Amination of ethers using chloramine-T hydrate and a copper(I) catalyst

Article abstract of DOI:10.1039/b410883c

Amination of C-H bonds activated by ether oxygen atoms is facile with chloramine-T as nitrene source and copper(I) chloride in acetonitrile as catalyst. For cyclic ethers the hemiaminal products are generally stable and can be isolated pure. For acyclic e

Full text of DOI:10.1039/b410883c

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A R T I C L E
Amination of ethers using chloramine-T hydrate and a copper(I)
catalyst
David P. Albone,a Stephen Challenger,b Andrew M. Derrick,b Shaun M. Fillery,c
Jacob L. Irwin,a Christopher M. Parsons,a Hiroya Takada,a Paul C. Taylor*a and
D. James Wilsona
a Department of Chemistry, University of Warwick, Coventry, UK CV4 7AL.
E-mail: p.c.taylor@warwick.ac.uk; Fax: 44 24 76524112; Tel: 44 24 76524375
b Pfizer Central Research, Sandwich, Kent, UK CT13 9NJ
c AstraZeneca Pharmaceuticals, Mereside, Alderley Park, UK SK10 4TG
Received 19th July 2004, Accepted 1st October 2004
First published as an Advance Article on the web 23rd November 2004
Amination of C–H bonds activated by ether oxygen atoms is facile with chloramine-T as nitrene source and copper(I)
chloride in acetonitrile as catalyst. For cyclic ethers the hemiaminal products are generally stable and can be isolated
pure. For acyclic ethers, the hemiaminal products, as expected, fragment with elimination of alcohol to yield imines.
When activation of benzylic positions is remote through a conjugated system, stable benzylamine derivatives are
isolated. Mechanistic studies are consistent with concerted insertion of an electrophilic nitrenoid into the C–H bond
in the rate-determining step, though in an asynchronous manner with a more activated substrate.
required.6 The Che group has introduced manganese and ruthe-
Introduction
7
=
nium porphyrins as catalysts for amination using TsN IPh.
In 1967 Kwart and Kahn reported the copper-catalysed decom-
position of benzenesulfonyl azide in the presence of cyclohexene
6b
Enantioselective intermolecular amination procedures have
6
been reported by the groups of Mu¨ller, Che and Katsuki8
7c
to yield products consistent with a nitrene-transfer mechanism
with ees of up to 89%.
(Scheme 1).1 Both the aziridine 1 and the allylic amination 2
products are synthetically very interesting, and throughout the
1980s the groups of Breslow and of Mansuy sought catalysts
which led to higher yields and selectivities for each of these two
classes of product.2 It was not until 1991 that an efficient and
general nitrene-transfer aziridination procedure was developed
by the group of Evans.3 Simple copper(I) and copper(II) salts
Scheme 4
were found to give high yields of aziridines from a wide range of
The main drawback with many of these procedures is the
=
alkenes and TsN IPh (Scheme 2), with only isolated examples
troublesome two-step synthesis of the nitrene-transfer agent.
Che’s group have addressed this to some extent with a modified
procedure that exploits the in situ generation of the iodinane
from TsNH2 and PhI(OAc)2.9 The Du Bois group has shown
that enantioselective intramolecular amination with “in situ”
iodinanes is a highly effective strategy for elaboration of
relatively unfunctionalised alcohols.10
of allylic insertions. A nitrene-transfer mechanism was formally
proposed by Jacobsen in 1995.4
The use of chloramine-T trihydrate as a nitrene source has
been a focus of activity both in our group11 and in others.12
=
=
In contrast to iodinanes such as NsI Ph and TsN IPh, which
require two-step syntheses,13 chloramine-T is an inexpensive,
commercially available reagent. We have been largely unsuc-
cessful in our search for catalysts for benzylic and allylic
amination using chloramine-T, this being consistent with the
report from the Bedekar group that bromamine-T, which is not
commerically available, was superior to chloramine-T in such
Scheme 1
Scheme 2
12b
reactions. On the other hand, the amination of methylene
groups activated by oxygen is facile using chloramine-T as
nitrene source with copper(I) catalysts. Our results in this area
are described herein. We note that an accidental amination of
dioxane, when chloramine-T was heated with a sulfoxide in the
presence of copper metal in dioxane as solvent, was reported
More recently, the need to find catalysts for amination, as
opposed to aziridination, has attracted a good deal of attention.5
For example, the Mu¨ller group described the amination of hydro-
=
carbons with NsN IPh as the nitrene source and rhodium(II)
catalysts. High yields of amination products were observed
with cycloalkenes (Scheme 3) and with benzylic substrates
(Scheme 4), but very large excesses of hydrocarbon were
12a
long ago. However, we believe this to be the first systematic
study of amination with chloramine-T.
Results and discussion
Scope and limitations
The previous report of amination of dioxane with chloramine-
12a
Scheme 3
T
led us to start our investigation with cyclic ethers. It quickly
T h i s j o u r n a l i s
T h e R o y a l S o c i e t y o f C h e m i s t r y 2 0 0 5
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 7 – 1 1 1
1 0 7
©

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became apparent that a very inexpensive catalyst, copper(I)
chloride with acetonitrile as ligand and solvent, was effective
in these reactions. Indeed, unless stated otherwise, all the
reactions described herein were carried out with a small excess of
chloramine-T and 10 mol% of copper(I) chloride in acetonitrile.
Amination of isochromane, tetrahydrofuran and dioxane pro-
ceeded smoothly to yield the hemiaminal products (Schemes 5
and 6), with tosyl amide TsNH2 being the only significant by-
product. With the exception of 5, the products were isolated
and fully characterised, although it was difficult to avoid de-
composition on chromatography, in particular with 5, hence our
inability to purify this compound. We were delighted to find that
our standard conditions were also effective for the amination
of acyclic ethers (Scheme 7). In these cases, the hemiaminal
products could not be isolated pure, since elimination of alcohols
leading to imines was observed. The fact that hemiaminals
are imine equivalents has been reported.14 Although it is clear
that the same elimination reaction will occur from the cyclic
hemiaminal products, in that case there is no entropic driving
force to the elimination.
characterised by its crude 1H NMR spectrum. We did not
observe any of the other proposed hemiaminal intermediates
7b, 7c and 7f–h; their presence is inferred from the formation
of the corresponding imine 8, the presence of which was clear
from the characteristic imine protons at ca. 9 ppm in the crude
1H NMR spectrum.
Assuming that the activating effect of the oxygen atom is
from a lone pair, it is to be expected that benzyl positions will
be activated towards amination not just by ether oxygen atoms
in the a-position, but by ether substituents in the ortho or para
positions of the aryl substituent, from where the effect of the
lone pair can be transmitted by conjugation. Indeed, substrates
9 to 11, including mono- and di-alkoxy substituted benzylic
substrates, were transformed to benzyl amines in acceptable
yields (Schemes 8, 9 and 10). It should be noted that amination
of 11b, which has two benzylic sites, occurred solely at the
remotely activated heterocyclic position (Scheme 10). Unlike
the hemiaminals described above, the sulfonamide products 12–
14 are of course configurationally stable. Hence, there is an
opportunity for inducing enantioselectivity in these reactions,
this being the subject of current research in our laboratories.
Scheme 5
Scheme 8
Scheme 6
Scheme 9
Scheme 7
Scheme 10
Insertion into the a-methylene group of simple dialkyl ethers
6a–d was observed. Interestingly, the reaction appears to be
much more sensitive to steric rather than electronic factors.
Hence, while the hemiaminal 7a resulting from amination of
diethyl ether could be isolated, though impure, in around 50%
yield, amination of di-n-butyl ether 6b proceeded with less
than 30% conversion using the standard procedure. Similarly,
as judged by the crude 1H NMR spectrum of the crude reaction
mixtures at the end of the standard procedure, amination of n-
butyl methyl ether 6c proceeded with around 50% conversion,
whereas amination of tert-butyl methyl ether 6d gave only traces
of the expected products of degradation of hemiaminal 7d.
With benzyl ethers 6e–h amination was, as expected, partic-
ularly facile, proceeding quantitatively. A trace of the benzylic
hemiaminal product 7e was observed in the 1H NMR spectrum
of the reaction mixture after ca. one hour, but decomposition to
the tosyl imine 8, which was then hydrolysed to benzaldehyde
under the reaction conditions, was rapid. As mentioned above,
the hemiaminal 7a derived from diethyl ether is sufficiently
stable to be isolated as part of a mixture and was tentatively
Finally, attempted amination of nitrogen analogues of the
substrates studied here yielded complex reaction mixtures and
we have not pursued these further.
Mechanistic studies
The mechanism of the amination procedure described herein
was also of interest. Mu¨ller showed that amination using
=
NsN IPh and dirhodium tetraacteate most probably proceeded
via concerted insertion of an intermediate nitrenoid into the C–
6a
H bond. On the other hand, the Che group have demonstrated
=
that amination using TsN IPh and ruthenium porphyrin cat-
alysts is a radical process, with the radical recombination step
7d
occurring with retention of stereochemistry.
The amination of substrates 15 lends itself to a Hammett-
type analysis. Competition experiments were carried out under
our standard conditions, but in addition to the usual one
equivalent of benzyl methyl ether, a further one equivalent of
a substituted benzyl methyl ether was added. The relative rates
of reaction of the two ethers were determined from the integrals
1 0 8
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 7 – 1 1 1

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of the benzylic protons of the residual starting materials in the
1H NMR spectrum. To permit comparison with the work of
the Mu¨ller group, Hammett plots were constructed for both
CuCl and Rh2(OAc)4 as catalysts. It should be noted that, while
the rhodium(II) catalyst was effective for amination of a range
of the substrates described above, the rates of the reactions were
consistently slower.
If insertion into the activated C–H bond is indeed the rate
determining step, further information can be gleaned from
kinetic isotope effects. We first carried out an intermolecular
competition experiment using THF and perdeutero THF. It
should be noted that in this experiment there is a significant
excess of the substrate relative to chloramine-T. The relative
rates of consumption of the H and D starting materials was
followed by gated 13C NMR spectroscopy with a very long
(2 min) delay time. The kH/kD value of 1.5 is low, but this is
consistent with a highly concerted transition state in which the
C–H–N bond angle is much less than the 180◦ required for a
maximum kH/kD value. Indeed, a similar value was reported by
Du Bois.15 It should be noted that the existence of an isotope
effect excludes the mechanism proposed to operate for reaction
of pentafluorophenylnitrene with THF, where the first, rate-
determining step is thought to be formation of an O–N ylide.16
Interestingly, an intramolecular competition experiment using
17 as substrate yielded a kH/kD value of around 4, This
is consistent with an asynchronous concerted mechanism as
described in the literature,17 falling part way between a truly
concerted three-centre transition state in which the C–H–N
bond angle is much less than 180◦ (as in Fig. 3) and a two-
The Hammett plot for the CuCl reactions is shown in Fig. 1
and that for Rh2(OAc)4 in Fig. 2. In both cases, an approximately
linear correlation with r was observed and q was found to be
both small in magnitude and negative. These data are clearly
inconsistent with the presence of highly charged or radical
benzylic intermediates in the rate-determining step. Instead,
following Mu¨ller and Du Bois,15 we propose that the data
6a
are more consistent with a relatively concerted insertion of an
electrophilic nitrenoid into the C–H bond (Fig. 3). It should
be noted that intermolecular competition experiments cannot
give an accurate q value, since the relative concentrations of
the substrates vary during the reaction. We had hoped that
intramolecular competition with substrates 16 would overcome
this limitation, but disappearance of starting material cannot be
used to monitor the relative rates in this case and quantitative de-
termination of the plethora of products from the decomposition
of the intermediate hemiaminals and susbsequent hydrolysis of
the imine products 8 was not possible in our hands. Nevertheless,
the approximate q values with substrates 16 were similar to those
from the intermolecular experiments.
7d
step mechanism, such as reported by Che, in which the C–H–
N bond angle is close to 180◦. In this analysis kH/kD should
increase, as in our case, with more highly activated substrates.
Conclusion
In summary, amination of C–H bonds activated by ether oxygen
atoms is facile with chloramine-T and a simple copper(I) salt
in acetonitrile. For cyclic ethers the hemiaminal products are
generally stable and can be isolated pure. For acyclic ethers, the
hemiaminal products, as expected, fragment with elimination of
alcohol to yield imines, with the exception of remotely activated
benzylic sites, when stable benzylamine derivatives are isolated.
Mechanistic studies are consistent with concerted insertion
of an electrophilic nitrenoid into the C–H bond in the rate-
determining step, though in an asynchronous manner with a
more activated substrate.
Experimental
Copper(I) chloride (99+%) was purchased from Aldrich. Ethers
15 were prepared by the standard Williamson synthesis.18 Their
NMR data were compared with literature reports.19 Ethers 16
and 17 were prepared by the literature methods.20 Chemical shifts
are relative to the residual solvent signal. Coupling constants are
in Hz.
Fig. 1 k(rel) vs. r for amination of 15 with copper(I) catalysis.
General procedure for amination of ethers
Substrate (1 mmol, 1 equiv), Cu(I)Cl (0.1 equiv) and chloramine-
T trihydrate (1.3 equiv) were dissolved in degassed MeCN
(6 cm3) under nitrogen. After stirring overnight, the green sus-
pension was filtered through a short plug of silica and the solvent
was removed under reduced pressure. The product was purified
by flash chromatography on silica gel (10% EtOAc in DCM).
N-(Isochroman-1-yl)-p-toluenesulfonamide 3. 74%; mp 169–
170 ◦C; mmax/cm-1 3150, 1376, 1150; dH (CDCl3, 300 MHz) 7.87
(2H, AAꢀ of AAꢀBBꢀ, J = 8.7), 7.34–7.18 (5H, m), 7.09 (1H,
m), 6.11 (1H, d, J = 8.7), 5.38 (1H, d, J = 8.7), 3.67 (2H, m),
2.86 (1H, m), 2.61 (1H, dd), 2.46 (3H, s); dC (CDCl3, 75 MHz)
143.3, 138.8, 134.5, 132.8, 129.5, 128.8, 128.4, 127.2, 126.8,
126.7, 79.9, 58.7, 27.5, 21.6; m/z (CI, NH3) found: 304.1009,
calc. for C16H17NO3S (M + H)+ 304.0929.
Fig. 2 k(rel) vs. r for amination of 15 with rhodium(II) catalysis.
7b
N-(Tetrahydrofuran-2-yl)-p-toluenesulfonamide 4 . Isolated
as an oil in 62% yield; mmax/cm−1 3250, 1377, 1151; dH (CDCl3,
300 MHz) 7.82 (2H, AAꢀ of AAꢀBBꢀ, J = 8.7), 7.21 (2H, BBꢀ of
AAꢀBBꢀ, J = 8.7), 5.79 (1H, d, J = 9.1), 5.47–5.34 (1H, m), 3.76
(2H, m), 2.45 (3H, s), 2.25–2.12 (1H, m), 2.00–1.80 (3H, m); dC
Fig. 3 Proposed concerted transition state for C–H insertion.
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 7 – 1 1 1
1 0 9

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(CDCl3, 75 MHz) 143.7, 138.8, 129.9, 127.5, 85.4, 67.6, 33.1,
24.4, 21.9; m/z (CI, NH3) 259 (M + NH4)+, found 242.0846,
calc. for C11H15NO2S (M + H)+ 242.0773.
(2H, s), 3.01 (2H, s), 1.52 (6H, s); dC (CDCl3, 100 MHz) 148.2,
143.5, 137.6, 128.8, 128.1, 127.7, 120.6, 118.3, 114.7 (1 Ar not
obs.), 87.7, 71.5, 43.7, 28.7; m/z (EI) 254 (M+).
12a
N-(1,4-Dioxan-2-yl)-p-toluenesulfonamide
5
.
Hemiami-
N-(7-Benzyloxy-2,2-dimethyl-2,3-dihydrobenzofuran-3-yl)-
p-toluenesulfonamide 14b. 48%; mp 164–165 ◦C. Found: C,
67.77; H, 5.88; N, 3.31; S, 7.55. Calc. for C24H25NO4S: C, 68.06;
H, 5.95; N, 3.31; S, 7.57%; mmax/cm−1 3286, 2923; dH (CDCl3,
400 MHz) 7.78 (2H, AAꢀ of AAꢀBBꢀ, J = 8.2), 7.34–7.20 (7H,
m), 6.75 (1H, d, J = 7.0), 6.60 (1H, t, J = 7.9), 6.15 (1H, d, J =
7.5), 5.10 (2H, s), 4.59 (1H, d, J = 8.9), 4.51 (1H, d, J = 8.9),
2.42 (3H, s), 1.43 (3H, s), 1.38 (3H, s); dC (CDCl3, 100 MHz)
148.0, 144.2 (2C), 138.4, 137.3, 130.3, 128.9, 128.3, 127.7, 127.5,
127.3, 121.6, 117.8, 116.1, 89.6, 71.4, 63.8, 27.6, 23.1, 22.0; m/z
(EI) 423 (M+).
nal 5 was the major product as judged by the NMR spectra,
but could not be isolated pure; mmax/cm−1 3200, 1377, 1150; dH
(CDCl3, 300 MHz) 7.83 (2H, AAꢀ of AAꢀBBꢀ, J = 8.7), 7.31 (2H,
BBꢀ of AAꢀBBꢀ, J = 8.7), 6.05 (1H, d, J = 8.5), 4.96 (1H, m),
3.79 (1H, dd, J = 11.7, 2.8), 3.70–3.35 (5H, m), 2.47 (3H, s); dC
(CDCl3, 75 MHz) 143.3, 138.9, 131.3, 126.2, 77.8, 69.2, 65.9,
62.1, 21.3; m/z (CI, NH3) 275 (M + NH4)+, 258 (M + H)+,
found 258.0792, calc. for C11H15NO4S (M + H)+ 258.0722.
N-(1-Ethoxyethyl)-p-toluenesulfonamide 7a. The hemiami-
nal could not be isolated pure; dH (CDCl3, 300 MHz) 7.73 (2H,
AAꢀ of AAꢀBBꢀ), 7.22 (2H, BBꢀ of AAꢀBBꢀ), 5.20 (1H, d, J =
9.5), 4.65 (1H, m, J = 9.5, 5.9), 3.49 (1H, m), 3.25 (1H, m), 2.39
(3H, s), 1.17 (3H, d, J = 5.9), 0.97 (t, 3H, J = 7.4).
Intermolecular kinetic isotope experiment
A Schlenk flask was charged with chloramine-T hydrate (211 mg,
750 lmol), 1,3,5-tris(tert-butyl)benzene (197 mg, 800 lmol)—
as an internal standard—and d3-acetonitrile (2.0 cm3) and
the mixture was thoroughly degassed before addition of THF
(122 lL, 1.50 mmol) and perdeutero THF (122 lL, 1.50 mmol).
An aliquot of ca. 1 cm3 was removed and passed through a small
plug of silica gel into an NMR tube which was then sealed under
N2 and stored at −18 ◦C prior to analysis. The reaction was
initiated by the addition of cop◦per(I) chloride (10 mg, 100 lmol)
and the reaction stirred at 25 C. After 3 h another aliquot of
ca. 1 cm3 was removed and filtered through a small plug of silica
into an NMR tube, which was sealed under N2. Quantitative
analysis was performed using a gated 13C NMR experiment with
a relaxation delay of 120 s.
N-[1-(4-Methoxyphenyl)ethyl]-p-toluenesulfonamide
12a.
Isolated as an oil in 62% yield. Found: C, 63.04; H, 6.24;
N, 4.61. Calc. for C16H19NO3S: C, 62.93; H, 6.27; N, 4.59%;
mmax/cm−1 3275, 1595, 1160; dH (CDCl3, 400 MHz) 7.61 (2H,
AAꢀ of AAꢀBBꢀ, J = 8.2), 7.18 (2H, BBꢀ of AAꢀBBꢀ, J = 8.2),
7.01 (AAꢀ of AAꢀBBꢀ, 2H, J = 8.5), 6.71 (2H, BBꢀ of AAꢀBBꢀ,
J = 8.5), 5.06 (1H, d, J = 6.3), 4.39 (1H, dt, J = 6.7, 6.3),
3.75 (3H, s), 2.38 (3H, s), 1.39 (3H, d, J = 6.7); dC (CDCl3,
100 MHz) 156.9, 141.1, 135.7, 132.2, 127.5, 125.4, 125.2, 111.9,
53.3, 51.1, 21.5, 19.5; m/z (EI) 305 (M+).
N-[1-(4-Methoxyphenyl)propyl]-p-toluenesulfonamide 12b21.
Isolated as an oil in 54% yield. Found: C, 64.11; H, 6.53; N, 4.36.
Calc. for C17H21NO3S: C, 63.92; H, 6.63; N, 4.39%; mmax/cm−1
3260; dH (CDCl3, 400 MHz) 7.54 (2H, AAꢀ of AAꢀBBꢀ, J = 8.2),
7.12 (2H, BBꢀ of AAꢀBBꢀ, J = 8.2), 6.92 (2H, AAꢀ of AAꢀBBꢀ,
J = 8.8), 6.67 (2H, BBꢀ of AAꢀBBꢀ, J = 8.8), 5.09 (1H, d, J =
6.8), 4.11 (1H, dd, J = 6.8, 7.1), 3.74 (3H, s), 2.36 (3H, s), 1.76
(2H, m), 0.76 (3H, t, J = 7.1); dC (CDCl3, 100 MHz) 158.8,
142.8, 137.8, 132.8, 129.3, 127.7, 127.1, 113.7, 59.4, 55.2, 30.5,
21.5, 10.5; m/z (EI) 319 (M+).
Intramolecular kinetic isotope experiment
In a procedure analogous to that for the intermolecular ex-
periment, d2-dibenzyl ether (200 mg, 1.00 mmol) was reacted in
d3-acetonitrile (2.0 cm3) with chloramine-T (281 mg, 1.00 mmol)
and copper(I) chloride (10 mg, 100 lmol). Again, 1,3,5-tris(tert-
butyl)benzene (81 mg, 330 lmol) was employed as the internal
standard.
N-[1-(3,4-Dimethoxyphenyl)ethyl]-p-toluenesulfonamide 13.
◦
74%; mp 101–102 C. Found: C, 60.54; H, 6.22; N, 4.13. Calc.
for C17H21NO4S: C, 60.87; H, 6.31; N, 4.18%. mmax/cm−1 3255,
1520, 1170, 1155; dH (CDCl3, 400 MHz) 7.57 (2H, AAꢀ of
AAꢀBBꢀ, J = 8.4), 7.13 (2H, BBꢀ of AAꢀBBꢀ, J = 8.4), 6.60 (2H,
m), 6.48 (1H, s), 5.08 (1H, br d), 4.36 (1H, m), 3.79 (3H, s), 3.68
(3H, s), 2.34 (3H, s), 1.40 (3H, s); dC (CDCl3, 100 MHz) 149.3,
148.8, 143.5, 134.9, 129.8, 127.5, 118.6, 111.3, 109.8 (1 Ar not
obs.), 56.3, 56.0, 53.8, 23.8, 21.8; m/z (EI) 335 (M+).
Acknowledgements
We thank Astra Zeneca, Pfizer and the EPSRC for financial
support, Dr Christopher Samuel for his mechanistic insight and
Dr Adam Clarke for help with NMR analysis.
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stirred solution of 2,2-dimethyl-2,3-dihydrobenzofuran (3.0 cm3,
19 mmol) in dry THF (100 cm3) was slowly added KOH (1.12 g,
20 mmol) to give a white suspension. To this suspension benzyl
bromide (2.4 cm3, 20 mmol) was added dropwise. After refluxing
overnight, the suspension was filtered and the solvent removed
under reduced pressure. Chromatography on silica gel with
DCM as eluent gave the product as an off-white powder. 4.65 g,
18.4 mmol, 92%; mp 74–76 ◦C. Found: C, 80.19; H, 7.12. Calc.
for C17H18O2: C, 80.28; H, 7.13%;mmax/cm−1 1590, 1390, 1055;
dH (CDCl3, 400 MHz) 7.43–7.29 (5H, m), 6.72 (3H, m), 5.19
1 1 0
O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 7 – 1 1 1

View Article Online
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O r g . B i o m o l . C h e m . , 2 0 0 5 , 3 , 1 0 7 – 1 1 1
1 1 1