Iron-catalyzed dehydrogenative phosphonation of N,N-dimethylanilines

Article abstract of DOI:10.1039/b913313e

Iron(ii) and iron(iii) salts catalyze the oxidative α-phosphonation of N,N-dimethylanilines with dialkyl H-phosphonates in the presence of tert-butylhydroperoxide.

Full text of DOI:10.1039/b913313e

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Iron-catalyzed dehydrogenative phosphonation of N,N-dimethylanilinesw
Wei Han and Armin R. Ofial*
Received (in Cambridge, UK) 6th July 2009, Accepted 10th August 2009
First published as an Advance Article on the web 24th August 2009
DOI: 10.1039/b913313e
Iron(II) and iron(III) salts catalyze the oxidative a-phosphonation
of N,N-dimethylanilines with dialkyl H-phosphonates in the
presence of tert-butylhydroperoxide.
Scheme
2
Electrochemical cross-coupling of tertiary amines with
a-Aminophosphonates and related a-aminophosphonic
acids are important mimics for structurally analogous
a-amino-carboxylic acids in which the planar carboxylic group
is replaced by a sterically more demanding tetrahedral
phosphonic acid moiety.1,2 Furthermore, a-aminophosphonates
and the corresponding phosphonopeptides possess useful
biological activity2–5 and have been studied, for example,
as protease2,3 and human collagenase inhibitors,2 catalytic
antibodies,2,6 neuroactive compounds,2 agrochemicals,2
antibacterial,7 antimicrobial,8 antifungal,9 anticancer,5 and
antithrombotic agents.2 The Kabachnik–Fields and the
Pudovik reaction which rely on reactions of dialkyl
H-phosphonates5 with iminium or imine species, respectively,
are generally applicable for the synthesis of differently
substituted a-aminophosphonates.10 The unbroken interest
in both types of reactions is reflected by continuous methodo-
logical advancements11 which include microwave-assisted
transformations12 as well as stereoselective13 and metal-catalyzed
or organocatalytic enantioselective syntheses.14,15
diethyl H-phosphonate (supporting electrolyte: collidine–H+ ClO4À).17a,b
bond in place of the C(sp3)–H and H–P bonds in the reagents
(Scheme 2).17a,b
These observations prompted us to investigate whether an
iron-catalyzed oxidative cross coupling18–20 could be used for
the selective transformation of a C–H bond21 of the N-methyl
group of an aromatic tertiary amine into a C–P bond. To the
best of our knowledge, such a metal-catalyzed oxidative
activation of C(sp3)–H bonds with subsequent formation of
a new C–P bond had been unknown at the time when we
started our work.
Very recently, Basle
´
and Li reported an aerobic
CuBr-catalyzed phosphonation of the benzylic position in
N-aryl tetrahydroisoquinolines (MeOH, 60 1C) with dialkyl
H-phosphonates22 as a novel application of the very versatile
cross-dehydrogenative-coupling (CDC) method.23
Herein, we report on the synthesis of a-aminophosphonates
by selective oxidation of N,N-dimethylanilines in the presence
of iron salts as catalysts and dialkyl H-phosphonates.
We started our studies by exploring potential catalyst
systems for the oxidative phosphonation of N,N-dimethyl-p-
toluidine (1) with diethyl phosphonate at room temperature in
the presence of different iron salts and varied the solvent24 and
the oxidant (Table 1).
On the other hand, only few syntheses of a-amino-
phosphonates from tertiary amines have been reported. Electro-
chemical activation of ring-substituted N,N-dimethylanilines
has previously been studied,16 but only moderate yields
(o30% at rt, in MeCN) of a-phosphonated products were
obtained with P-nucleophiles.17 Nevertheless, the work by
Genies et al. showed that during anodic oxidation of mixtures
of diethyl phosphonate and N,N-dimethyl-p-toluidine (1) only
the latter was oxidized to generate nitrogen-centered radical
Methanol was the best solvent for the FeCl2-catalyzed
phosphonation of the N-methyl group in 1 with diethyl
phosphonate in the presence of tert-butylhydroperoxide
(entry 1, Table 1).24 This result agrees with our previous
cations which, after proton loss, underwent
a second
one-electron oxidation (Scheme 1).17a,b The intermediate
iminium ions were sufficiently reactive to be intercepted by
the diethyl phosphonate that survived the oxidative reaction
conditions. Hence, products were formed with a new C–P
observations for the FeCl2-catalyzed a-cyanation of
and other tertiary amines with tert-butylhydroperoxide and
trimethylsilyl cyanide.20 Analogously, Basle
and Li reported
1
´
the aerobic CuBr-catalyzed phosphonation of N-aryl-tetrahydro-
isoquinolines to be most efficient in methanol.22,25
Further iron salts were also investigated as catalysts.26
Significantly lower yields of 2 were obtained when FeCl2 was
replaced by FeF2, Fe(OAc)2, or Fe(ClO4)2 (entries 2–4,
Table 1). On the other hand, the iron(III) salts FeBr3 or FeCl3
proved to be comparably active (entries 5 and 6, Table 1) as
FeCl2.
Scheme 1 Generation of iminium ions through anodic oxidation of
tertiary amines.17a,b
Only trace amounts of phosphonation product 2 could be
isolated when the reaction was performed either without
catalyst (entry 7, Table 1), under conditions similar to those
Department Chemie und Biochemie, Ludwig-Maximilians-Universitat
¨
E-mail: ofial@lmu.de; Fax: +49 (0)89 21809977715;
Tel: +49 (0)89 218077715
w Electronic supplementary information (ESI) available: Synthetic
procedures and product characterization. See DOI: 10.1039/b913313e
¨
Munchen, Butenandtstr. 5–13 (Haus F), 81377 Munchen, Germany.
¨
described by Basle
´
and Li22 [HP(O)(OEt)2 (2 equiv.), O2
(1 atm), 10 mol% CuBr, MeOH, 60 1C, 24 h], or in the
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Table 1 Optimization of the catalysta
N,N-dimethyl-p-toluidine (1) as diethyl phosphonate.
The position adjacent to nitrogen in 1 was also efficiently
phosphonated with dimethyl phosphonate, though this reaction
required longer reaction times than the corresponding trans-
formations with the diethyl or di-isopropyl derivatives
(entries 4–6). This behavior was observed also for reactions
with further tertiary amines (entries 1–3), however, the differ-
ences were so small (entries 8–10) that a conclusive reactivity
order for the three dialkyl H-phosphonates used in this work
could not be derived from the results summarized in Table 2.
N,N-Dimethylanisidine could be a-phosphonated in good
yields at room temperature (entries 1–3) when the amount of
catalyst was slightly increased. The products are valuable
synthetic intermediates because they contain two different,
easily removable groups, the p-methoxyphenyl and the alkyl
substituents of the phosphonic ester moiety,15b and can,
therefore, be stripped down to the phosphonic acid analogue
of N-methyl glycine.
Catalyst
Oxidant
Yieldb (%)
1
2
3
4
5
6
7
8
FeCl2
FeF2
Fe(OAc)2
Fe(ClO4)2ÁH2O
FeBr3
FeCl3
None
FeCl2
FeCl2
tert-BuOOH
tert-BuOOH
tert-BuOOH
tert-BuOOH
tert-BuOOH
tert-BuOOH
tert-BuOOH
(tert-BuO)2
84
43
19
55
66
76
Trace
Trace
37
9
10
11
Benzoyl peroxide
Cumylhydroperoxide
O2 (1 atm)
FeCl2
FeCl2
27
61c
a
The unsubstituted N,N-dimethylaniline was efficiently
converted at room temperature (entry 7) in the presence of
20 mol% FeCl2. Under similar reaction conditions, N-phenyl-
pyrrolidine27 and N-phenyl-1,2,3,4-tetrahydroisoquinoline28
were found to be poor substrates for the phosphonation.
Nevertheless, even N,N-dimethylaniline derivatives that
carried electron-withdrawing substituents (entries 8–11) could
be converted successfully at elevated reaction temperature.
For the m-nitro derivative a moderate yield was obtained with
the most reactive dialkyl phosphonate in the presence of
30 mol% catalyst under reflux conditions (entry 11).
Because many different iron species are conceivable18c that
might be involved in the phosphonation reaction presented in
this work, we do not want to speculate about the mechanism
at this point of our studies. Detailed mechanistic studies will
be the subject of future investigations.
Reaction conditions: N,N-dimethyl-p-toluidine (1.0 mmol), diethyl
H-phosphonate (2.0 mmol), peroxide (2.5 mmol), and methanol
b
(2.0 mL), dry N2 atmosphere. Yield of isolated product after column
c
chromatography on silica gel. Extended reaction time: 36 h.
presence of di-tert-butylperoxide as oxidant instead of tert-
butylhydroperoxide (entry 8, Table 1). The use of other
peroxides gave moderate yields of 2 (entries 9 and 10,
Table 1). With dioxygen as oxidant, however, a promising
level of the phosphonation of 1 was achieved at extended
reaction time (entry 11, Table 1).
The substrate variability of the FeCl2-catalyzed oxidative
phosphonation was then investigated by combining different
dialkyl phosphonates with different ring-substituted N,N-di-
methylanilines (Table 2).
Di-isopropyl phosphonate (entry 6 in Table 2) was found to
be a comparably reactive phosphonation reagent towards
In summary, within short time two different approaches for
metal-catalyzed oxidative a-phosphonations of tertiary amines
have been reported that use the concept of C(sp3)–H activa-
tion with subsequent C–P bond formation. The scope of the
aerobic copper(I)-catalyzed version by Li22 and the substrate
variability of the iron-catalyzed system with tert-butyl-
hydroperoxide as oxidant described in this work complement
each other and add a new method to the synthetic tool kit of
chemists which allows for the formation of new C–P bonds at
unfunctionalized starting materials.
Table 2 FeCl2-catalyzed oxidative phosphonation of X-substituted
N,N-dimethylanilines with dialkyl H-phosphonatesa
Entry
X
FeCl2/mol%
R
t/h T/1C
Yieldb (%)
We thank the Chinese Scholarship Council for a fellowship
to W.H. Generous support by Prof. Herbert Mayr is gratefully
acknowledged.
1
2
3
4
5
6
7
8
p-OMe 15
Me
Et
i-Pr 18
Me
Et
i-Pr 15
Et
Me
Et
i-Pr 24
Et 36
36
18
rt
rt
rt
rt
rt
rt
rt
60
rt
60
77
83
80
78
84
74
71
84
80
68
—
—
p-Me
—
—
H
p-Br
—
15
15
10
10
10
20
15
15
15
24
15
Notes and references
14
24
24
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9
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—
m-NO2 30
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a
Reaction conditions: amine (1.0 mmol), iron(II) chloride
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GC-MS.
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mixture was obtained, and we could not isolate the corresponding
a-aminophosphonate from the reaction of the amine with
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Chem. Commun., 2009, 6023–6025 | 6025