iron-catalyzed oxidative mono- and bis-phosphonation of n,n-dialkylanilines

DOI: 10.1002/adsc.201000092

Iron-Catalyzed Oxidative Mono- and Bis-Phosphonation ofN,N-Dialkylanilines

Wei Han,a Peter Mayer,a and Armin R. Ofiala,*a Department Chemie, Ludwig-Maximilians-Universit�t M�nchen, Butenandtstr. 5–13, 81377 M�nchen, Germany

Fax: (+49)-89-2180-99-77715; e-mail : [email protected]

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 underhttp://dx.doi.org/10.1002/adsc.201000092.

Abstract: The dehydrogenative a-phosphonation ofsubstituted N,N-dialkylanilines by dialkyl H-phos-phonates was achieved under mild conditions byusing environmentally benign iron(II) chloride ascatalyst and tert-butyl hydroperoxide as oxidant. Thereaction proceeded in the presence of electron-do-nating (methoxy, methyl, benzyl) and electron-with-drawing ring-substitutents (bromo, carbonyl, carbox-yl, m-nitro) in moderate to good yields. The X-raycrystal structure of N-(5,5-dimethyl-2-oxo-2l5-[1,3,2]dioxaphosphinan-2-yl-methyl)-N-methyl-p-tol-uidine was determined. Bis-(4-(dimethylamino)phe-

nyl)methane and bis-4,4’-(dimethylamino)benzophe-none underwent bisphosphonation selectively by re-spective monophosphonation at the remote dimethyl-amino groups. Furthermore, the use of excess di-ACHTUNGTRENNUNGalkyl H-phosphonate and oxidant allowed us tofunctionalize both methyl groups of N ACHTUNGTRENNUNG(CH3)2 in N,N-dimethyl-p-toluidine and N,N-dimethylaminomesi-dine, respectively, to obtain a,a’-bisphosphonato-ACHTUNGTRENNUNGamines in high yield.

Keywords: C�H activation; iron catalysis; oxidation;phosphonation; regioselectivity

Introduction

a-Aminophosphonates and related a-aminophosphon-ic acids are structural analogues of a-amino acids.[1–3]

They carry a tetrahedral phosphonic acid moiety thatmimics the transition state of nucleophilic substitutionreactions at the carboxyl group of natural aminoacids,[4] which makes them efficient competitors forthe active sites of enzymes and other cell receptors.[1,3]

As a consequence, the chemical and, even more im-portant, biological properties of aminophosphonatesand related phosphonopeptides have been studied ex-tensively.[1–4] Furthermore, a-aminophosphonates havefound 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 athree-component reaction of a dialkyl phosphonate, acarbonyl compound, and a primary or secondaryamine.[9,10] Additions of phosphorus compounds witha labile H�P bond to unsaturated compounds are

summarized as Pudovik reactions. Hence, the Pudovikreaction gives rise to the formation of a-amino-phosphonates if an imine is employed as p-system.[11]

Continuous efforts are being made to improve thesynthesis of a-aminophosphonates[12] and recent ad-vances of the Kabachnik–Fields and the Pudovik reac-tions comprise stereoselective[13] and catalytic enantio-

Scheme 1. Synthetic routes to a-aminophosphonates.

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selective[14,15] syntheses as well as the use of micro-wave techniques.[16]

Selective activation of CACHTUNGTRENNUNG(sp3)�H bonds for subse-quent cross-coupling reactions is an attractive conceptthat has strongly developed during the last decade be-cause it removes the need for reactant prefunctionali-zation.[17] As it is known that metal catalysts, such ascopper[18] or iron salts,[19–23] are capable of activatingC ACHTUNGTRENNUNG(sp3)�H bonds adjacent to nitrogen in tertiaryamines under oxidative conditions, we were curiouswhether the formation of a-aminophosphonates fromunfunctionalized tertiary amine precursors could beachieved by a metal-catalyzed cross-coupling(Scheme 1, lower path).

During the course of our studies, Basl� and Li re-ported a novel cross-dehydrogenative coupling(CDC),[18] in which a CuBr-catalyzed phosphonationof the benzylic position in N-aryltetrahydroisoquino-lines (MeOH, 60 8C) with dialkyl H-phosphonates wasperformed under aerobic conditions.[24] However, inour hands, CuBr/O2 was inefficient for the analogousphosphonation of the NMe2 group in N,N-dimethyl-p-toluidine.[25]

The few studies on the double activation of C ACHTUNGTRENNUNG(sp3)�H bonds in the a- and in the a’-positions to nitrogenof tertiary amines have so far concentrated on its usefor subsequent C�C bond forming reactions.[18d,23,26]

Methods for efficient and selective a,a’-bisphospho-nations of tertiary amines are presently still lacking.

In this paper, we report the selective synthesis of a-aminophosphonates under mild conditions by oxida-tion of tertiary amines in the presence of an inexpen-sive and non-toxic iron salt without designed ligands.Moreover, the usefulness of the catalyst system de-scribed in this work is substantiated by the findingthat direct a,a’-bisphosphonations of Ar-N ACHTUNGTRENNUNG(CH3)2

groups are feasible when both the oxidant and thephosphonation agent are employed in excess.

Results and Discussion

a-Phosphonation

The conditions tested in order to optimize the catalystsystem 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 FeCl2 t-BuOOH[c] MeOH 15 842 FeF2 t-BuOOH[c] MeOH 15 433 Fe ACHTUNGTRENNUNG(OAc)2 t-BuOOH[c] MeOH 15 194 Fe ACHTUNGTRENNUNG(ClO4)2·H2O t-BuOOH[c] MeOH 15 555 FeBr3 t-BuOOH[c] MeOH 15 666 FeCl3 t-BuOOH[c] MeOH 15 767 None t-BuOOH[c] MeOH 15 trace8 CuCl t-BuOOH[c] MeOH 15 519 CuBr t-BuOOH[c] MeOH 15 4610 FeCl2 ACHTUNGTRENNUNG(t-BuO)2 MeOH 15 trace11 FeCl2 benzoyl peroxide MeOH 15 3712 FeCl2 cumylhydroperoxide MeOH 15 2713 FeCl2 O2 (1 atm) MeOH 36 6114 CuBr O2 (1 atm) MeOH 24 trace15 FeCl2 t-BuOOH[c] EtOH 15 3416 FeCl2 t-BuOOH[c] i-PrOH 15 2617 FeCl2 t-BuOOH[c] t-BuOH 15 2118 FeCl2 t-BuOOH[c] CH2Cl2 15 2919 FeCl2 t-BuOOH[c] CH3CN 15 47

[a] Reaction conditions: 1a (1.0 mmol), 2a (2.0 mmol), oxidant (2.5 mmol), and solvent (2.0 mL), dry N2 atmosphere, roomtemperature (r.t.) was 23�2 8C.

[b] Yield of isolated product after column chromatography on silica gel.[c] A 5.5 M solution in decane was used.

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Table 1.[25] We had chosen N,N-dimethyl-p-toluidine(1a) as standard substrate and found that the combi-nation of catalytic amounts of FeCl2 (10 mol%) with2.5 equivalents of tert-butyl hydroperoxide as oxidantin methanol[27] was more efficient than other catalyst/oxidant/solvent combinations that were investigated.By using two equivalents of diethyl phosphonate (2a),the optimum yield of the a-aminophosphonate 3a(Table 1, entry 1) was already obtained at ambienttemperature (84% yield of isolated 3a).[25] Differentiron and copper salts were tested as catalysts (Table 1,entries 1–9), but only FeCl3 and FeBr3 were found toperform with comparable catalytic activity as FeCl2

under otherwise analogous reaction conditions (en-tries 5 and 6).

Replacing t-BuOOH by other organic peroxides re-sulted in low yields of 3a, (Table 1, entries 10–12).Noteworthy however, the use of dioxygen as oxidantin combination with FeCl2 as catalyst delivered 3a in61% yield after 36 h reaction time (Table 1, entry 13),but gave only traces of 3a when CuBr was employedas the catalyst[24] (Table 1, entry 14). Substitution ofthe standard solvent methanol by other alcohols, di-

chloromethane, or acetonitrile reduced the yields of3a to below 50% (Table 1, entries 15–19).

The optimized reaction conditions (Table 1,entry 1) could be successfully applied for the reactionsof different aliphatic dialkyl H-phosphonates. Similarreaction times for diethyl (2a), dimethyl (2b), diiso-propyl (2c), and di-n-butyl phosphonates (2d) indicatethat the reactivities of these dialkyl phosphonates arealmost independent of the alkyl moieties (Table 2, en-tries 1–5). Only when dibenzyl phosphonate (2e), wasemployed, were reflux conditions required to achievea high degree of conversion (Table 2, entry 6).

Hydrolysis of dimethyl phosphonate (2b) was as-sumed to be responsible for the low yields of theCuBr-catalyzed oxidative phosphonation of N-arylte-trahydroisoquinolines in aqueous solution.[24]

For the reactions listed in Table 2, which were car-ried out in methanolic solution, we have not observedan exchange of the alkyl groups. Nevertheless, the re-action of N,N-dimethyl-p-toluidine (1a) with bis(2,2,2-trifluoroethyl) phosphonate (2f) generated the mixedester 4 in high yield (Scheme 2). The formation of 4can 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 4-CH3 (1a) Et (2a) 10 15 r.t.[c] 3a (84) 50.3 1622 Et (2a)[d] 10 15 r.t.[c] 3a (63)[d]

3 Me (2b) 10 24 r.t.[c] 3b (78) 49.8 1624 i-Pr (2c) 10 15 r.t.[c] 3c (74) 51.2 1665 n-Bu (2d) 15 18 r.t.[c] 3d (63) 50.2 1616 CH2Ph (2e) 20 20 reflux 3e (79) 50.7 1597 4-OCH3 (1b) Et (2a) 15 18 r.t.[c] 3f (83) 51.2 1628 Me (2b) 15 36 r.t.[c] 3g (77) 50.7 1629 i-Pr (2c) 15 18 r.t.[c] 3h (80) 52.0 16610 H (1c) Et (2a) 20 14 r.t.[c] 3i (71) 49.9 16211 4-Br (1d) Et (2a) 15 24 r.t.[c] 3j (80) 49.8 16212 Me (2b) 15 24 60 3k (84) 49.1 16113 i-Pr (2c) 15 24 60 3l (68) 50.5 16414 4-C�CH (1e) Et (2a)[e] 30 24 reflux 3m (trace) – –15 4-COPh (1f) Et (2a)[e] 30 24 reflux 3n (65) 48.9 16116 4-CO2Et (1g) Et (2a) 30 24 reflux 3o (61) 48.8 16017 4-COOH (1h) Et (2a) 30 24 reflux 3p (78) 48.8 16018 3-NO2 (1i) Et (2a) 30 36 reflux 3q (57) 49.3 16119 4-NO2 (1j) Et (2a) 30 24 reflux 3r (trace) – –

[a] Reactants 1, 2, and t-BuOOH were used in a molar ratio of 1.0:2.0:2.5 if not indicated otherwise.[b] Yields of isolated products after column chromatography on silica gel.[c] Room temperature (r.t.) was 23�2 8C.[d] In the presence of 1.0 equivalent of 3,5-di-tert-butyl-4-hydroxytoluene.[e] In the presence of 3 equivalents of 2a.

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Iron-Catalyzed Oxidative Mono- and Bis-Phosphonation of N,N-Dialkylanilines


2,2,2-trifluoroethoxy groups by a methoxy group thatoriginates from the solvent methanol.

The reaction of the cyclic phosphonate 5,5-dimeth-yl-1,3,2-dioxaphosphorinan-2-one (2g) with 1a fur-nished 3s in moderate yield already at room tempera-ture (Scheme 3), analogous to the behavior of theacyclic dialkyl phosphonates 2a–d. Precipitation froma CH2Cl2/n-pentane/ethyl acetate mixture (10/10/1,v/v/v) delivered crystals of 3s that were suitable for

X-ray analysis.[28] Details of the crystal structure of 3 sare discussed in the Supporting Information.

The phosphonations of methyl-, methoxy-, bromo-,and 3-nitro-substituted substrates show that severalfunctional groups are tolerated as ring substitutents inthe N,N-dimethylanilines (Table 2, entries 1–13 and18). Whereas the use of 4-ethynyl- (1e) and 4-nitro-N,N-dimethylaniline (1j) did not allow us to isolate aphosphonation product,[29] the p-benzoyl substitutedN,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-carboxylgroups to the aniline substrates either as ethyl ester in1g (Table 2, entry 16) or as free carboxylic acid in 1h(Table 2, entry 17) was compatible with the phospho-nation reaction and gave acceptable yields of 3o(61%) and 3p (78%), respectively.

Michler�s ketone 5 (Table 3, entry 1) was chosen asa model for studying the relative reactivities of theN�CH3 group as part of either a N ACHTUNGTRENNUNG(CH3)2 or an N-ACHTUNGTRENNUNG(CH3)CH2P(O) ACHTUNGTRENNUNG(OEt)2 unit. In the presence of 4equivalents of 2a, the symmetrically substituted tet-raethyl bis-phosphonate 7 was obtained as the majorproduct (51%) together with the mono-phosphona-tion product (6, 34%). This result indicates that thefirst phosphonation of an NACHTUNGTRENNUNG(CH3)2 is much faster thana 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 themono- 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 addressthe chemoselectivity of the oxidative phosphonationreaction (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 ofthe heterocycles in N-phenylpyrrolidine (17) and N-phenylpiperidine (19) (Table 3, entries 5–8) provedthat the scope of the FeCl2-catalyzed phosphonationreaction can be extended also to other tertiaryamines, beyond those that carry dimethylaminogroups.

Although N-phenyl-1,2,3,4-tetrahydroisoquinoline(21) was almost quantitatively converted under thereaction conditions, we were not able to isolate theexpected 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 2. Phosphonation and transesterification in the reac-tion of 1a with 2f in methanol (in CDCl3: dC ACHTUNGTRENNUNG(NCH2P)=50.3 ppm, 1JC,P =162 Hz).

Scheme 3. Formation and crystal structure determinationof 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 23�2 8C; the shown ther-mal ellipsoids are drawn at the 50% probability level; inCDCl3: dC ACHTUNGTRENNUNG(NCH2P)=50.6 ppm, 1JC,P =159 Hz).




position of the substrate (Table 3, entry 9). A success-ful phosphonation of N-aryltetrahydroisoquinolines(i.e., 21!22) with CuBr as catalyst under aerobicconditions has been reported.[24]

The products of the phosphonation rections werecharacterized by NMR spectroscopic methods whichunambiguously indicate the formation of a carbon-phosphorus bond. As noted in Table 2 and Scheme 2and Scheme 3, the 13C NMR chemical shifts for the

NCH2P carbon atom in 3 and 4 are in a narrow rangeof 48.8–52.0 ppm with characteristic 1JC,P couplingconstants from 159 to 164 Hz. In the a-aminophosph-onates listed in Table 2, the 31P nuclei resonate be-tween 22.2 and 24.8 ppm. Slight changes in the elec-tronic environment of the phosphorus atom are de-tected in the presence of a trifluoroethoxy group (4 :dP =26.1 ppm) or a 2-oxo-[1,3,2]dioxaphosphinanering (3s : dP =20.0 ppm).

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 2a (4 equiv.), t-BuOOH (4 equiv.),FeCl2 (20 mol%), 24 h, reflux[b]

2 8 2a (1.5 equiv.), t-BuOOH (2.5 equiv.),FeCl2 (15 mol%), 24 h, 60 8C

3 8 2a (4 equiv.), t-BuOOH (4 equiv.),FeCl2 (15 mol%), 24 h, 60 8C

4 11 2a (2 equiv.), t-BuOOH (2.5 equiv.),FeCl2 (20 mol%), 24 h, 60 8C

5 13 2a (2 equiv.), t-BuOOH (2.5 equiv.),FeCl2 (20 mol%), 24 h, 60 8C[c]

6 15 2b (2 equiv.), t-BuOOH (2.5 equiv.),FeCl2 (30 mol%), 24 h, 60 8C[c]

7 17 2a (3 equiv.), t-BuOOH (2.5 equiv.),FeCl2 (30 mol%), 24 h, reflux



[a] Yields of isolated products after column chromatography on silica gel.[b] In the presence of 2a (2 equiv.) and t-BuOOH (2.5 equiv.) 6 and 7 were isolated in 41% and 27% yield, respectively

(20 mol% FeCl2, 24 h, reflux).[c] Not optimized.




Our attempts to directly synthesize an a-amino-phosphonic acid by combining 1a with phosphorusacid HP(O)(OH)2 and tert-butyl hydroperoxide failedand delivered N,4’-dimethylformanilide (24).[36,37]

Trialkyl phosphites might be considered as alterna-tive P-nucleophiles. Indeed, the reaction of tributylphosphite with 1a (Scheme 4) furnished 3d in a yieldcomparable to that of the analogous reaction (atroom temperature) of 1a with dibutyl phosphonate(2d) but required elevated reaction temperatures.

a,a’-Bisphosphonations[38]

Metal-catalyzed oxidative cross-coupling reactionsoffer the potential for two-fold functionalizations ofthe a,a’-positions of tertiary amines. Nevertheless,only few one-pot procedures of such reactions thatavoid the isolation of mono-functionalized intermedi-ates have been reported.[18d,23]

As shown in Table 4, the reactions of 1a (entries 1–4) and N,N-dimethylmesidine (1l, entries 5–7) in the

presence of excess diethyl H-phosphonate (2a) andoxidant delivered mixtures of mono-phosphonated(3a and 3t) and bisphosphonated products (25a and25b).

Maximum yields of 25a and 25b were reachedwhen 4 to 5 equivalents of phosphonate 2a were used.The presence of 10 equivalents of 2a reduced theoverall yield and the yield of the two-fold functional-ized products 25.

N,N-Dimethylmesidine (1l) was slightly more proneto undergo a,a’-bisphosphonations than 1a, and theisolated yields of the amino-a,a’-bisphosphonates 25reached levels between 65 and 80% with different di-alkyl phosphonates, even in the presence of stericallydemanding isopropyl groups (Table 4, entries 6, 8–10).

The higher acidity of the NCH3 groups in the radi-cal cation 1lC+ than in 1aC+ has been discussed earlierin the context of anodic oxidations. Genies and co-workers rationalized the different regioselectivities of1aC· and 1lC in radical dimerizations by the reduced de-localization of the unpaired electron in the radicalcation 1lC+ because of the twist between the plane ofthe aromatic ring and the plane containing the nitro-gen and the carbons of the a-methyl groups.[39]

Later, the groups of Dinnocenzo, Fari, and Gouldquantified Genies� assumption and calculated a twistangle of 428 between the aryl ring and the dimethyl-ACHTUNGTRENNUNGamino group in the radical cation 1lC+ (B3LYP/6-31G*), significantly larger than the 98 twist angle ofthe parent N,N-dimethylaniline radical cation 1cC+.[40]

Scheme 4. Iron-catalyzed formation of a-aminophosphonate3d from 1a and tributyl phosphite (2 equiv.).

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 4-CH3 (1a) Et (2a) (2 equiv.)[c] 10 15 r.t.[b] 3a (84)2 Et (3 equiv.)[c] 20 24 60 3a (61)+ 25a (18)3 Et (5 equiv.)[d] 20 24 60 3a (45)+ 25a (43)4 Et (10 equiv.)[d] 20 24 60 3a (24)+ 25a (40)5 2,4,6-(CH3)3 (1l) Et (2a) (2 equiv.)[c] 10 24 60 3t (39) +25b (56)6 Et (4 equiv.)[d] 20 24 reflux 3t (19) +25b (65)7 Et (10 equiv.)[d] 20 24 reflux 3t (17) +25b (59)8 i-Pr (2c) (5 equiv.)[d] 20 24 reflux 3u (15)[e] +25c (69)9 n-Bu (2d) (5 equiv.)[d] 20 24 reflux 3v (12)+ 25d (80)10 n-Bu (10 equiv.)[d] 20 24 reflux 3v (11)+ 25d (65)

[a] Yields of isolated products after column chromatography on silica gel.[b] Room temperature (r.t.) was 23�2 8C.[c] In the presence of 2.5 equivalents of t-BuOOH.[d] In the presence of 5 equivalents of t-BuOOH.[e] It was not possible to isolate 3u. Therefore, the yield of 3 u was estimated from the isolated yield of 25c and the product

ratio 3u/25c obtained from the GC-MS of the crude product.




Mechanism

Numerous iron complexes have been used to mimicenzymatic oxidations which involve the activation ofC�H bonds under mild and selective conditions. In-vestigations by different groups have shown that inthe presence of hydroperoxides a variety of rathercomplex mechanistic scenarios can be derived forthese iron-catalyzed reactions, which have been re-viewed.[41] In particular, the question whether radicalor non-radical species are formed as intermediates inFe2+/ROOH systems has given rise to controversialdiscussions.

To gain some insight into the initial C�H activationat the tertiary amines that is required for the subse-quent phosphonation, we have studied our standardreaction in the presence of a radical scavenger. WithN,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/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 theradical inhibitor BHT may, on the one hand, indicatethat the oxidation of carbon-centered radicals to imi-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 requirementfor the benzylic alkylation of the tetrahydroisoquino-line 21 with nitromethane when a CuBr/t-BuOOHcatalyst/oxidant combination, that is related to ourFeCl2/t-BuOOH system, was used because compara-ble yields were obtained in the absence and in thepresence of 2 equivalents of BHT.[18d] As an alterna-tive to the radical mechanism, Li suggested an ionicmechanism. Further studies on the iron-catalyzed oxi-dation of tertiary amines are, therefore, needed toclarify the mechanism of the formation of the imini-um ions 26 that are ultimately trapped by nucleo-philes (Scheme 5).

The N-aryl-substituted iminium ions 26 are suffi-ciently reactive[42] to be intercepted by the nucleophil-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.

As tetravalent dialkyl H-phosphonatesHP(O)(OR)2 are in equilibrium with their dialkylphosphite tautomers P(OH)(OR)2,

[2,44,45] the forma-tion of the carbon-phosphorus bond can be explainedby the reaction of the iminium ion with P(OH)(OR)2.

N,O-Acetals derived from aliphatic amines reactwith dialkyl H-phosphonates also under neutral con-ditions in benzene or THF solution.[10,46] Therefore,

we tested whether acid catalysis is necessary to con-vert the N,O-acetal 27a[47] into the corresponding imi-nium ion which then reacts with diethyl phosphonate(2a) to afford the a-aminophosphonate 3a(Scheme 6).

Under analogous reactions conditions, the isolatedyields of 3a from the reaction of 27a with 2a were in-dependent (within experimental error) of the pres-ence of FeCl2. This result indicates that in methanolthe N,O-acetal/iminium ion equilibrium[48] sufficientlyprovides electrophiles that can react with the nucleo-philic dialkyl phosphite tautomers to form the finalproduct. The presence of acid catalysts is not necessa-ry for this step.

Conclusions

In summary, the use of the environmentally benigniron salt FeCl2 in combination with tert-butyl hydro-peroxide efficiently activated C ACHTUNGTRENNUNG(sp3)�H bonds in thea-position to nitrogen of N,N-dialkylanilines for asubsequent C�P bond formation. Substrates with vari-ous functional groups tolerated the oxidative reactionconditions and reacted with acylic or cyclic dialkyl

Scheme 5. Plausible mechanism for the formation of a-ami-nophosphonates from tertiary aromatic amines and dialkylphosphonates under oxidative conditions.

Scheme 6. Reactions of the N,O-acetal 27a with 2a in thepresence of catalytic amounts of FeCl2 (10 mol%) and with-out FeCl2.




phosphonates to give a-aminophosphonates in moder-ate to good yields.

The formation of different types of dimers, oftenfound in other oxidations that generate radical cationsof N,N-dimethyl anilines,[49] as well as competing acti-vation of CACHTUNGTRENNUNG(sp3)�H bonds in benzylic positions werenot observed. Only N-phenyltetrahydroisoquinolinewas oxidized to the corresponding lactam,[50] insteadof being phosphonated.

The efficient a,a’-bisphosphonation of N,N-dimeth-yl-p-toluidine and N,N-dimethylmesidine in the pres-ence of an excess of dialkyl phosphonates and oxidantis one of the few examples for a one-pot, double func-tionalization with initial C ACHTUNGTRENNUNG(sp3)�H activation.[18d,23,26] Itis the first time that sequential C ACHTUNGTRENNUNG(sp3)�H activation attwo different carbons attached to the same nitrogenhas been used for the formation of carbon-phospho-rus bonds.

Mechanistic studies clarifying the nature of the cat-alytically active iron species[19e,51,52] as well as the rolesof the N,O-acetal/iminium ion equilibrium and theHP(O)(OR)2/P(OH)(OR)2 tautomerism are in prog-ress.

Experimental Section

Typical Procedure for the Iron CatalyzedPhosphonation of Tertiary Amines

Under an atmosphere of dry N2, a 25-mL Schlenk flask wascharged with iron(II) chloride (10 mol%, 13 mg). The terti-ary amine (1.0 mmol), dialkyl phosphonate (2.0 mmol), andMeOH (2.0 mL) were added successively by syringe. To themixture was added dropwise tert.-butyl hydroperoxide(2.5 mmol, 0.47 mL, 5.5 M solution in decane) over a periodof 5 min. The mixture was stirred at room temperature (ca.23 8C) for the indicated time. At the end of the reaction, thereaction mixture was poured into a saturated aqueous NaClsolution (20 mL) and extracted with ethyl acetate (3 �20 mL). The organic phases were combined, and the volatilecomponents were removed in a rotary evaporator. Thecrude product was purified by column chromatography onsilica gel (n-pentane/ethyl acetate/triethylamine). Productsof double phosphonation generally required longer retentiontimes than mono-phosphonation products.

Supporting Information

Experimental details and spectroscopic characterization ofproducts 3, 4, 6, 7, 9, 10, 12, 14, 16, 18, 20, and 23–25 as wellas details of the crystal structure of 3s are given in the Sup-porting Information.

Acknowledgements

We thank the Chinese Scholarship Council for a fellowship(to W.H.), Prof. Peter Kl�fers for generous allocation of dif-

fractometer time, and Dr. David S. Stephenson for helpfuldiscussions. Generous support of this work by Prof. HerbertMayr is gratefully acknowledged.

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iron-catalyzed oxidative mono- and bis-phosphonation of n,n-dialkylanilines

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