Microwave-assisted cycloaddition of diisopropyl diazomethylphosphonate to electron-deficient alkenes: synthesis of multifunctionalized phosphonopyrazolynes and phosphonopyrazoles

Tetrahedron xxx (2014) 1e7

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Microwave-assisted cycloaddition of diisopropyl diazomethylphosphonate to electron-deficient alkenes: synthesis of multifunctionalized phosphonopyrazolynes and phosphonopyrazoles Maura Marinozzi a, *, Silvia Tondi a, Gloria Marcelli a, Gianluca Giorgi b a b

 degli Studi di Perugia, Via del Liceo 1, 06123 Perugia, Italy Dipartimento di Scienze Farmaceutiche, Universita  di Siena, Via A. Moro, 53100 Siena, Italy Dipartimento di Biotecnologie, Chimica e Farmacia, Universita

a r t i c l e i n f o

a b s t r a c t

Article history: Received 30 July 2014 Received in revised form 21 October 2014 Accepted 28 October 2014 Available online xxx

An efficient method for the synthesis of functionalized phosphonopyrazolines has been developed. The procedure involved the microwave-assisted cycloaddition of diisopropyl diazomethylphosphonate to dipolarophiles, such as a,b-unsaturated-nitriles and -esters, performed in neat conditions. By oxidative aromatization the phosphonopyrazolines, thus obtained, were converted into the corresponding phosphonopyazoles. Alternatively, phosphonopyazoles could be obtained by a one-pot, two step procedure directly from dipolarophiles, thus avoiding the isolation of the intermediate pyrazolines. Full spectroscopic characterization of the compounds has been also reported. Ó 2014 Elsevier Ltd. All rights reserved.

Keywords: Phosphorous-containing diazo compounds Phosphonopyrazolines Phosphonopyrazoles 1,3-Dipolar cycloaddition Privileged structures

1. Introduction Phosphorus-containing a-diazo compounds (PCDCs) represent a vast class of derivatives characterized by the presence of a phosphorus functionality at the a-position with respect to the diazo moiety. The phosphonate group is the phosphorous functionality that is most common in known PCDCs. Due to the enormous number of transformations that can occur with the diazo moiety,1 PCDCs are endowed with a high potential in organic synthesis because they actually represent useful tools to prepare a vast array of different phosphorus-functionalized molecules. Among them, phosphonic acids and phosphonate esters have attracted much attention because they exhibit intriguing biological activities.2 In the literature their ability to function as bioisosteric replacement of phosphate,3 sulfate4 and carboxylate moieties5 is well documented. The most known application of PCDCs, is the Seyferth-Gilbert homologation i.e. the one-pot conversion of carbonyl compounds to the corresponding terminal or internal alkynes using dimethyl diazomethylphosphonate (1) under basic conditions.6 Thus, as a paradox, PCDCs become notorious for a reaction in which their phosphorous functionality is lost. On the contrary, their other synthetic potentialities have received very little attention,

especially if compared with those of a-diazocarbonyl compounds.7 Applications in 1,3-dipolar cycloaddition chemistry are known, including the reaction of diphenyl diazomethylphosphinoxide, dimethyl a-methyl- and a-phenyl-diazomethylphosphonates with activated vinyl compounds.8 Recently, the base-mediated cycloaddition of 1-diazo-2-oxopropylphosphonate (Bestmann-Ohira reagent, BOR, 2)9 with different classes of dipolarophiles has been reported.10 All these methodologies led to the formation of the corresponding phosphonopyrazoles and generally required basic conditions. Encouraged by this recent application of BOR (2) we were interested in exploring the sofar unreported possibility of achieving the construction of phosphonopyrazolines directly by the reaction of diisopropyl diazomethylphosphonate (DIDAMP, 3)11 with a,b-unsaturated-nitriles 4aed and -esters 6aeh being confident that the merging of the phosphonate moiety with a privileged scaffold, such as pyrazoline nucleus, could be of interest in medicinal chemistry as well as in other research areas.12

* Corresponding author. Fax: þ39 0755855161; e-mail address: [email protected] (M. Marinozzi). http://dx.doi.org/10.1016/j.tet.2014.10.069 0040-4020/Ó 2014 Elsevier Ltd. All rights reserved.

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2. Results and discussion In initial experiments, we examined the reaction of DIDAMP (3) with acrylonitrile (4a) in neat conditions. Since over a long time no reaction or a very slow conversion of the reagents could be observed at room temperature and on heating, the microwave irradiation was investigated. Thus, an equivalent amount of the reagents, placed in a seal vial, was irradiated for 30 min at 100  C. Analysis of the crude reaction mixture by 1H NMR spectroscopy indicated 90% conversion of the reagents into a product, which was isolated in 82% yield by crystallization (Table 1, entry 1). The obtained cycloadduct was assigned as isomerically pure pyrazoline (±) 5a exhibiting tautomerism in solution. Two tautomers, (±)5a (5-P) and (±)5a (3-P) were indeed, observed in w2:1 ratio in a noninteracting solvent such as CDCl3 on the basis of their characteristic CeP chemical shift and coupling constants at 64.55 ppm (d, JCP¼168.00 Hz) and 145.05 (d, JC-P¼233.4 Hz), respectively. The formation of (±)5a could be explained by an initial 1,3-dipolar cycloaddition followed by a subsequent 1,3(5)-hydrogen shift of the initially formed 1-pyrazoline (Scheme 1).

Table 1 Microwave-assisted 1,3-dipolar cycloaddition of conjugated nitriles 4aed and DIDAMP (3)

Entry

Nitrile

R

Reagent ratio (3/4)

Reaction time (min)

Yielda (%)

1 2 3 4 5 6

4a 4b 4b 4c 4c 4d

H Me Me Et Et Ph

1.0 1.0 1.5 1.0 1.5 1.0

30 40 40 80 80 180

90 60 90 57 95 76

(82)b (49)b (76)b (42)c (82)c (73)b

a Calculated by 1H NMR on the crude mixture; values in parentheses represent isolated yield. b Isolated by crystallization. c Isolated by chromatography on silica gel.

phosphonopyrazolines (±)5bed existed in solution (CDCl3) as a single tautomer (5-P), evidencing that the direction of double bond isomerization is dependent on the substituents. Next, a,b-unsaturated esters 6aeh were explored (Table 2). Thus, equivalent amounts of ethyl acrylate (6a) and DIDAMP (3) gave, after 30 min irradiation at 100  C, a complete conversion into isomerically pure pyrazoline 7a, appearing by 1H NMR spectroscopy as a single (5-P) tautomer (Table 2, entry 1). Analogously to the previous series of dipolarophiles, a,b-unsaturated esters substituted at the b-position by sterically demanding and electronrich groups were less reactive: indeed, starting from 6bee, longer reaction times were required (Table 2, entries 2e9). Furthermore, a difference in the reactivity of some substrates in comparison to that of the corresponding a,b-unsaturated nitriles was observed. Thus, the reaction of ethyl but-2-enoate (6b) with 3 gave a mixture of two different compounds (Table 2, entry 2). The complexity of the 1H NMR spectrum of the crude product allowed us to identify the structure of only one of the two products, the pyrazoline (±)7b, which corresponded to the more polar compound isolated by chromatography. For the other component, appearing quite unstable on silica, the structure of the corresponding 1-pyrazoline was tentatively assigned. By repeating the reaction with a 1.5 fold excess of DIDAMP (3) a quantitative conversion of the reagents could be achieved, whereas no changes in terms of the obtained products were observed (Table 2, entry 3). An analogous trend was observed starting from ethyl hex-2-enoate (6c) and ethyl 3-phenylacrylate (6d) (Table 2, entries 4e7). With the aim to explore the influence of a heteroatom-containing dipolarophile, the commercially available ethyl (2E)-4-bromobut-2-enoate (6e) was employed. In this case, the 1H NMR spectrum of the crude denoted the formation of the expected pyrazoline (±)7e, as the unique product (Table 2, entry 8). Analogously to the previous examples, the reaction yield benefitted from a slight excess of 3 (Table 2, entry 9). Use of more activated dipolarophiles led to quantitative conversion yields in short time just working with equivalent DIDAMP (3) (Table 2, entries 10e13). An identical single cycloadduct (±)7f (or (±)8f because R¼CO2R1) was obtained from dimethyl (2E)-but-2-enedioate [(E)6f] and dimethyl (2Z)-but-2-enedioate [(Z)-6f] showing that the cycloaddition proceeded without retention of the dipolarophile configuration. Starting from tert-butyl, ethyl (2E)-but-2-enedioate

Scheme 1. 1,3-Dipolar cycloaddition between 4a and DIDAMP (3) produces 1-pyrazoline, which readily isomerize to 2-pyrazolines.

These reaction conditions were then applied to three commercially available a,b-unsaturated nitriles 4bed. The substituent at the b-position of the dipolarophile, by virtue of its electronic and steric characteristics, negatively influenced both the reaction rate and the conversion yield (Table 1, entries 2e6). Indeed, it is known that the presence of an electron-donating group reduces the reactivity of dipolarophiles. By working in the presence of a slight excess of DIDAMP (3) a substantial yield improvement was observed, whereas the rate of the cycloaddition was not influenced (Table 1, cfr entries 2 and 3, and entries 4 and 5). In all cases, the desired phosphonopyrazoline was obtained in very good yield as single isomers showing that the cycloaddition proceeded with complete regio- and stereo-control. In contrast to (±)5a, the

(6g) and ethyl 4-oxo-4-phenylbut-2-enoate (6h), dipolarophiles characterized by the presence of two different electronwithdrawing substituents, two regioisomeric phosphonopyrazolines were expected. This was the case of the reaction performed with 6h, affording (±)8h and (±)7h in 55 and 34% yield, respectively (Table 2, entry 13), but not of that with 6g, which furnished the phosphonopyrazoline (±)8g, as a single regioisomer (Table 2, entry 12). To further improve the synthetic applicability, we explored the oxidative aromatization of our substituted phosphonopyrazolines to their corresponding pyrazoles. The only example reported in the literature for this transformation used PDC.12 In our hands, MnO2 in dichloromethane proved to be the oxidant of choice.

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Table 2 Microwave-assisted 1,3-dipolar cycloaddition of conjugated esters 6aeh with DIDAMP (3)

Entry

Ester

R

R0

Reagent ratio (3/6)

Reaction time (min)

Yielda (%)

1 2 3 4 5 6 7 8 9 10 11 12 13

6a 6b 6b 6c 6c 6d 6d 6e 6e (E)-6f (Z)-6f (E)-6g 6h

H Me Me n-Pr n-Pr Ph Ph CH2Br CH2Br CO2Me CO2Me CO2tBu COPh

Et Et Et Et Et Et Et Et Et Me Me Et Et

1.0 1.0 1.5 1.0 1.5 1.0 1.5 1.0 1.5 1.0 1.0 1.0 1.0

30 30 30 80 80 80 80 80 80 30 30 30 30

Quantitative (80 of 79 (42 of ()7b)b Quantitative (68 of 79 (47 of ()7c)b Quantitative (68 of 53 (25 of ()7d)b 81 (54 of ()7d)b 60 (44 of ()7e)b Quantitative (79 of Quantitative (91 of Quantitative (87 of Quantitative (86 of Quantitative (55 of (34 of ()8h)b

a b c

()7a)b ()7b)b ()7c)b

()7e)b ()7f)c) ()7f)c) ()8g)b ()7h)b

Calculated by 1H NMR on the crude mixture; values in parentheses represent isolated yield. Isolated by crystallization. Isolated by chromatography on silica gel.

Thus, ethyl 5-(diisopropoxyphosphoryl)-4-phenyl-4,5-dihydro1H-pyrazole-3-carboxylate (7d) was converted in very good yield into the corresponding pyrazole 9d (Scheme 2). Encouraged by this result, we tested the possibility to avoid the isolation of the phosphonopyrazoline. Thus, 6b was reacted with 1.5 equiv of DIDAMP (3) under the conditions above described, and the crude product was directly submitted to oxidative conditions. After stirring for 24 h at room temperature, the complete transformation into an unique compound, corresponding to the pyrazole 9b was evidenced (Table 3, entry 1). This result also confirmed our assumption, that the unidentified compound deriving from the cycloaddition step was 1-pyrazoline. Similarly, the electrondeficient alkenes 6c and 6d were efficiently converted by this one-pot, two-step protocol into the corresponding 5phosphonopyrazoles 9c and 9d (Table 3, entries 2 and 3).

Table 3 One-pot, two-step conversion of conjugated esters 6bed into phosphonopyrazols 9bed

Entry

Ester

R

Reagent ratio (3/6)

Irradiation time (min)

Yielda (%)

1 2 3

6b 6c 6d

Me n-Pr Ph

1.5 1.5 1.5

30 80 80

85 82 72

a

Isolated yield.

Scheme 2. Oxidative aromatization of phosphonopyrazolines to phosphonopyrazoles.

Since it has been known that 1,3-dipolar cycloaddition of diazo ester to electron-deficient alkenes proceeded with regiocontrol, with the carbon atom of the dipole attacking the b-carbon of the dipolarophile, we were quite confident about the regioisomeric nature of our pyrazoline cycloadducts. Nevertheless we decided to finally establish the structural assignment by single crystal X-ray diffraction of (±)5d (Fig. 1). X-ray analysis confirmed that the regioisomer (±)5d derived from Michael-type attack of the carbon atom of DIDAMP (3) onto the dipolarophile and that the phosponate group and the substituent at C-4 position lay in a trans disposition. In the 1H NMR spectrum the reciprocal orientation of the groups was also evident from the coupling constant H4eH5 equal to 9.8 Hz. Similar values were then observed in all phosphonopyrazolines we obtained. Another characteristic feature in the 1H NMR

Fig. 1. ORTEP diagram (50% ellipsoid probability) of phosphonopyrazoline (±)5d.

spectra of compound (±)5d is the pattern of 5-H-proton, that appears at d 4.10 ppm (dd, JH-P¼3.2 Hz, and JH-H¼9.8 Hz); a close resemblance with the corresponding protons of (±)5b and (±)5c was observed. Also, the C-5 carbon, by virtue of its very large coupling constant with the phosphorous atom (162e168 Hz) was a traceable

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feature in the spectra of all pyrazolines (±)5aed. Spectroscopic analogies were also evidenced in the case of posphonopyrazolines derived from the second series of dipolarophiles, even if the interpretation of the spectra was complicated by the presence of tautomers for derivatives (±)6bed. The assignment of the structure to the regioisomers (±)7h/(±)8h and (±)8g was based on NOESY experiments, as it was not possible to obtain suitable crystals for X-ray analysis either with phosphonopyrazolines or with the corresponding phosphonopyrazoles. In the case of phosphonopyrazole 9h (obtained by oxidative aromatization of (±)7h) a NOE occurred between the methylene of the ethyl carboxylate moiety and methyl groups of the diisopropyl phosphonate, whereas NOEs were observed between aromatic protons and methyl groups of the diisopropyl phosphonate in the spectrum of 10h (obtained by oxidative aromatization of (±)8h) (Fig. 2). NOESY experiment performed on 10g (obtained by oxidative aromatization of (±)8g) evidenced NOEs between the tert-butyl and methylene protons of the ethyl carboxylate moieties and between the latter and methyl groups of the diisopropyl phosphonate (Fig. 2) suggesting a steric control in the cycloaddition.

a JASCO FT/IR-410, 420 IR spectrometer using solutions in KBr pellets. 1H and 13C NMR spectra were recorded on a Bruker AC400 spectrometer as solutions in CDCl3. Chemical shifts were recorded in ppm (d) downfield of tetramethylsilane. The spin multiplicities are indicated by the symbols s (singlet), d (doublet), t (triplet), q (quartet), m (multiplet), dt (doublet of triplet) tt (triplet of triplet) and bs (broad). The LC/MS analysis were run on an Agilent 6540 UHD accurate mass Q-TOF LC/MSMS system governed by Agilent MassHunter software (B.05.00 version). Microwave heating was accomplished with a CEM Discover S-Class instrument with reaction temperatures monitored by an internal IR probe. All reactions were run in a glass vessel sealed with an IntelliVentÒ snapon cap. Reaction times were measured starting from the point, which the solution reached the target temperature (fixed hold time) and cooling was accomplished with compressed air once the programmed reaction time had expired.

4.2. General procedure for cycloaddition between DIDAMP (3) and conjugated nitriles 4 or conjugated esters 6 In a 10 mL microwave glass vessel, DIDAMP (3, 1.5 equiv) and the dipolarophile were placed and the reaction vial closed with a snapon cap. The vial was placed in the microwave reactor and the program started after setting up the following parameters: temperature, 100  C; power, 300 W; powermax, off; stirring, on. Once the program had expired, the reaction crude was directly submitted to crystallization or chromatography.

Fig. 2. NOESY correlations for phosphonopyrazoles 9h, 10h and 10g.

3. Conclusions In conclusion, we have reported the microwave-assisted 1,3dipolar cycloaddition reaction of DIDAMP (3) with electrondeficient dipolarophiles, such as a,b-unsaturated-nitriles 4aed and -esters 6aeh. This transformation, that proceeds in neat conditions with very good yield, gives directly access to functionalized phosphonopyrazolines, an almost unknown class of compounds potentially endowed both with a vast array of synthetic applications and biological activities. It is worth noting that our methodology has the ability to stop the cycloaddition at the pyrazoline stage in the opposite way to similar procedures using BOR (2). In addition, the absence of basic conditions allows the use of basesensitive dipolarophiles. Moreover, we have developed an efficient one pot, two-step protocol (cycloaddition and aromatic oxidation) for the conversion of a,b-unsaturated-nitriles and -esters into the corresponding phosphonopyrazoles. The paper also reported a detailed spectroscopic analysis for all compounds thus constituting substantial value added to the poor scenario of spectroscopic data on phosphorous-containing derivatives. 4. Experimental section 4.1. General methods Melting points were determined by the capillary method on € chi 535 electrothermal apparatus. IR spectra were recorded on a Bu

4.2.1. Diisopropyl (3-cyano-4,5-dihydro-1H-pyrazol-5-yl)phosphonate [()5a]. Obtained as white crystals from light petroleum/ EtOAc in 82% yield; m. p. 77e79  C. 1H NMR (400 MHz, CDCl3): d¼7.10e6.75 (br s, 1H, NH), 4.93e4.77 (m, 2H, CH(CH3)2), 4.63 (t, J¼8.6 Hz, 1H, 5-CH, 3-P tautomer), 4.19e4.13 (m, 1H, 5-CH, 5-P tautomer), 3.29e3.12 (m, 2H, 4-CH2), 1.5e1.25 (m, 12H, CH(CH3)2). 13 C NMR (100 MHz, CDCl3): d¼145.05 (d, J¼232 Hz, 3-P tautomer), 122.88 (d, J¼10 Hz, 5-P tautomer), 118.36 (3-P tautomer), 114.13 (5P tautomer), 72.70, 72.63, 72.38, 72.25, 72.19, 71.92, 71.85, 57.14 (d, J¼165 Hz, 5-P tautomer), 48.40 (3-P tautomer), 39.78 (d, J¼23 Hz, 5-P tautomer), 35.19 (3-P tautomer), 24.15, 24.02, 23.83. IR (KBr): ṽ¼3226, 2981, 2221, 1550, 1256, 995.57 cm1. HRMS (ESIþ): calcd for C10H19N3O3P; [MþH]þ 260.1164; found 260.1160. 4.2.2. Diisopropyl (3-cyano-4-methyl-4,5-dihydro-1H-pyrazol-5-yl) phosphonate [()5b]. Obtained as white crystals from light petroleum/EtOAc in 76% yield; m. p. 83e85  C. 1H NMR (CDCl3, 400 MHz): d¼6.95e6.80 (br s, 1H, NH), 4.75e4.68 (m, 2H, CH(CH3)2), 3.61e3.57 (dd, JH5-P¼2.6 Hz, JH5-H4¼11.7 Hz, 1H, CHPO3iPr2), 3.40e3.30 (m, 1H, CHeCH3), 1.36e1.22 (m, 15H, CH(CH3)2 and CH3). 13C NMR (CDCl3, 100.6 MHz): d¼128.55, 113.57, 72.54 (d, JC-P¼7.0 Hz), 71.74(d, JC-P¼8.0 Hz), 64.55 (d, JC-P¼168.0 Hz), 43.31, 24.13 (d, JC-P¼3.1 Hz), 24.03 (d, JC-P¼5.0 Hz), 23.93 (d, JC-P¼3.1 Hz), 23.79 (d, JC-P¼5.0 Hz), 16.96, 16.87. IR (KBr): ṽ¼3062, 2213, 2908, 1234 cm1. HRMS (ESIþ) calcd for C11H21N3O3P; [MþH]þ 274.1321; found 274.1317. 4.2.3. Diisopropyl (3-cyano-4-ethyl-4,5-dihydro-1H-pyrazol-5-yl) phosphonate [()5c]. Obtained by medium pressure chromatography (light petroleum/EtOAc 70:30) as pale yellow oil in 82% yield. 1 H NMR (CDCl3, 400 MHz): d¼7.6 (br s, 1H, NH), 4.85e4.7 (m, 2H, CH(CH3)2), 3.84 (d, JH5-H4¼9.0 Hz, 1H, 5-CH), 3.44e3.33 (m, 1H, 4CH), 1.80e1.69, (m, 2H, CH2CH3), 1.41e1.27 (m, 12H, CH(CH3)2), 1.03 (t, J¼7.5 Hz, 3H, CH2CH3). 13C NMR (CDCl3, 100.6 MHz): d¼125.65 (d, JC-P¼9.1 Hz), 114.21, 72.51 (d, JC-P¼7.0 Hz), 71.67 (d, JCP¼6.03 Hz), 61.21 (d, JC-P¼164.0 Hz), 49.32, 24.48, 24.36, 24.02, 23.93, 23.89, 23.79, 23.61, 23.56, 10.06. IR (KBr): ṽ¼3213, 2981,

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2348, 2214, 2101, 1238, 1102, 578, 438 cm1. HRMS (ESIþ): calcd for C12H23N3O3P; [MþH]þ 288.1477; found 288.1473. 4.2.4. Diisopropyl (3-cyano-4-phenyl-4,5-dihydro-1H-pyrazol-5-yl) phosphonate [()5d]. Obtained as white crystals from light petroleum/EtOAc in 73% yield; m. p. 98e102  C. 1H NMR (CDCl3, 400 MHz): d¼7.50e7.38 (m, 3H, aromatics), 7.31e7.23 (m, 2H, aromatics), 7.1 (br s, 1H, NH), 4.92e4.72 (m, 2H, CH(CH3)2), 4.54 (dd, JH4-P¼25.5 Hz, JH4-H5¼9.85 Hz, 1H, 4-CH), 4.1 (dd, JH5-P¼3.2 Hz, JH5H4¼9.8 Hz, 1H, 5-CH), 1.43 (d, JH-P¼6.7 Hz, 3H, CH(CH3)2), 1.37 (d, JHP¼6.7 Hz, 3H, CH(CH3)2), 1.35 (d, JH-P¼6.7 Hz, 3H, CH(CH3)2), 1.2 (d, JH-P¼6.7 Hz, 3H, CH(CH3)2). 13C NMR (CDCl3, 100.6 MHz): d¼137,15 (d, JC-P¼10 Hz), 129.31, 128.59, 127.81, 113.63, 72.69, 72.06, 71.98, 66.15 (d, JC-P¼162.0 Hz), 53.95, 24.17, 23.99, 23.79. IR (KBr): ṽ¼3209, 2308, 2219, 2100, 1961, 1295, 1241, 1104, 991, 700, 646, 585 cm1. HRMS (ESIþ): calcd. for C16H23N3O3P; [MþH]þ 336.1477; found 336.1474. 4.2.5. Ethyl 5-(diisopropoxyphosphoryl)-4,5-dihydro-1H-pyrazole-3carboxylate [()7a]. Obtained by medium pressure chromatography (light petroleum/EtOAc 50:50) as pale yellow oil in 80% yield. 1 H NMR (CDCl3, 400 MHz): d¼6.5 (br s, 1H, NH), 4.88e4.76 (m, 2H, CH(CH3)2), 4.3 (q, J¼7.1 Hz, 2H, CH2CH3), 4.2 (t, JH5-H4¼11.6 Hz, 1H, 5-CH), 3.33e3.18 (m, 2H, 4-CH2), 1.5e1.25 (m, 15H, CH(CH3)2 and CH2CH3). 13C NMR (CDCl3, 100.6 MHz): d¼161.91, 142.07 (d, JCP¼10.1 Hz), 72.04 (d, JC-P¼6.0 Hz), 71.18 (d, JC-P¼7.0 Hz), 60.95, 57.44 (d, JC-P¼166.0 Hz), 32.91, 23.91, 23.71, 13.97. IR (KBr): ṽ¼3236, 2982, 1705, 1565, 1375, 1242, 1105, 996.54 cm1. HRMS (ESIþ): calcd. for C12H24N2O5P; [MþH]þ 307.1423; found 307.1417. 4.2.6. Ethyl 5-(diisopropoxyphosphoryl)-4-methyl-4,5-dihydro-1Hpyrazole-3-carboxylate [()7b]. Obtained by medium pressure chromatography (light petroleum/EtOAc 50:50) as pale yellow oil in 68% yield. 1H NMR (CDCl3, 400 MHz): d¼4.85e4.58 (m, 4H, CH(CH3)2), 4.43e4.29 (m, 6H, CH2CH3, 4-CH and 5-CH of 3-P tautomer, CH2CH3 of 5-P tautomer), 3.7 (dd, JH5-P¼1.7 Hz, JH5H4¼9.4 Hz, 1H, 5-CH of 5-P tautomer), 3.62e3.5 (m, 1H, 4-CH), 1.42e1.23 (m, 36H, CH(CH3)2, 4-CH3 e CH2CH3). 13C NMR (CDCl3, 100.6 MHz): d¼161.79 (d, JC-P¼22.1 Hz), 158.93 (d, JC-P¼41.2 Hz), 145.11 (d, JC-P¼9.0 Hz), 134.36 (d, JC-P¼222.3 Hz, 3-P tautomer), 126.08 (d, JC-P¼20.1 Hz), 72.33 (d, JC-P¼7.0 Hz), 71.93 (d, JCP¼6.0 Hz), 71.89 (d, JC-P¼5.0 Hz), 71.44 (d, JC-P¼7.0 Hz), 64.61 (d, JCP¼162.0 Hz, 5-P tautomer), 62.53, 60.74 (d, JC-P¼5.0 Hz), 41.30 (d, JCP¼4.0 Hz), 23.96, 23.93, 23.82, 23.77, 23.60, 23.55, 23.50, 23.42, 17.76, 14.07, 14.00, 13.73, 9.28. IR (KBr): ṽ¼3298, 3187, 1723, 1001 cm1. HRMS (ESIþ): calcd. for C13H26N2O5P; [MþH]þ 321.1579; found 321.1576. 4.2.7. Ethyl 5-(diisopropoxyphosphoryl)-4-npropyl-4,5-dihydro-1Hpyrazole-3-carboxylate [()7c]. Obtained by medium pressure chromatography (light petroleum/EtOAc 50:50) as pale yellow oil in 68% yield. 1H NMR (CDCl3, 400 MHz): d¼4.75 (m, 2H, CH(CH3)2), 4.4e4.3 (m, 3H, CH2CH3 e 5-CH), 2.8 (m, 1H, 4-CH), 1.58 (m, 2H, CH2CH2CH3), 1.5e1.2 (m, 17H, CH(CH3)2, CH2CH3 and CH2CH2CH3), 0.98e0.82 (m, 3H, CH2CH2CH3). 13C NMR (CDCl3, 50.3 MHz): d¼161.77 (d, JC-P¼23.7 Hz), 159.30, 144.45, 138.66 (d, JC-P¼15.8 Hz), 134.7 (d, JC-P¼233.9 Hz, 3-P tautomer), 131.17 (d, JC-P¼20.4 Hz), 72.05 (d, JC-P¼7.1 Hz), 71.84, 71.35 (d, JC-P¼7.1 Hz), 70.47, 66.52 (d, JCP¼15.4 Hz), 61.53 (d, JC-P¼154.8 Hz, 5-P tautomer), 60.40, 45.95, 29.07, 23.79, 19.18, 14.04, 13.71. IR (KBr): ṽ¼3425, 3176, 1173, 991 cm1. HRMS (ESIþ): calcd. for C15H30N2O5P; [MþH]þ 349.1892; found 349.1877. 4.2.8. Ethyl 5-(diisopropoxyphosphoryl)-4-phenyl-4,5-dihydro-1Hpyrazole-3-carboxylate [()7d]. Obtained by medium pressure chromatography (light petroleum/EtOAc 50:50) as pale yellow oil

5

in 54% yield. 1H NMR (CDCl3, 400 MHz): d¼7.5e7.25 (m, 5H, aromatics), 7.00 (br s, 1H, NH), 4.89e4.72 (m, 1H, CH(CH3)2 5-P tautomer), 4.70e4.60 (m, 2H, 4-CH and CH(CH3)2), 4.35 (q, J¼7.1 Hz, 2H, CH2CH3), 4.27e4.15 (m, 3H, CH2CH3 e 5-CH), 4.1 (dd, JH5P¼2.7 Hz, JH5-H4¼7.8 Hz, 1H, 5-CH), 1.5e1.06 (m, 15H, CH(CH3)2 e CH2CH3). 13C NMR (CDCl3, 100.6 MHz): d¼161.42 (d, JC-P¼20.1 Hz), 143.35 (d, JC-P¼8.0 Hz), 140.29 (d, JC-P¼14.1 Hz), 139.55 (d, JCP¼15.1 Hz), 134.03 (d, JC-P¼222.4 Hz, 3-P tautomer), 130.74, 130.27, 129.94, 129.75, 128.98, 128.66, 128.23, 128.09, 127.81, 127.57, 127.35, 127.18, 72.50 (d, JC-P¼7.0 Hz), 72.27 (d, JC-P¼6.0 Hz), 71.67 (d, JCP¼7.0 Hz), 66.40 (d, JC-P¼157.9 Hz, 5-P tautomer), 62.59, 60.75, 60.57, 60.22, 51.86, 24.02, 23.84, 23.8, 23.59, 23.34, 23.3, 20.83, 13.99, 13.85, 13.77. IR (KBr): ṽ¼3204, 2984, 1745, 1256, 1103 cm1. HRMS (ESIþ): calcd. for C18H28N2O5P; [MþH]þ 383.1736; found 383.1731. 4.2.9. Ethyl 4-(bromomethyl)-5-(diisopropoxyphosphoryl)-4,5dihydro-1H-pyrazole-3-carboxylate [()7e]. Obtained by medium pressure chromatography (light petroleum/EtOAc 50:50) as pale yellow oil in 79% yield. 1H NMR (CDCl3, 400 MHz): d¼6.5 (br s, 1H, NH), 4.78e4.70 (m, 4H, CH(CH3)), 4.31e4.25 (m, 1H, 3-CH), 4.18 (m, 2H, CH2CH3), 4.1 (dd, JH5-P¼3.5 Hz, JH5-H4¼9.6 Hz, 1H, 5-CH), 4.00e3.76 (m, 3H, CHbBr and 4-CH), 3.50 (dd, J¼2.5 Hz, J¼10.4 Hz, 1H, CHaBr), 1.25 (m, 15H, CH(CH3)2 and CH2CH3). 13C NMR (CDCl3, 50.3 MHz): d¼161.68, 139.79 (d, JC-P¼8.5 Hz), 72.44 (d, JC-P¼5.5 Hz), 71.74(d, JC-P¼6.5 Hz), 60.98, 60.94 (d, JC-P¼165.8 Hz), 48.22, 33.30 (d, JC-P¼14.4 Hz), 31.29, 23.80, 22.29, 20.55, 15.56, 13.99. IR (KBr): ṽ¼3501, 3201, 1734, 1102, 997 cm1. HRMS (ESþ): calcd. for C13H25BrN2O5P; [MþH]þ 399.0684; found 399.0689. 4.2.10. Dimethyl 5-(diisopropoxyphosphoryl)-4,5-dihydro-1H-pyrazole-3,4-dicarboxylate [()7f]. Obtained as white crystals from light petroleum/EtOAc in 91% yield; m. p. 105e109  C. 1H NMR (CDCl3, 400 MHz): d¼6.8 (br s, 1H, NH), 4.8 (m, 2H, CH(CH3)2), 4.4 (dd, JH5-P¼3.4 Hz, JH5-H4¼11.2 Hz, 1H, 5-CH), 4.3 (dd, JH4-H5¼11.2 Hz, JH4-P¼24.6 Hz, 1H, 4-CH), 3.78 (s, 3H, CH3), 3.74 (s, 3H, CH3), 1.25 (m, 12H, CH(CH3)2). 13C NMR (CDCl3, 100.6 MHz) d¼170.4 (d, JCP¼12.1 Hz), 161.74, 138.52 (d, JC-P¼9.0 Hz), 72.66 (d, JC-P¼6.0 Hz), 71.93 (d, JC-P¼7.0 Hz), 62.70 (d, JC-P¼167.0 Hz), 52.88, 52.30, 51.31, 24.05, 23.84. IR (KBr): ṽ¼3455, 2982, 2356, 1739, 1361, 1003 cm1. HRMS (ESIþ): calcd. per C13H24N2O7P [MþH]þ 351.1321; found 351.1316. 4.2.11. 3-tert-Butyl 4-ethyl 5-(diisopropoxyphosphoryl)-4,5-dihydro1H-pyrazole-3,4-dicarboxylate [()8g]. Obtained by medium pressure chromatography (light petroleum/EtOAc 50:50) as pale yellow oil in 86% yield. 1H NMR (CDCl3, 400 MHz): d¼6.5 (br s, 1H, NH), 4.77e4.79 (m, 2H, CH(CH3)2), 4.37e4.22 (m, 4H, CO2CH2CH3, 4-CH, 5-CH of 5-P tautomer and 5-CH of 3-P tautomer), 1.48e1.59 (m, 24H, CO2C(CH3)3, CH(CH3)2, CO2CH2CH3). 13C NMR (CDCl3, 100.6 MHz): d¼169.86 (d, JC-P¼20.1 Hz), 168.77 (d, JC-P¼11.8 Hz), 159.93 (d, JC-P¼41.2 Hz), 142.11 (d, JC-P¼10.1 Hz), 137.75 (d, JCP¼231.4 Hz, 5-P tautomer), 122.08 (d, JC-P¼23.1 Hz), 82.30, 72.87 (d, JC-P¼6.7 Hz), 71.94 (d, JC-P¼6.7 Hz), 62.70, 61.45 (d, JC-P¼165.9 Hz, 5P tautomer), 52.07 (d, JC-P¼5.3 Hz), 51.88, 27.92, 27.74, 24.06, 23.84, 23.69, 23.53, 14.13, 13.97. IR (KBr): ṽ¼3502.56, 3210.45, 1734.45, 1722.56, 1020.45 cm1. HRMS (ESIþ): calcd. per C17H32N2O7P [MþH]þ 407.1947; found 407.1943. 4.2.12. Ethyl 3-benzoyl-5-(diisopropoxyphosphoryl)-4,5-dihydro-1Hpyrazole-4-carboxylate [()7h]. Obtained by medium pressure chromatography (light petroleum/EtOAc 50:50) as yellow oil in 55% yield. 1H NMR (CDCl3, 400 MHz): d¼8.20 (m, 2H, aromatics),7.80 (m, 1H, aromatic), 7.50 (m, 1H, aromatic), 7.10 (br s, 1H, NH), 4.80 (m, 2H, CH(CH3)2), 4.50 (m, 2H, 5-CH and 4-CH), 4.25 (m, 2H, CO2CH2CH3), 1.40 (m, 15H, CH(CH3)2 and CO2CH2CH3). 13C NMR

Please cite this article in press as: Marinozzi, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.069

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M. Marinozzi et al. / Tetrahedron xxx (2014) 1e7

(CDCl3, 100.6 MHz): d¼186.24, 170.38 (d, JC-P¼12.1 Hz), 146.35 (d, JCHz), 136.46, 133.31, 132.44, 130.00, 129.83, 128.22, 127.92, 72.73 (d, JC-P¼7.0 Hz), 71.03 (d, JC-P¼7.0 Hz), 61.93 (d, JC-P¼166.1 Hz), 61.76, 51.62, 23.99, 23.83, 23.65, 23.60, 14.07, 13.80 (d, JC-P¼14.1 Hz). IR (KBr): ṽ¼3456.67, 3215.54, 1756.44, 1702.45, 1286.89, 990.67 cm1. HRMS (ESIþ): calcd. per C19H28N2O6P [MþH]þ 411.1685; found 411.1665.

CH2CH3), 1.51e1.27 (m, 12H, CH(CH3)2), 1.16e1.15 (m, 3H, CH2CH3). C NMR (CDCl3, 100.6 MHz) d¼161.55, 140.16 (d, JC-P¼14.3 Hz), 133.73 (d, JC-P¼221.5 Hz), 130.75, 130.34, 130.08, 129.9, 129.1, 128.81, 127.94, 127.75, 127.33, 72.48 (d, JC-P¼5.0 Hz), 60.97, 23.98, 23.71, 23.67, 23.47, 23.42, 13.94. IR (KBr): nmax/cm1: 3456.56(NH), 3245.43, 1734.23(C]O), 110.23(P]O). HRMS (ESIþ) calcd per C18H26N2O5P; [MþH]þ 381.1579; found 381.1578.

4.2.13. Ethyl 4-benzoyl-5-(diisopropoxyphosphoryl)-4,5-dihydro-1Hpyrazole-3-carboxylate [()8h]. Obtained by medium pressure chromatography (light petroleum/EtOAc 50:50) as yellow oil in 34% yield. 1H NMR (CDCl3, 400 MHz): d¼8.20 (d, J¼7.9 Hz, 2H, aromatics),7.80 (m, 1H, aromatic), 7.50 (m, 1H, aromatic), 6.60 (br s, 1H, NH), 5.30 (dd, JH4-H5¼10.7 Hz, JH4-P¼24.2 Hz, 1H, 4-CH), 4.75 (m, 2H, CH(CH3)2), 4.50 (dd, JH4-H5¼10.7 Hz, JH5-P¼2.1 Hz, 1H, 5-CH), 4.20 (q, J¼7.1 Hz, 2H, CO2CH2CO3), 1.20e1.30 (m, 15H, CH(CH3)2, CO2CH2CH3). 13C NMR (CDCl3, 100.6 MHz): d¼197.00 (d, JCP¼8.0 Hz), 161.23, 141.14 (d, JC-P¼10.1 Hz), 136.20, 133.68, 129.65, 128.21, 72.63 (d, JC-P¼7.0 Hz), 71.92 (d, JC-P¼6.0 Hz), 63.72 (d, JCP¼167.0 Hz), 61.79, 52.27, 24.07, 23.65, 14.07, 13.88 (d, JC-P¼14.1 Hz). IR (KBr): ṽ¼3346.87, 3157.67, 1734.56, 1710.55, 1267.98, 994.12 cm1. HRMS (ESIþ): calcd. per C19H28N2O6P [MþH]þ 411.1685; found 411.1679.

Supplementary data

P¼8.0

4.3. General procedure for the preparation of phosphonopyrazoles 9bed by cycloaddition/oxidation sequence In a 10 mL microwave glass vessel, DIDAMP (3, 1.5 mmol) and the dipolarophile (6bed, 1.0 mmol) were placed and the reaction vial closed with a snap-on cap. The vial was placed in the microwave reactor and the program started after setting up the following parameters: time, see Table 3; temperature, 100  C; power, 300 W; powermax, off; stirring, on. Once the program had expired, the reaction crude was diluted with CH2Cl2 (10 mL) and MnO2 was added (5 mmol). After stirring for 24 h at room temperature, the reaction mixture was filtered through a small pad of Celite and the solvent evaporated in vacuo to give the title compound. 4.3.1. Ethyl 5-(diisopropoxyphosphoryl)-4-methyl-1H-pyrazole-3carboxylate (9b). Obtained by filtration (CH2Cl2) as a pale yellow oil in 89% yield. 1H NMR (CDCl3, 400 MHz) d¼4.76 (m, 2H, CH(CH3)2), 4.48 (q, J¼7.2 Hz, 2H, CH2CH3), 2.5 (d, J¼1.2 Hz, CH3), 1.50e1.38 (m, 12H, CH(CH3)2), 1.30 (m, 3H, CH2CH3). 13C NMR (CDCl3, 100.6 MHz) d¼162.04, 140.03 (d, JC-P¼15.1 Hz), 134.12 (d, JCP¼220.6 Hz), 126.16 (d, JC-P¼19.1 Hz), 72.04 (d, JC-P¼5.3 Hz), 60.89, 23.92(d, JC-P¼5.0 Hz), 23.74 (d, JC-P¼5.0 Hz), 23.65, 23.55 (d, JC1 P¼5.0 Hz), 14.18 (d, JC-P¼11.1 Hz), 9.45. IR (KBr): nmax/cm : 3543.45(NH), 3134.34(C]N), 1765.34(C]O), 993.23(P]O). HRMS (ESIþ) calcd for C13H24N2O5P; [MþH]þ 319.1423; found 319.1412. 4.3.2. Ethyl 5-(diisopropoxyphosphoryl)-4-npropyl-1H-pyrazole-3carboxylate (9c). Obtained by filtration as pale yellow oil in 91% yield. 1H NMR (CDCl3, 400 MHz) d¼4.40 (m, 2H, CH(CH3)2), 4.36 (q, J¼7.2 Hz, 2H, CH2CH3), 2.79 (t, J¼7.82 Hz, 2H, CH-(CH2)CH3), 1.6e1.5 (m, 2H, CH2CH3), 1.37e1.16 (m, 15H, CH(CH3)2 e CH2CH3), 0.94e0.82 (m, 3H, CH(CH3)2). 13C NMR (CDCl3, 100.6 MHz) d¼161.66, 139.20 (d, JC-P¼15.0 Hz), 134.23 (d, JC-P¼224.9 Hz), 131.25 (d, JC-P¼20.1 Hz), 72.09 (d, JC-P¼6.0 Hz), 60.87, 24.10, 23.91, 23.64, 23.59, 14.16, 13.87, 13.74. IR (KBr): nmax/cm1: 3522.42(NH), 3200.43(C]N), 1735.34(C]O), 1003.13(P]O). HRMS (ESIþ) calcd for C15H28N2O5P; [MþH]þ 347.1736; found 347.1741. 4.3.3. Ethyl 5-(diisopropoxyphosphoryl)-4-phenyl-1H-pyrazole-3carboxylate (9d). Obtained by filtration (CH2Cl2) as a pale yellow oil in 82% yield. 1H NMR (CDCl3, 400 MHz) d¼7.5 (m, 4H, aromatics), 7.25 (s, 1H, aromatic), 4.67 (m, 2H, CH(CH3)2), 4.34 (q, J¼7.2 Hz, 2H,

13

Copies of the 1H NMR and 13C NMR spectra of compounds. CCDC-1012504, contains the supplementary crystallographic data for compound (±)5d described in this paper. These data can be obtained free of charge from the Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif. Supplementary data related to this article can be found at http://dx.doi.org/10.1016/ j.tet.2014.10.069. References and notes 1. For recent examples, see: (a) Zhang, Y.; Wang, J. Eur. J. Org. Chem. 2011, 1015; (b) Zhao, X.; Zhang, Y.; Wang, J. Chem. Commun. 2012, 1016; (c) Padwa, A.; Cheng, B.; Zou, Y. Aust. J. Chem. 2014, 67, 3433; (d) Gillingham, D.; Fei, N. Chem. Soc. Rev. 2013, 42, 4918; (e) Liu, Z.; Wang, J. J. Org. Chem. 2013, 78, 10024; (f) da Silva, F. C.; Jordao, A. K.; da Rocha, D. R.; Ferreira, S. B.; Cunha, A. C.; Ferreira, V. F. Curr. Org. Chem. 2012, 16, 224; (g) Slattery, C. N.; Ford, A.; Maguire, A. R. Tetrahedron 2010, 66, 6681. 2. (a) Dutta, S.; Malla, R. K.; Bandyopadhyay, S.; Spilling, C. D.; Dupureur, C. M. Bioorg. Med. Chem. 2010, 18, 2265; (b) Al Aziz Al Quntar, A.; Gallily, R.; Katzavian, G.; Srebnik, M. Eur. J. Pharmacol. 2007, 556, 9; (c) De Clercq, E.; Holy, A.; Rosenberg, I.; Sakuma, T.; Balzarini, J.; Maugdal, P. C. Nature 1986, 323, 464; (d) Marcellin, P.; Chang, T. T.; Lim, S. G.; Tong, M. J.; Sievert, W.; Shiffman, M. L.; Jeffers, L.; Goodman, Z.; Wulfsohn, M. S.; Xiong, S.; Fry, J.; Brosgart, C. L. Engl. J. Med. 2003, 348, 808; (e) De Clercq, E.; Holy, A. Nat. Rev. Drug Discov. 2005, 4, 928; (f) Bonate, P. L.; Arthaud, L.; Cantrell, W. R., Jr.; Stephenson, K.; Secrist, J. A.; Weitman, S. Nat. Rev. Drug Discov. 2006, 5, 855; (g) Van der Veken, P.; Soroka, A.; Brandt, I.; Chen, Y. S.; Maes, M. B.; Lambeir, A. M.; Chen, X.; Haemers, A.; Scharpe, S.; Augustyns, K.; De Meester, I. J. Med. Chem. 2007, 50, 5568; (h) Shie, J.-J.; Fang, J.-M.; Wang, S.-Y.; Tsai, K.-C.; Cheng, Y.-S. 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M. Marinozzi et al. / Tetrahedron xxx (2014) 1e7 Smietana, M. Eur. J. Org. Chem. 2011, 3184; With conjugated enones, dienones, tropone, and quinone: Verma, D.; Mobin, S.; Namboothiri, I. N. N. J. Org. Chem. 2011, 76, 4764; With vinylsulfones: Kumar, R.; Nair, D.; Namboothiri, I. N. N. Tetrahedron 2014, 70, 1794; With alkynes: Kumar, R.; Verma, D.; Mobin, S. M.; Namboothiri, I. N. N. Org. Lett. 2012, 14, 4070; With ynones: Pramanik, M. M. D.; Kant, R.; Rastogi, N. Tetrahedron 2014, 70, 5214.

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11. DIDAMP (3) was prepared in multi-gram scale in 70% yield from diisopropyl [(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)methyl]phosphonate. DIDAMP (3) remains for months when properly stored at temperature below 0  C. 12. Conti, P.; Pinto, A.; Tamborini, L.; Rizzo, V.; De Micheli, C. Tetrahedron 2007, 63, 5554.

Please cite this article in press as: Marinozzi, M.; et al., Tetrahedron (2014), http://dx.doi.org/10.1016/j.tet.2014.10.069