,
3
) δ = 6.92 – 6.84 (1H, m, ArCH), 6.83 – 6.77 (1H,
and FeSO
4
2
.7H O (12 mg, 0.045). The RM was stirred at 0 C for 1 h. The
2
),
RM was basified using 2 M NaOH (pH 9). The two phases were separated
and the aqueous phase was extracted with DCM (3 × 15 mL). The organic
phases were combined, dried over MgSO and concentrated in vacuo.
4
4
2
3
3
3
Purification by column chromatography, eluting with DCM in hexane
afforded 8a as inseparable regioisomers, o:m:p, 3.6:7.2:5.5 (42 mg, 0.13
mmol, 29%) as a colourless oil. NMRs reported as a mixture of the three
-
1
6
2
9.2, 52.1, 36.1, 14.1; IR υma× (neat) / cm 3065, 3039, 2972, 2929, 2875,
+
+
820, 1604, 1499; LCMS (ESI ): C19H22NO [M + H] : calculated 164.2,
found 164.4
regioisomers. 1H NMR (400 MHz, CDCl
3
) δ = 7.99 – 7.93 (2H, m), 7.57
(1H, ddd, J = 7.9, 2.3, 1.1), 7.48 (2H, dd, J 11.6, 4.2), 7.18 (0.22H, d, J =
8
×
.8, ArCH, o), 7.15 (0.44H, t, J = 7.7, ArCH, m), 7.07 (0.68H, d, J = 8.2, 2
ArCH, p), 6.88 (0.68H, d, J = 8.2, 2 × ArCH,p), 6.83 – 6.65 (1.98H, m, 6
4
-Butyl-3-methyl-3,4-dihydro-2H-benzo[b][1,4]oxazine 2q:
general procedure was followed, using chloroamine 1q (100 mg, 0.41
mmol), MeSO H (270 µL, 4.10 mmol) and FeSO .7H O (11 mg, 0.04
The
ArCH, o and m), 3.79 – 3.65 (2H, m, NCH
2H, m, NCH ), 2.33 (0.66H, s, CH3, o), 2.32 (1.32H, s, CH
(1.02H, s, CH , p), 2.01 – 1.92 (4H, m, 2 × CH
CH); 13C NMR (101 MHz,
CDCl ) δ = 202.5, 151.7, 150.3, 149.6, 138.8, 136.3, 136.1, 136.0, 133.1,
33.0, 129.7, 129.4, 129.0, 128.8, 128.3, 120.6, 119.2, 117.6, 117.1, 115.5,
2
), 3.43 – 3.32 (1H, m, CH), 2.85
3
4
2
(
2
3
, m), 2.27
mmol). Purification by column chromatography, eluting with 10% EtOAc in
hexane afforded 2q (13 mg, 0.06 mmol, 15%) as a colourless oil. 1H NMR
3
2
3
(
300 MHz, CDCl
3
) δ = 6.93 – 6.77 (2H, m, 2 × ArCH), 6.68 – 6.55 (2H, m,
× ArCH), 4.13 – 3.97 (2H, m, OCH ), 3.54 – 3.41 (1H, m, CH), 3.40 –
.27 (1H, m, CH ), 3.21 – 3.04 (1H, m, CH ), 1.71 – 1.52 (2H, m, CH ),
), 1.22 (3H, d, J = 6.5, CHCH ), 1.04 – 0.94 (3H,
1
1
3
2
3
1
2
-1
13.8, 50.1, 49.6, 43.6, 28.7, 28.7, 28.5, 21.8, 20.5; IR υmax (neat) / cm
2
2
2
+
057, 3026, 2948, 2921, 2807, 2748, 1678, 1595; LCMS (ESI ) 280.4 [M
.47 – 1.32 (2H, m, CH
2
3
+
); 13C NMR (101 MHz, CDCl
+ H] . Accurate mass data could not be obtained.
m, CH
1
3
3
) δ = 143.4, 134.5, 121.8, 116.3, 116.1,
11.8, 69.1, 50.9, 48.7, 29.5, 20.4, 15.9, 14.0; IR υmax (neat) / cm- 3065,
1
+
3039, 2958, 2930, 2872, 1605, 1578, 1502; HRMS (ESI ): C13
H20NO [M +
1-Methylphenyl-4-phenylpiperidine 8b To a stirred solution of the
chloroamine 6b (100 mg, 0.51 mmol) in DCM (0.45 mL) at 0 C was added
+
o
H] : calculated 206.1539, found 206.1538.
toluene (545 µL, 5.10 mmol) MeSO
FeSO .7H
was basified using 2 M NaOH (pH 9). The two phases were separated and
the aqueous phase was extracted with DCM (3 × 15 mL). The organic
3
H
(330 µL, 5.10 mmol) and
o
4
2
O (14 mg, 0.051). The RM was stirred at 0 C for 1 h. The RM
Synthesis
yl)piperidine 7a: To a stirred solution of the chloroamine 6a (100 mg,
.45 mmol) in DCM (0.45 mL) at 0 oC was added tetralin (610 µL, 4.50
of
4-benzoyl-1-(5,6,7,8-tetrahydronaphthalen-2-
0
4
phases were combined, dried over MgSO and concentrated in vacuo.
mmol) MeSO
3
H (295 µL, 4.50 mmol) and FeSO
4
.7H
2
O (12 mg, 0.045). The
o
Purification by column chromatography, eluting with DCM in hexane
afforded 8b as inseperable regioisomers, o:m:p, 3.5:4.7:5.0 (39 mg, 0.14
mmol, 39%) as a colourless oil. All data reported as a mixture of the three
RM was stirred at 0 C for 1 h. The RM was basified using 2 M NaOH (pH
9
). The two phases were separated and the aqueous phase was extracted
with DCM (3 × 15 mL). The organic phases were combined, dried over
MgSO and concentrated in vacuo. Purification by column chromatography,
eluting with DCM in hexane afforded 7a (48 mg, 0.15 mmol, 33%) as a
colourless oil. 1H NMR (500 MHz, CDCl
) δ = 8.00 – 7.93 (2H, m, 2 ×
ArCH), 7.60 – 7.54 (1H, m, ArCH), 7.48 (2H, t, J = 7.6, 2 × ArCH), 6.97
1H, d, J = 8.3, ArCH), 6.76 (1H, d, J = 7.7, ArCH), 6.68 (1H, s, ArCH),
.69 (2H, dt, J = 6.1, 2.8, NCH ), 3.42 – 3.31 (1H, m, CHCO), 2.88 – 2.77
), 2.73 – 2.68 (4H, m, 2 × C ), 2.04 – 1.91 (4H, m, 2 ×
); 1 C NMR (126 MHz, CDCl
) δ =
regioisomers. 1H NMR (400 MHz, CDCl
3
) δ = 7.23 – 7.07 (5H, m, 5 ×
4
ArCH), 7.08 – 7.01 (0.36H, m, ArCH, m), 6.99-6.95 (1.05H, m, 2 × ArCH,
p), 6.82 – 6.77 (1.05H, m, 2 × ArCH, p), 6.72 – 6.67 (0.72H, m, includes o
and m ArCH), 6.58-6.53 (0.26H, d, J = 7.4, ArCH, o), 3.71 – 3.56 (2H, m,
3
NCH
(
2
), 2.73 – 2.44 (3H, m, NCH
1.08H, s, CH , m), 2.16 (1.14H, s, CH
CH); 13C NMR (101 MHz, CDCl
) δ =151.9, 149.7, 146.2, 138.8, 136.1,
2
, and CH), 2.22 (0.78H, s, CH
3
, o), 2.21
(
3
3
3
, p); 1.94-1.76 (4H, m, include 2 ×
2
CH
2
3
(2H, m, NCH
2
b 2
H
3
131.0 129.6, 129.0, 128.5, 128.4, 127.0, 126.9, 126.8, 126.3, 126.2, 120.5,
19.0, 117.6, 117.1, 113.8, 51.3, 50.7 42.6, 42.5, 33.9, 29.7, 20.5; IR υmax
CH
2
CH), 1.82 – 1.74 (4H, m, 2 × C
H
a 2
3
1
202.5, 137.6, 136.1, 133.0, 129.7, 128.9, 128.8, 128.3, 117.4, 115.1, 50.2,
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European Journal of Organic Chemistry
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neat) / cm- 3060, 3028, 2948, 2923, 2810, 2748, 1595, 1425; LCMS
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European Journal of Organic Chemistry
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Entry for the Table of Contents
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Heterocyclic Synthesis
G. E. Douglas, S. A. Raw, S. P.
Marsden
Page No. – Page No.
Iron-Catalysed Direct Aromatic
An optimized procedure for the direct intra- and intermolecular amination of
aromatic C-H bonds with aminium radicals generated from N-chloroamines under
iron catalysis is reported. A range of substituted tetrahydroquinolines could be
readily prepared, while extension to the synthesis of benzomorpholines was more
limited in scope. A direct one-pot variant was developed, allowing direct formal
oxidative N-H/C-H coupling.
Amination with N-Chloroamines
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