N-( 1-Acylaminoalkyl ) amidinium salts derived from DBU or related bases as reactive intermediates in α-amidoalkylation reactions

1-(N-Acylamino)alkyltriphenylphosphonium salts 4, when treated with DBU, DBN or TBD in CD3CN or MeCN, were transformed immediately into the corresponding 1-(Nacylamino)alkylamidinium or guanidinium salts 5. Salts 5 with a proton at the α-position underwent slow transformation to the corresponding enamides 6. 1-(NAcylamino)alkyltriphenylphosphonium salts 4, amidinium or guanidinium salts 5, as well as enamides 6 reacted readily with β-dicarbonyl compounds in the presence of corresponding base under microwave irradiation at 60 o C to give the expected product of α-amidoalkylation of the enolate anion. The role of 1-(N-acylamino)alkylamidinium or guanidinium salts 5 as reactive intermediates in α-amidoalkylation with 1-(N-acylamino)alkyltriphenylphosphonium salts is discussed.


Scheme 2
The availability of a large variety of natural α-amino acids (both proteinogenic and unproteinogenic ones), as well as an infinite number of unnatural α-amino acids provides potential access to a wide variety of structurally diverse 1-(Nacylamino)alkyltriphenylphosphonium salts 4.This markedly broadens the scope for the synthetic application of the amidoalkylating properties of these compounds.
Phosphonium salts 4 react smoothly with relatively acidic heteroatom nucleophiles, such as imides, mercaptanes or phenols in the presence of i-Pr 2 EtN (Hünig's base), whereas the amidoalkylation of carbon nucleophiles, e.g., malonic or acetylacetic acid derivatives, requires the use of stronger bases, like DBU. 15,21 In the present communication we report our investigations of some unexpected reactions of phosphonium salts 4 with DBU and related bases (e.g., DBN or TBD), which generate the corresponding N-(1-acylaminoalkyl)amidinium or N-(1acylaminoalkyl)guanidinium salts (so far unknown).The role of these salts as intermediates in αamidoalkylation with phosphonium salts 4 will be also discussed.

Results and Discussion
1-(N-Acylaminoalkyl)triphenylphosphonium salts 4a-j (Table 1) reacted immediately with DBU, DBN or TBD in MeCN or CD 3 CN, which allowed the reaction to be monitored directly by 1 H NMR spectroscopy.Upon treatment with DBU, DBN or TBD, the signal of the α-methylene or α-methine group in the 1 H NMR spectrum of the phosphonium salts at 5.08-6.96ppm was immediately replaced by a signal in the range of 5.01-6.94ppm, without the characteristic J P-H coupling constant (3.3-7.5 Hz) (Figure 1). 13C NMR spectra of the reaction mixture also gave evidence of the disappearance of the initial phosphonium salt and the formation of free triphenylphosphine and another compound.In most cases, evaporation of the solvent and washing out of triphenylphosphine and other impurities with toluene gave the main reaction product, as a thick oil, in good purity and yield (Table 1).Attempts to obtain these compounds in a crystalline form failed.

Scheme 3
High-resolution mass spectroscopy with ESI-ionisation of the obtained compounds revealed that, in all of the cases, the molecular formula of the molecular ion matched the cation of the corresponding N-(1-acylaminoalkyl)amidinium or N-(1-acylaminoalkyl)guanidinium salts 5 formed by amidoalkylation of DBU, DBN or TBD (Scheme 3, Table 1).Further spectroscopic investigations of the salts 5a-m confirmed their structures.In 13 C NMR spectra the characteristic signals of C α carbons (60.3 -67.8 ppm), C=O groups (156.4 -181.5 ppm) and C=N + groups (152.1 -168.4 ppm), as well as signals of the other carbons were present (see Experimental).In IR spectra the NH , C=O and C=N bonds were observed at 3355-3394 cm -1 , 1625-1723 cm -1 and 1598-1660 cm -1 , respectively.It is surprising that DBU and related bases, which are considered to be sterically hindered and, therefore, "non-nucleophilic," 35 react so easily with phosphonium salts 4.[38]  Properties of α-substituted amidinium or guanidinium salts with a proton at the β-position (5e-m, R 2 = CHR 3 R 4 ) differ in some respects from the properties of α-substituted salts without such a proton (e.g., 5c-d) or α-unsubstituted amidinium salts 5a-b (R 2 = H).In contrast to the salts 5a-d, α-substituted salts with a proton at the β-position underwent slow transformation in the reaction mixture to the corresponding enamides 6d-j.E.g. in the reaction of 1-(Nbenzyloxycarbonylamino)ethyltriphenylphosphonium tetrafluoroborate 4f with DBU in CD 3 CN at 20 o C at a 1:1.25 molar ratio of 4f to DBU, the 5h:6f molar ratio was 50:50 after eight minutes, 28:72 after twenty minutes, and after 3 hours the 5h:6f molar ratio levelled out at a value of 17:83.The reaction mixture contained also a trace amount of another compound, which was finally identified as dimer 7 (see below).In most cases we were able to isolate enamides 6 in a pure form by the evaporation of the solvent and separation of the residue by column chromatography (Table 2), however, isolated yields of enamides were usually much lower than their contents in reaction mixtures.Attempts to isolate enamide 6j failed, in spite of its formation in the reaction mixture in a yield of 94%.In the case of phosphonium salt 4f, a compound 7 formed by the condensation of two molecules of phosphonium salt was isolated in a yield of 33%, in addition to the expected N-acylenamide 6f, isolated in a yield of 17% (Scheme 4).

Scheme 4
Investigations on this reaction are in progress; nevertheless it is evident that compound 7 results from a novel aza-Morita-Baylis-Hillman-like reaction between the corresponding Nacylimine (as the electrophilic component) and N-deprotonated amidinium salt 5h (as the nucleophilic component). 42It seems, that dimer 7 is formed mainly during the work-up of the reaction mixture, as the isolated yield of this compound is much higher than its contents in the reaction mixture before the work-up.The increase of the concentration of reagents during evaporation of the solvent should facilitate the formation of the dimer in a second order reaction.The findings described above can be rationalised assuming that 1-(Nacylamino)alkyltriphenylphosphonium salts 4, when treated with base, undergo β-elimination to primarily produce the corresponding N-acylimines 2 by the expulsion of triphenylphosphine and the corresponding acid.The resulting N-acylimines, are strong amidoalkylation reagents and they in turn react with DBU, DBN or TBD to give amidinium or guanidinium salts 5. Salts 5 with a proton at the β-position undergo slow transformation directly, or more probably via Nacylimines, to the corresponding, more thermodynamically stable, enamides 6. Tautomerisation of N-acylimines into the corresponding enamides is a well-known phenomenon. 7,43In a few cases (compounds 5c, 5d, 5h and 5k), the amidinium salts transformation to the corresponding enamides or N-acylimines is probably so rapid that attempts to separate the polar salts from less polar compounds by extraction with toluene failed.
These conclusions were confirmed by the observation that not only phosphonium salts 4, but also amidinium or guanidinium salts 5 and enamides 6 all react easily with β-dicarbonyl compounds in the presence of the corresponding base under microwave irradiation at 60 o C to give the expected product of α-amidoalkylation of the corresponding enolate anion (Scheme 5, Table 3).It is well known that enamides can act as α-amidoalkylating reagents, although usually alkylation occurs in acidic conditions with participation of the acyliminium cation resulting from the β-C-protonation of the enamide. 44The results of these experiments can be explained assuming that phosphonium salts 4, amidinium or guanidinium salts 5, enamides 6 and Nacylimines 2 all remain in equilibrium under the applied reaction conditions.
At least two reasons can be responsible for the isolation of enamides 6 in much lower yields if compare with their contents in reaction mixtures: (i) enamides, remaining in equilibrium with highly reactive N-acylimines 2, can be used up in side reactions with nucleophiles (eg.water from moisture) during their isolation and (ii) enamides, as components of the equilibrium mixture, can also be consumed in the aforementioned aza-Morita-Baylis-Hillman-like reaction.
Easily accessible 1-(N-acylamino)alkylamidinium or guanidinium salts 5 can be considered as new convenient α-amidoalkylating reagents that do not introduce any by-products into the post-reaction mixture except for the required base.It is noteworthy that, in the case of these new α-amidoalkylation agents, the base used plays a double role, acting as both the basic catalyst and the nucleofugal leaving group.

Conclusions
In conclusion, 1-(N-acylamino)alkyltriphenylphosphonium salts 4, when treated with DBU, DBN or TBD, undergo immediate β-elimination to the corresponding N-acylimines 2 by the loss of triphenylphosphine and the corresponding acid.N-Acylimines, as strong amidoalkylation reagents, quickly react in turn with the corresponding base to give amidinium or guanidinium salts 5. Salts 5 with a proton at the β-position undergo slow transformation directly, or more probably, via N-acylimines to the corresponding enamides 6, as more thermodynamically stable compounds.Phosphonium salts 4, amidinium or guanidinium salts 5, enamides 6 and Nacylimines 2 remain in equilibrium under the applied reaction conditions.As a result, not only salts 4, but also amidinium or guanidinium salts 5 and enamides 6 all react easily in the presence of the corresponding base under the influence of microwave irradiation at 60 o C with βdicarbonyl compounds to give the expected product of α-amidoalkylation.Easily accessible 1-(N-acylamino)alkylamidinium or guanidinium salts 5 are novel, interesting amidoalkylating reagents that do not result in the production of any by-products (except for the base) in the postreaction mixture.

Experimental Section
General.Commercial grade CH 2 Cl 2 , MeCN, AcOEt, toluene and hexane were distilled and dried over molecular sieves (4Å).The following reagents were purchased from the Sigma-Aldrich company and were used as supplied: DBU, DBN, TBD, dimethyl malonate, ethyl acetoacetate, ethyl 2-methylacetoacetate and diethyl malonate.Melting points were determined in capillary tubes in a Stuart Scientific SMP3 melting point apparatus, and were uncorrected.IR spectra were recorded on a Nicolet 6700 FT-IR or Zeiss Specord 80. NMR spectra were recorded in CD 3 CN or CDCl 3 in FT mode using TMS as an internal standard. 1H and 13 C NMR spectra were recorded on a Varian UNITY INOVA-300 spectrometer at 300 and 75 MHz, respectively.Mass spectra were recorded on a AMD604 Intectra GmbH spectrometer using Electron Ionisation, on a Mariner spectrometer using Electrospray Ionisation or on a GCT Premier (Waters) specrometer using Field Desorption Ionisation.Reactions requiring microwave irradiation were carried out using a CEM Matthews microwave reactor.Kieselgel 60 (Merck, 0.063-0.200mm) was used for column chromatography.
Procedure for the synthesis of amidinium or guanidinium salts (5) DBU, DBN or TBD in amounts given in Table 1, was added to a suspension of phosphonium salt 4 (1 mmol) in MeCN (11 mL) at 20 o C.After 10 min, the solvent was evaporated under reduced pressure, and the residue was washed with toluene at room temperature and dried under reduced pressure to give amidinium or guanidinium salts 5 in varying yields (Table 1).Spectral properties and analytical data of amidinium salts 5a, 5b, 5e and 5m were already reported in our previous paper. 15