Iron-catalyzed oxidative mono- And bis-phosphonation of N,N-dialkylanilines

Article abstract of DOI:10.1002/adsc.201000092

The dehydrogenative a-phosphonation of substituted N,N-dialkylanilines by dialkyl H-phosphonates was achieved under mild conditions by using environmentally benign iron(II) chloride as catalyst and teri-butyl hydroperoxide as oxidant. The reaction proceed

Full text of DOI:10.1002/adsc.201000092

FULL PAPERS
DOI: 10.1002/adsc.201000092
Iron-Catalyzed Oxidative Mono- and Bis-Phosphonation of
N,N-Dialkylanilines
Wei Han,a Peter Mayer,a and Armin R. Ofiala,*
a
Department Chemie, Ludwig-Maximilians-Universitꢀt Mꢁnchen, Butenandtstr. 5–13, 81377 Mꢁnchen, Germany
Fax : (+49)-89-2180-99-77715; e-mail: ofial@lmu.de
Received: February 3, 2010; Revised: May 4, 2010; Published online: June 10, 2010
Dedicated to Professor Rolf Huisgen on the occasion of his 90th birthday.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adsc.201000092.
Abstract: The dehydrogenative a-phosphonation of nyl)methane and bis-4,4’-(dimethylamino)benzophe-
substituted N,N-dialkylanilines by dialkyl H-phos- none underwent bisphosphonation selectively by re-
phonates was achieved under mild conditions by spective monophosphonation at the remote dimethyl-
using environmentally benign iron(II) chloride as amino groups. Furthermore, the use of excess di-
catalyst and tert-butyl hydroperoxide as oxidant. The
ACHTUNGTRENNUNG
reaction proceeded in the presence of electron-do- functionalize both methyl groups of NAHCUTNGTRENNUNG
nating (methoxy, methyl, benzyl) and electron-with- dimethyl-p-toluidine and N,N-dimethylaminomesi-
drawing ring-substitutents (bromo, carbonyl, carbox- dine, respectively, to obtain a,a’-bisphosphonato-
yl, m-nitro) in moderate to good yields. The X-ray
crystal structure of N-(5,5-dimethyl-2-oxo-2l5-
[1,3,2]dioxaphosphinan-2-yl-methyl)-N-methyl-p-tol-
ACHTUNGTRENaNUNG mines in high yield.
ꢀ
Keywords: C H activation; iron catalysis; oxidation;
uidine was determined. Bis-(4-(dimethylamino)phe- phosphonation; regioselectivity
Introduction
summarized as Pudovik reactions. Hence, the Pudovik
reaction gives rise to the formation of a-amino-
a-Aminophosphonates and related a-aminophosphon- phosphonates if an imine is employed as p-system.[11]
ic acids are structural analogues of a-amino acids.[1–3] Continuous efforts are being made to improve the
They carry a tetrahedral phosphonic acid moiety that synthesis of a-aminophosphonates[12] and recent ad-
mimics the transition state of nucleophilic substitution vances of the Kabachnik–Fields and the Pudovik reac-
reactions at the carboxyl group of natural amino tions comprise stereoselective[13] and catalytic enantio-
acids,[4] which makes them efficient competitors for
the active sites of enzymes and other cell receptors.[1,3]
As a consequence, the chemical and, even more im-
portant, biological properties of aminophosphonates
and related phosphonopeptides have been studied ex-
tensively.[1–4] Furthermore, a-aminophosphonates have
found a multitude of applications in medicinal, agri-
cultural, and industrial chemistry.[1–8]
The standard procedures for the syntheses of a-
aminophosphonates mainly rely on the Kabachnik–
Fields
reaction
or
the
Pudovik
reaction
(Scheme 1).[1,2] The Kabachnik–Fields reaction is a
three-component reaction of a dialkyl phosphonate, a
carbonyl compound, and a primary or secondary
amine.[9,10] Additions of phosphorus compounds with
ꢀ
a labile H P bond to unsaturated compounds are Scheme 1. Synthetic routes to a-aminophosphonates.
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Wei Han et al.
FULL PAPERS
3
selective[14,15] syntheses as well as the use of micro-
wave techniques.[16]
The few studies on the double activation of C
(sp )
ꢀ
H bonds in the a- and in the a’-positions to nitrogen
3
ꢀ
Selective activation of C
(sp ) H bonds for subse- of tertiary amines have so far concentrated on its use
[18d,23,26]
ꢀ
quent cross-coupling reactions is an attractive concept for subsequent C C bond forming reactions.
that has strongly developed during the last decade be- Methods for efficient and selective a,a’-bisphospho-
cause it removes the need for reactant prefunctionali- nations of tertiary amines are presently still lacking.
zation.[17] As it is known that metal catalysts, such as
In this paper, we report the selective synthesis of a-
copper[18] or iron salts,[19–23] are capable of activating aminophosphonates under mild conditions by oxida-
3
ꢀ
C
N
amines under oxidative conditions, we were curious sive and non-toxic iron salt without designed ligands.
whether the formation of a-aminophosphonates from Moreover, the usefulness of the catalyst system de-
unfunctionalized tertiary amine precursors could be scribed in this work is substantiated by the finding
achieved by
(Scheme 1, lower path).
During the course of our studies, Baslꢃ and Li re- phosphonation agent are employed in excess.
a
metal-catalyzed cross-coupling that direct a,a’-bisphosphonations of Ar-N
ACHTUNGTRENNUNG(CH3)2
groups are feasible when both the oxidant and the
ported
a
novel cross-dehydrogenative coupling
(CDC),[18] in which a CuBr-catalyzed phosphonation
of the benzylic position in N-aryltetrahydroisoquino- Results and Discussion
lines (MeOH, 608C) with dialkyl H-phosphonates was
performed under aerobic conditions.[24] However, in a-Phosphonation
our hands, CuBr/O2 was inefficient for the analogous
phosphonation of the NMe2 group in N,N-dimethyl-p- The conditions tested in order to optimize the catalyst
toluidine.[25]
system for the a-phosphonations are listed in
Table 1. Optimization of the catalyst system for the a-phosphonation of N,N-dimethyl-p-toluidine (1a) with diethyl H-phos-
phonate (2a).[a]
Entry
Catalyst
Oxidant
Solvent
t [h]
Yield[b] [%]
1
2
3
4
5
6
7
8
FeCl2
FeF2
t-BuOOH[c]
t-BuOOH[c]
t-BuOOH[c]
t-BuOOH[c]
t-BuOOH[c]
t-BuOOH[c]
t-BuOOH[c]
t-BuOOH[c]
t-BuOOH[c]
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
EtOH
15
15
15
15
15
15
15
15
15
15
15
15
36
24
15
15
15
15
15
84
43
19
55
66
76
trace
51
46
trace
37
27
61
trace
34
26
21
29
47
Fe
Fe
U
FeBr3
FeCl3
None
CuCl
CuBr
FeCl2
FeCl2
FeCl2
FeCl2
CuBr
FeCl2
FeCl2
FeCl2
FeCl2
FeCl2
9
10
11
12
13
14
15
16
17
18
19
A
benzoyl peroxide
cumylhydroperoxide
O2 (1 atm)
O2 (1 atm)
t-BuOOH[c]
t-BuOOH[c]
i-PrOH
t-BuOH
CH2Cl2
CH3CN
t-BuOOH[c]
t-BuOOH[c]
t-BuOOH[c]
[a]
Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), oxidant (2.5 mmol), and solvent (2.0 mL), dry N2 atmosphere, room
temperature (r.t.) was 23ꢁ28C.
[b]
[c]
Yield of isolated product after column chromatography on silica gel.
A 5.5M solution in decane was used.
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Iron-Catalyzed Oxidative Mono- and Bis-Phosphonation of N,N-Dialkylanilines
Table 1.[25] We had chosen N,N-dimethyl-p-toluidine chloromethane, or acetonitrile reduced the yields of
(1a) as standard substrate and found that the combi- 3a to below 50% (Table 1, entries 15–19).
nation of catalytic amounts of FeCl2 (10 mol%) with
The optimized reaction conditions (Table 1,
2.5 equivalents of tert-butyl hydroperoxide as oxidant entry 1) could be successfully applied for the reactions
in methanol[27] was more efficient than other catalyst/ of different aliphatic dialkyl H-phosphonates. Similar
oxidant/solvent combinations that were investigated. reaction times for diethyl (2a), dimethyl (2b), diiso-
By using two equivalents of diethyl phosphonate (2a), propyl (2c), and di-n-butyl phosphonates (2d) indicate
the optimum yield of the a-aminophosphonate 3a that the reactivities of these dialkyl phosphonates are
(Table 1, entry 1) was already obtained at ambient almost independent of the alkyl moieties (Table 2, en-
temperature (84% yield of isolated 3a).[25] Different tries 1–5). Only when dibenzyl phosphonate (2e), was
iron and copper salts were tested as catalysts (Table 1, employed, were reflux conditions required to achieve
entries 1–9), but only FeCl3 and FeBr3 were found to a high degree of conversion (Table 2, entry 6).
perform with comparable catalytic activity as FeCl2
under otherwise analogous reaction conditions (en- sumed to be responsible for the low yields of the
tries 5 and 6). CuBr-catalyzed oxidative phosphonation of N-arylte-
Replacing t-BuOOH by other organic peroxides re- trahydroisoquinolines in aqueous solution.[24]
sulted in low yields of 3a, (Table 1, entries 10–12). For the reactions listed in Table 2, which were car-
Hydrolysis of dimethyl phosphonate (2b) was as-
Noteworthy however, the use of dioxygen as oxidant ried out in methanolic solution, we have not observed
in combination with FeCl2 as catalyst delivered 3a in an exchange of the alkyl groups. Nevertheless, the re-
61% yield after 36 h reaction time (Table 1, entry 13), action of N,N-dimethyl-p-toluidine (1a) with bis(2,2,2-
but gave only traces of 3a when CuBr was employed trifluoroethyl) phosphonate (2f) generated the mixed
as the catalyst[24] (Table 1, entry 14). Substitution of ester 4 in high yield (Scheme 2). The formation of 4
the standard solvent methanol by other alcohols, di- can be rationalized by the substitution of one of the
Table 2. a-Phosphonation of ring-substituted N,N-dimethylanilines.
Entry
R
R’[a]
FeCl2 [mol%]
t [h]
T [8C]
Yield[b] [%]
dC (NCH2P) [ppm]
1JC,P [Hz]
1
2
3
4
5
6
7
8
4-CH3 (1a)
Et (2a)
10
10
10
10
15
20
15
15
15
20
15
15
15
30
30
30
30
30
30
15
15
24
15
18
20
18
36
18
14
24
24
24
24
24
24
24
36
24
r.t.[c]
r.t.[c]
r.t.[c]
r.t.[c]
r.t.[c]
reflux
r.t.[c]
r.t.[c]
r.t.[c]
r.t.[c]
r.t.[c]
60
3a (84)
3a (63)[d]
3b (78)
3c (74)
3d (63)
3e (79)
3f (83)
3g (77)
3h (80)
3i (71)
3j (80)
3k (84)
3l (68)
3m (trace)
3n (65)
3o (61)
3p (78)
3q (57)
3r (trace)
50.3
162
Et (2a)[d]
Me (2b)
i-Pr (2c)
n-Bu (2d)
CH2Ph (2e)
Et (2a)
49.8
51.2
50.2
50.7
51.2
50.7
52.0
49.9
49.8
49.1
50.5
–
48.9
48.8
48.8
49.3
–
162
166
161
159
162
162
166
162
162
161
164
–
161
160
160
161
–
4-OCH3 (1b)
Me (2b)
i-Pr (2c)
Et (2a)
9
10
11
12
13
14
15
16
17
18
19
H (1c)
4-Br (1d)
Et (2a)
Me (2b)
i-Pr (2c)
Et (2a)[e]
Et (2a)[e]
Et (2a)
Et (2a)
Et (2a)
60
ꢂ
4-C CH (1e)
reflux
reflux
reflux
reflux
reflux
reflux
4-COPh (1f)
4-CO2Et (1g)
4-COOH (1h)
3-NO2 (1i)
4-NO2 (1j)
Et (2a)
[a]
Reactants 1, 2, and t-BuOOH were used in a molar ratio of 1.0:2.0:2.5 if not indicated otherwise.
Yields of isolated products after column chromatography on silica gel.
Room temperature (r.t.) was 23ꢁ28C.
[b]
[c]
[d]
[e]
In the presence of 1.0 equivalent of 3,5-di-tert-butyl-4-hydroxytoluene.
In the presence of 3 equivalents of 2a.
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X-ray analysis.[28] Details of the crystal structure of 3s
are discussed in the Supporting Information.
The phosphonations of methyl-, methoxy-, bromo-,
and 3-nitro-substituted substrates show that several
functional groups are tolerated as ring substitutents in
the N,N-dimethylanilines (Table 2, entries 1–13 and
18). Whereas the use of 4-ethynyl- (1e) and 4-nitro-
N,N-dimethylaniline (1j) did not allow us to isolate a
phosphonation product,[29] the p-benzoyl substituted
N,N-dimethylaniline 1f was phosphonated in the pres-
ence of 3 equivalents of 2a (65% yield, Table 2,
entry 15). Furthermore, the linkage of p-carboxyl
Scheme 2. Phosphonation and transesterification in the reac-
tion of 1a with 2f in methanol (in CDCl3: dC
G
1
50.3 ppm, JC,P =162 Hz).
2,2,2-trifluoroethoxy groups by a methoxy group that groups to the aniline substrates either as ethyl ester in
originates from the solvent methanol. 1g (Table 2, entry 16) or as free carboxylic acid in 1h
The reaction of the cyclic phosphonate 5,5-dimeth- (Table 2, entry 17) was compatible with the phospho-
yl-1,3,2-dioxaphosphorinan-2-one (2g) with 1a fur- nation reaction and gave acceptable yields of 3o
nished 3s in moderate yield already at room tempera- (61%) and 3p (78%), respectively.
ture (Scheme 3), analogous to the behavior of the
Michlerꢄs ketone 5 (Table 3, entry 1) was chosen as
acyclic dialkyl phosphonates 2a–d. Precipitation from a model for studying the relative reactivities of the
ꢀ
a CH2Cl2/n-pentane/ethyl acetate mixture (10/10/1, N CH3 group as part of either a N
G
v/v/v) delivered crystals of 3s that were suitable for
A
G
equivalents of 2a, the symmetrically substituted tet-
raethyl bis-phosphonate 7 was obtained as the major
product (51%) together with the mono-phosphona-
tion product (6, 34%). This result indicates that the
first phosphonation of an NACHTNUGTRNEUNG(CH3)2 is much faster than
a second phosphonation at the same amino group.
Employing the more activated bis[4-(dimethylami-
no)phenyl]methane (8) in the presence of 1.5 equiva-
lents of 2a produced already a 4:3-mixture of the
mono- and bis-phosphonation products 9 and 10, re-
spectively, which could be separated by column chro-
matography (Table 3, entry 2). Finally, the symmetri-
cal bis-phosphonation product 10 (76%) formed selec-
tively when 4 equivalents of 2a were used (Table 3,
ꢀ
entry 3). Competing C H bond activation at the cen-
tral benzylic methylene group was not observed.[30–32]
N-Ethyl-N-methylaniline (11) allows one to address
the chemoselectivity of the oxidative phosphonation
reaction (Table 3, entry 4). The high yield of 12 (83%)
demonstrates that preferential oxidation of the N-
methyl group takes place.[27a,33]
Nevertheless, formation of 14 and 16 from N,N-di-
ethylaniline (13) and N,N-dibutylaniline (15), respec-
tively, as well as the successful a-phosphonation of
the heterocycles in N-phenylpyrrolidine (17) and N-
phenylpiperidine (19) (Table 3, entries 5–8) proved
that the scope of the FeCl2-catalyzed phosphonation
reaction can be extended also to other tertiary
amines, beyond those that carry dimethylamino
groups.
Although N-phenyl-1,2,3,4-tetrahydroisoquinoline
(21) was almost quantitatively converted under the
reaction conditions, we were not able to isolate the
expected a-aminophosphonate 22.[34] Instead, we ob-
tained the lactam 2-phenyl-3,4-dihydro-2H-isoquino-
lin-1-one (23)[35] owing to oxidation of the benzylic
Scheme 3. Formation and crystal structure determination
of
N-(5,5-dimethyl-2-oxo-2l5-[1,3,2]dioxaphosphinan-2-yl-
methyl)-N-methyl-p-toluidine (3s) from 1a with 2g in metha-
nol (room temperature, r.t., was 23ꢁ28C; the shown ther-
mal ellipsoids are drawn at the 50% probability level; in
1
CDCl3: dC
N
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Iron-Catalyzed Oxidative Mono- and Bis-Phosphonation of N,N-Dialkylanilines
Table 3. Oxidative FeCl2-catalyzed a-phosphonations of N,N-dialkylanilines with the dialkyl phosphonates 2a,b in methanol.
Entry
Amine
Conditions
Products (Yield [%])[a]
1
5
8
2a (4 equiv.), t-BuOOH (4 equiv.),
FeCl2 (20 mol%), 24h, reflux[b]
2
3
2a (1.5 equiv.), t-BuOOH (2.5 equiv.),
FeCl2 (15 mol%), 24h, 608C
8
2a (4 equiv.), t-BuOOH (4 equiv.),
FeCl2 (15 mol%), 24h, 608C
4
5
11
13
15
2a (2 equiv.), t-BuOOH (2.5 equiv.),
FeCl2 (20 mol%), 24h, 608C
2a (2 equiv.), t-BuOOH (2.5 equiv.),
FeCl2 (20 mol%), 24h, 608C[c]
6
7
8
2b (2 equiv.), t-BuOOH (2.5 equiv.),
FeCl2 (30 mol%), 24h, 608C[c]
2a (3 equiv.), t-BuOOH (2.5 equiv.),
FeCl2 (30 mol%), 24h, reflux
17
19
2a (3 equiv.), t-BuOOH (2.5 equiv.),
FeCl2 (30 mol%), 24h, reflux
9
2a (2 equiv.), t-BuOOH (2.5 equiv.),
FeCl2 (20 mol%), 24h, reflux
21
[a]
Yields of isolated products after column chromatography on silica gel.
In the presence of 2a (2 equiv.) and t-BuOOH (2.5 equiv.) 6 and 7 were isolated in 41% and 27% yield, respectively
[b]
(20 mol% FeCl2, 24 h, reflux).
Not optimized.
[c]
position of the substrate (Table 3, entry 9). A success- NCH2P carbon atom in 3 and 4 are in a narrow range
1
ful phosphonation of N-aryltetrahydroisoquinolines of 48.8–52.0 ppm with characteristic JC,P coupling
(i.e., 21!22) with CuBr as catalyst under aerobic constants from 159 to 164 Hz. In the a-aminophosph-
conditions has been reported.[24]
onates listed in Table 2, the 31P nuclei resonate be-
The products of the phosphonation rections were tween 22.2 and 24.8 ppm. Slight changes in the elec-
characterized by NMR spectroscopic methods which tronic environment of the phosphorus atom are de-
unambiguously indicate the formation of a carbon- tected in the presence of a trifluoroethoxy group (4:
phosphorus bond. As noted in Table 2 and Scheme 2 dP =26.1 ppm) or
a 2-oxo-[1,3,2]dioxaphosphinane
and Scheme 3, the 13C NMR chemical shifts for the ring (3s: dP =20.0 ppm).
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presence of excess diethyl H-phosphonate (2a) and
oxidant delivered mixtures of mono-phosphonated
(3a and 3t) and bisphosphonated products (25a and
25b).
Maximum yields of 25a and 25b were reached
when 4 to 5 equivalents of phosphonate 2a were used.
The presence of 10 equivalents of 2a reduced the
overall yield and the yield of the two-fold functional-
Scheme 4. Iron-catalyzed formation of a-aminophosphonate
3d from 1a and tributyl phosphite (2 equiv.).
Our attempts to directly synthesize an a-amino- ized products 25.
phosphonic acid by combining 1a with phosphorus
N,N-Dimethylmesidine (1l) was slightly more prone
acid HP(O)(OH)2 and tert-butyl hydroperoxide failed to undergo a,a’-bisphosphonations than 1a, and the
and delivered N,4’-dimethylformanilide (24).[36,37]
isolated yields of the amino-a,a’-bisphosphonates 25
Trialkyl phosphites might be considered as alterna- reached levels between 65 and 80% with different di-
tive P-nucleophiles. Indeed, the reaction of tributyl alkyl phosphonates, even in the presence of sterically
phosphite with 1a (Scheme 4) furnished 3d in a yield demanding isopropyl groups (Table 4, entries 6, 8–10).
comparable to that of the analogous reaction (at
room temperature) of 1a with dibutyl phosphonate cal cation 1lC than in 1aC has been discussed earlier
The higher acidity of the NCH3 groups in the radi-
+ +
(2d) but required elevated reaction temperatures.
a,a’-Bisphosphonations[38]
in the context of anodic oxidations. Genies and co-
workers rationalized the different regioselectivities of
1aC· and 1lC in radical dimerizations by the reduced de-
localization of the unpaired electron in the radical
cation 1lC+ because of the twist between the plane of
Metal-catalyzed oxidative cross-coupling reactions the aromatic ring and the plane containing the nitro-
offer the potential for two-fold functionalizations of gen and the carbons of the a-methyl groups.[39]
the a,a’-positions of tertiary amines. Nevertheless,
Later, the groups of Dinnocenzo, Fari, and Gould
only few one-pot procedures of such reactions that quantified Geniesꢄ assumption and calculated a twist
avoid the isolation of mono-functionalized intermedi- angle of 428 between the aryl ring and the dimethyl-
ates have been reported.[18d,23]
As shown in Table 4, the reactions of 1a (entries 1– 31G*), significantly larger than the 98 twist angle of
4) and N,N-dimethylmesidine (1l, entries 5–7) in the the parent N,N-dimethylaniline radical cation 1cC .
amino group in the radical cation 1lC+ (B3LYP/6-
ACHTUNGTRENNUNG
+ [40]
Table 4. a-Mono- and a,a’-bis-phosphonation of N,N-dimethyl-p-toluidine (1b) and N,N-dimethylmesidine (1l).
Entry
R
R’
mol% FeCl2
t [h]
T [8C]
Products (Yield [%])[a]
1
2
3
4
5
6
7
8
9
10
4-CH3 (1a)
Et (2a) (2 equiv.)[c]
Et (3 equiv.)[c]
10
20
20
20
10
20
20
20
20
20
15
24
24
24
24
24
24
24
24
24
r.t.[b]
60
60
60
60
reflux
reflux
reflux
reflux
reflux
3a (84)
3a (61)+25a (18)
3a (45)+25a (43)
3a (24)+25a (40)
3t (39)+25b (56)
3t (19)+25b (65)
3t (17)+25b (59)
3u (15)[e] +25c (69)
3v (12)+25d (80)
3v (11)+25d (65)
Et (5 equiv.)[d]
Et (10 equiv.)[d]
2,4,6-(CH3)3 (1l)
Et (2a) (2 equiv.)[c]
Et (4 equiv.)[d]
Et (10 equiv.)[d]
i-Pr (2c) (5 equiv.)[d]
n-Bu (2d) (5 equiv.)[d]
n-Bu (10 equiv.)[d]
[a]
Yields of isolated products after column chromatography on silica gel.
Room temperature (r.t.) was 23ꢁ28C.
[b]
[c]
[d]
[e]
In the presence of 2.5 equivalents of t-BuOOH.
In the presence of 5 equivalents of t-BuOOH.
It was not possible to isolate 3u. Therefore, the yield of 3u was estimated from the isolated yield of 25c and the product
ratio 3u/25c obtained from the GC-MS of the crude product.
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Iron-Catalyzed Oxidative Mono- and Bis-Phosphonation of N,N-Dialkylanilines
Mechanism
Numerous iron complexes have been used to mimic
enzymatic oxidations which involve the activation of
ꢀ
C H bonds under mild and selective conditions. In-
vestigations by different groups have shown that in
the presence of hydroperoxides a variety of rather
complex mechanistic scenarios can be derived for
these iron-catalyzed reactions, which have been re-
viewed.[41] In particular, the question whether radical
or non-radical species are formed as intermediates in
Fe2+/ROOH systems has given rise to controversial
discussions.
ꢀ
To gain some insight into the initial C H activation
at the tertiary amines that is required for the subse-
quent phosphonation, we have studied our standard
reaction in the presence of a radical scavenger. With
N,N-dimethyl-p-toluidine (1a) as substrate, the addi-
tion of one equivalent of 3,5-di(tert-butyl)-4-hydroxy-
toluene (BHT) to the FeCl2 (10 mol%)/t-BuOOH/
Scheme 5. Plausible mechanism for the formation of a-ami-
nophosphonates from tertiary aromatic amines and dialkyl
phosphonates under oxidative conditions.
HP(O)ACHTUNGTRENNUNG(OEt)2 mixture reduced the yield of the a-ami-
nophosphonate 3a only slightly (63% yield, Table 2,
entry 2). A similar lowering of the yield in the pres-
ence of BHT was reported earlier by Miura for analo-
gous FeCl3-catalyzed oxidations of tertiary amines[21]
via iminium intermediates. The only partially sup-
pressed phosphonation reaction in the presence of the
radical inhibitor BHT may, on the one hand, indicate
Scheme 6. Reactions of the N,O-acetal 27a with 2a in the
presence of catalytic amounts of FeCl2 (10 mol%) and with-
that the oxidation of carbon-centered radicals to imi- out FeCl2.
nium ions is faster than the trapping by the radical in-
hibitor. On the other hand, Li and co-workers con-
cluded that a free radical process is not a requirement
for the benzylic alkylation of the tetrahydroisoquino- we tested whether acid catalysis is necessary to con-
line 21 with nitromethane when a CuBr/t-BuOOH vert the N,O-acetal 27a[47] into the corresponding imi-
catalyst/oxidant combination, that is related to our nium ion which then reacts with diethyl phosphonate
FeCl2/t-BuOOH system, was used because compara- (2a) to afford the a-aminophosphonate 3a
ble yields were obtained in the absence and in the (Scheme 6).
presence of 2 equivalents of BHT.[18d] As an alterna-
Under analogous reactions conditions, the isolated
tive to the radical mechanism, Li suggested an ionic yields of 3a from the reaction of 27a with 2a were in-
mechanism. Further studies on the iron-catalyzed oxi- dependent (within experimental error) of the pres-
dation of tertiary amines are, therefore, needed to ence of FeCl2. This result indicates that in methanol
clarify the mechanism of the formation of the imini- the N,O-acetal/iminium ion equilibrium[48] sufficiently
um ions 26 that are ultimately trapped by nucleo- provides electrophiles that can react with the nucleo-
philes (Scheme 5).
philic dialkyl phosphite tautomers to form the final
The N-aryl-substituted iminium ions 26 are suffi- product. The presence of acid catalysts is not necessa-
ciently reactive[42] to be intercepted by the nucleophil- ry for this step.
ic solvent methanol.[43] Under the acidic reaction con-
ditions, the thus formed N,O-acetals 27 are in equilib-
rium with the corresponding iminium ions 26.
Conclusions
As tetravalent dialkyl H-phosphonates
HP(O)(OR)2 are in equilibrium with their dialkyl In summary, the use of the environmentally benign
phosphite tautomers P(OH)(OR)2,[2,44,45] the forma- iron salt FeCl2 in combination with tert-butyl hydro-
3
ꢀ
tion of the carbon-phosphorus bond can be explained peroxide efficiently activated C
(sp ) H bonds in the
by the reaction of the iminium ion with P(OH)(OR)2. a-position to nitrogen of N,N-dialkylanilines for a
ꢀ
N,O-Acetals derived from aliphatic amines react subsequent C P bond formation. Substrates with vari-
with dialkyl H-phosphonates also under neutral con- ous functional groups tolerated the oxidative reaction
ditions in benzene or THF solution.[10,46] Therefore, conditions and reacted with acylic or cyclic dialkyl
Adv. Synth. Catal. 2010, 352, 1667 – 1676
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
1673

Wei Han et al.
FULL PAPERS
fractometer time, and Dr. David S. Stephenson for helpful
discussions. Generous support of this work by Prof. Herbert
Mayr is gratefully acknowledged.
phosphonates to give a-aminophosphonates in moder-
ate to good yields.
The formation of different types of dimers, often
found in other oxidations that generate radical cations
of N,N-dimethyl anilines,[49] as well as competing acti-
3
ꢀ
vation of C
G
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Experimental Section
Typical Procedure for the Iron Catalyzed
Phosphonation of Tertiary Amines
Under an atmosphere of dry N2, a 25-mL Schlenk flask was
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Supporting Information
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We thank the Chinese Scholarship Council for a fellowship
(to W.H.), Prof. Peter Klꢀfers for generous allocation of dif-
1674
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