WANG Fan-Fan HOU Xian-Hui ZHU Cheng-Ben LI Hai-Pu YANG Ying

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Synthesis and Structural Characterization of,-disubstituted Acylguanidines①

WANG Fan-Fan HOU Xian-Hui ZHU Cheng-Ben LI Hai-Pu YANG Ying②

(410083)

acylguanidine, acylthiourea, intramolecular hydrogen bond;

1 INTRODUCTION

Guanidines that contain the Y-shaped CN3core have long attracted extensive attention in different fields including chemistry[1, 2], biology[3], catalysts[4]and pharmacology[5]. In the synthetic or applied aspect, they can act as nucleophile and devolve chiral information to the substrate via hydrogen bonding or ionic non-covalent interactions[6]. When acyl substituent was introduced, acylguanidines[7]were formed to play as,-chelating ligands for different metal cations[8-10]. In solid state, the intramolecular hydrogen bonds were always present in the-mono-substituted acylguanidines[3,11-18]R1C(O)N= C[N(H)R2]-N(H)R3(Scheme 1) in spite of tautomeric or con- formational preferences[19]. In contrast, the presence of intramolecular hydrogen bonds seems to be elusive in the,-disubstituted acylguanidines R1C(O)N=C[N(H)R2]NR32(Scheme 1) as suggested by1H NMR spectroscopy in one case[20]or excluded by the solid structural characterization in other cases[21-24].

Scheme 1. Acylguanidines concerned in study

It arouses our research interestin investigating how the R groups of,-disubstituted acylguani- dines affect the presence or absence of intramolecular hydrogen bonds. Herein, we report the synthesis and structural characterization of,-disubstituted acylguanidines R1C(O)N=C[N(H)R2]NR32(R1= Mes or Ph; R2= Ar?? or Ar?; R3= Cy, Bn,Pr, or Et) (Mes = 2,4,6-Me3C6H2, Ar?? = 2,6-Pr2C6H3, Ar? = 2,6-Me2C6H3) by reacting respective acylthioureas with secondary amines.

2 EXPERIMENTAL

2.1 Materials and measurements

All chemicals commercially available were of analytical grade and used as received. Melting points were measured in a sealed glass tube using a Büchi B-540 instrument without correction. Elemental analyses for carbon, hydrogen, and nitrogen were performed with a Thermo Quest Italia SPA EA1110 instrument. The1H and13C NMR spectra were recorded with 5 mm tubes in CDCl3solution using AVANCE III 400 and AVANCE III HD 500 spectrometers. Infrared spectra were recorded by using KBr pellets with a NEXUS670 (Thermo Fisher Scientific) FT-IR spectrometer. Acylthioureas were prepared according to the previous procedures[25-27].

2.2 General synthetic procedure

To a solution of the parent acylthiourea (20 mmol) in 50 mL of CH3CN were added the corresponding second amines (20 mmol) and Et3N (40 mmol, 5.6 mL). Then NaBiO3(20 mmol, 5.60 g) and BiI3(10 mmol, 0.6 g) were added to the above solution with vigorous magnetic stirring. The suspension was left stirring for 10 min at room temperature and became black. The progress of the reaction was monitored by TLC (Hexane-EtOAc). After complete conversion, the solvent was evaporated and the obtained residue was re-dissolved in CH2Cl2(50 mL). The suspension was filtered through a pad of Celite and the filtrate was dried in a rotary evaporator under reduced pressure to give a white solid.

2.3 MesC(O)N=C[N(H)Ar??]NCy2 (1)

-(2,6-diisopropylphenyl)-?-(2,4,6-trimethyl benzoyl)thiourea (20 mmol, 7.61 g) and dicyclohexylamine (20 mmol, 4.0 mL) were used for the synthesis of 1. Yield 46.5%. m.p.: 163～164 °C.1H NMR (500 MHz, CDCl3, ppm)= 12.26 (s, 1H, N), 7.15～7.19 (m, 1H, Ar–), 7.09～7.11 (m, 2H, Ar–), 6.71 (s, 2H, Mes–), 3.19 (sept,= 6.6 Hz, 2H, C(CH3)2), 2.44～2.94 (br., 2H, N–C), 2.27 (s, 6H, Mes-C3), 2.19 (s, 3H, Mes-C3), 1.27～1.78 (m, 20H, Cy–), 1.27 (d,= 6.9 Hz, 6H, CH(C3)2), 1.11 (d,= 6.8 Hz, 6H, CH(C3)2).13C NMR (126 MHz, CDCl3, ppm)= 180.83 (=O), 160.91 (=N), 145.09, 140.33, 135.66, 135.49, 132.66, 127.63, 127.52, 123.57 (Mes/Ar–), 57.68 (N–H), 31.48 (Cy–), 28.82 (H(CH3)2), 25.59, 25.32 (Cy–), 21.58 (CH(H3)2), 21.09, 19.55 (Ar–H3). FT-IR (KBr, cm–1): 3070.97 (vw, NH). Anal. Calcd. for C35H51N3O (529.81): C, 79.35; H, 9.70; N, 7.93%.Found: C, 79.22; H, 9.79; N, 7.90%.

2.4 PhC(O)N=C[N(H)Ar??]NBn2 (2)

-(2,6-diisopropylphenyl)-?-benzoyl thiourea (20 mmol, 6.81 g) and dibenzylamine (20 mmol, 4.0 mL) were used. Yield 67.9%. m.p.: 146～147 °C.1H NMR (500 MHz, CDCl3,ppm)= 12.66 (s, 1H, N), 8.25～8.30 (m, 2H, Ar–), 7.38～7.44 (m, 1H, Ar–), 7.33～7.37 (m, 2H, Ar–), 7.15～7.24 (m, 6H, Ar–), 7.03～7.14 (m, 5H, Ar–), 6.97～7.00 (m, 2H, Ar–), 4.48 (br., 4H, Ph–C2), 3.03 (sept,= 6.8 Hz, 2H, C(CH3)2), 1.03 (d,= 6.8 Hz, 6H, CH(C3)2), 0.80 (d,= 6.9 Hz, 6H, CH(C3)2).13C NMR (101 MHz, CDCl3, ppm)= 175.72 (=O), 160.28 (=N), 144.09, 137.82, 135.90, 133.15, 130.07, 128.16, 127.61, 126.88, 126.73, 126.44, 122.61 (Ar/Ph–), 49.47 (Ph–H2), 27.53 (H(CH3)2), 23.92, 20.54 (CH(H3)2). FT-IR (KBr, cm–1): 3060.21 (vw, NH). Anal. Calcd. For C34H37N3O (503.69): C, 81.08; H, 7.40; N, 8.34%. Found: C, 81.19; H, 7.55; N, 8.27%.

2.5 PhC(O)N=C[N(H)Ar??]NiPr2 (3)

-(2,6-diisopropylphenyl)-?-benzoyl thiourea (20 mmol, 6.81 g) and diisopropylamine (20 mmol, 2.8 mL) were used. Yield 24.5%. m.p.: 215～216 °C.1H NMR (500 MHz, CDCl3, ppm)= 12.25 (s, 1H, N), 8.25～8.29 (m, 2H, Ar–), 7.43～7.49 (m, 2H, Ar–), 7.23～7.30 (m, 2H, Ar–), 7.18～7.19 (m, 2H, Ar–), 3.93～3.40 (br., 2H, N–C), 3.28 (sept,= 6.8 Hz, 2H, Ar–C(CH3)2), 1.28 (d,= 6.9 Hz, 12H, CH(C3)2), 1.15 (d,= 6.8 Hz, 12H, CH(C3)2).13C NMR (126 MHz, CDCl3, ppm)= 175.72 (=O), 161.45(=N), 145.19, 135.47, 130.69, 129.00, 127.84, 127.56, 123.70 (Ar/Ph–), 48.16 (N–H(CH3)2), 28.62 (C6H3-H(CH3)2), 25.02, 21.64 (CH(H3)2). FT-IR (KBr, cm–1): 3066.54 (s, NH). Anal. Calcd. for C26H37N3O (407.60): C, 76.62; H, 9.15; N, 10.31%. Found: C, 76.66; H, 9.23; N, 10.18%.

2. 6 PhC(O)N=C[N(H)Ar?]NCy2 (4)

-(2,6-diisopropylphenyl)-?-benzoyl thiourea (20 mmol, 6.81 g) and dicyclohexylamine (20 mmol, 4.0 mL) were used. Yield 14.6%. m.p.: 172～173 °C.1H NMR (400 MHz, CDCl3, ppm)= 12.04 (s, 1H, N), 8.19～8.25 (m, 2H, Ar–), 7.33～7.41 (m, 3H, Ar–), 6.98 (s, 3H, Ar–), 3.03 (br., 2H, N–C), 2.22 (s, 6H, C3), 0.54～1.96 (br., 20H, Cy–).13C NMR (126 MHz, CDCl3, ppm)= 174.23 (=O), 160.65 (=N), 138.31, 137.47, 133.96, 129.65, 127.95, 127.59, 126.76, 125.53 (Ar/Ph–), 57.07, 30.37, 25.27, 24.45 (Cy–), 17.70 (H3). FT-IR (KBr, cm–1): 3137.64(m, NH). Anal. Calcd. for C28H37N3O (431.62): C, 77.92; H, 8.64; N, 9.74%. Found: C, 77.84; H, 8.71; N, 9.73%.

2. 7 PhC(O)N=C[N(H)Ar?]NEt2 (5)

-(2,6-dimethylphenyl)-?-benzoyl thiourea (20 mmol, 5.60 g) and diethylamine (20 mmol, 2.1 mL) were used. Yield 15.4%. m.p.: 118～119 °C.1H NMR (500 MHz, CDCl3, ppm)= 11.85 (s, 1H, N), 8.17～8.21 (m, 2H, Ar/Ph–), 7.32～7.40 (m, 3H, Ar/Ph–), 6.98 (s, 3H, Ar/Ph–), 3.23 (br., 4H, C2CH3), 2.19 (s, 6H, Ar–C3), 0.93 (br., 6H, CH2C3).13C NMR (126 MHz, CDCl3, ppm)= 175.15 (=O), 160.52 (=N), 137.95, 136.51, 133.52, 129.88, 127.97, 127.60, 126.76, 125.51 (Ar/Ph–), 41.73 (H2CH3), 17.59 (Ar–H3), 11.71 (CH2H3). FT-IR (KBr, cm–1): 3461.34 (m, NH). Anal. Calcd. for C20H25N3O (323.44): C, 74.27; H, 7.79; N, 12.99%. Found: C, 74.37; H, 7.77; N, 13.02%.

2.8 X-ray structure determination and refinement

Colorless crystals of 1～6 in X-ray quality were grown from concentrated ethanol solutions. The single crystals with dimensions around 0.20mm × 0.20mm × 0.20mm were used for structure determi-nation. The crystallographic data were collected on a Bruker SMART APEX II CCD diffractometer equipped with a graphite-monochromated Moradiation (= 0.71073 ?) at room temperature using an-2scan technique. Empirical absorption co-rrection was applied using the SADABS program[28]. Structures were solved by direct methods and refined by full-matrix least-squares on2using the SHELXL-97 program[29, 30]. All non-hydrogen atoms were located by difference Fourier synthesis and refined anisotropically, and hydrogen atoms were included using the riding model withisorelated toisoof the parent atoms. The final= 0.0522 in 1 for 359 parameters and 5640 observed reflections with> 2() and= 0.1621 (= 1/[2(F2) + (0.0861)2+ 0.6739], where= (F2+ 2F2)/3) for all 40683 reflections; (D)max= 0.317 and (D)min= –0.212 e/?3. And in 2 the final= 0.0497 for 347 parameters and 5113 observed reflections with> 2() and= 0.1398 (= 1/[2(F2) + (0.0796)2+ 0.2790] for all 26512 reflections; (D)max= 0.272 and (D)min= –0.282 e/?3. In 3 the final= 0.0514 for 279 parameters and 4452 observed reflections with> 2() and= 0.1522 (= 1/[2(F2) + (0.0727)2+ 0.5274] for all 37280 reflections; (D)max= 0.304 and (D)min= –0.342 e/?3. In 4 the final= 0.0453 for 291 parameters and 4723 observed reflections with> 2() and= 0.1331 (= 1/[2(F2) + (0.0682)2+ 2.5601] for all 23753 reflections; (D)max= 0.260 and (D)min= –0.238 e/?3. In 5 the final= 0.0603 for 222 parameters and 2821 observed reflections with> 2() and= 0.1972 (= 1/[2(F2) + (0.1311)2+ 0.1375] for all 24112 reflections; (D)max= 0.260 and (D)min= –0.238 e/?3.

（2）重當(dāng)前輕發(fā)展。產(chǎn)品質(zhì)量大數(shù)據(jù)需要對(duì)產(chǎn)品全生命周期各離散環(huán)節(jié)的信息進(jìn)行全面采集。我國(guó)對(duì)產(chǎn)品質(zhì)量信息的采集主要集中于產(chǎn)品的設(shè)計(jì)和生產(chǎn)過(guò)程，特別是成品的標(biāo)準(zhǔn)符合性信息。近年來(lái)，售后服務(wù)信息也成為企業(yè)信息采集的重點(diǎn)，但物料采購(gòu)環(huán)節(jié)和進(jìn)貨環(huán)節(jié)的信息仍較為匱乏。同時(shí)，各地、各部門、各行業(yè)都在采集信息、發(fā)布信息，而這些數(shù)據(jù)都是從某一主體自身當(dāng)前需要出發(fā)進(jìn)行采集、發(fā)布的，缺乏系統(tǒng)化、前瞻性設(shè)計(jì)，相對(duì)于企業(yè)、產(chǎn)業(yè)發(fā)展需要的整體數(shù)據(jù)而言，往往呈現(xiàn)碎片化特征。企業(yè)、特別是大多數(shù)中小微企業(yè)，其不熟悉產(chǎn)品質(zhì)量大數(shù)據(jù)的應(yīng)用場(chǎng)景，質(zhì)量基礎(chǔ)設(shè)施和信息化建設(shè)薄弱，故數(shù)據(jù)的碎片化特征更為明顯。

3 RESULTS AND DISCUSSION

The reaction of-(2,6-diisopropylphenyl)-?-(2,4,6-trimethylbenzoyl) thiourea[26]with dicyclo-hexylamine was carried out in acetonitrile in the presence of bismuth salts and Et3N (Scheme 2) using a modified one-pot protocol[20]. MesC(O)N=C[N(H)Ar??]NCy2(1) was separated as a while solid in a moderate yield (46.5%).

Scheme 2. Synthesis of acylguanidines 1～4

In the FT-IR spectrum of 1 the weak band observed at 3070.97 cm–1can be assigned to the N–H stretching vibration, which is in consistence with the formation of intramolecular hydrogen bond for those related-mono-substituted acylguanidines[5,16]. Likewise, in the1H NMR spectrum of 1 recorded in CDCl3, the low-field singlet at=12.26 ppm was due to the NH proton, also suggesting the presence of hydrogen bond within 1 in solution[5,16].

The methine protons of the isopropyl groups give a signal in the form of a septet at=3.19 ppm, and the signals of their methyl groups were observed as two doublets at=1.11 and 1.27 ppm, respectively. Signals resonate at=2.27 and 2.19 ppm due to the methyl protons of Mes group. Peaks between=1.27 and 1.78 ppm were for cyclohexyl protons with correct integral ratios. The composition of 1 was further confirmed by13C NMR spectroscopy and elemental analysis. Single crystals suitable for X-ray structural analysis were obtained from saturated ethanol solution of 1 by slow evaporation at room temperature. The molecular structure of 1 is depicted in Fig. 1 and the selected bond lengths and bond angles are listed in Table 1. MesC(O)N=C[N(H)Ar??]-NCy2(1) crystallizes in the monoclinic space group21/. It shows that a single intramolecular hydrogen bond is present within the solid structure of 1 involving the atoms N(1)–H(1)···O(1) (Table 2)to form a pseudo six-membered ring. Under such a condition, the O(1) atom almost locates on the least-squares plane NCNC fitted through the atoms N(l), C(1), N(2), and C(2) by only slight deviation of 0.168 ?. When reviewingthe structure of parent-(2,6-diisopropylphenyl)-?-(2,4,6-trimethylbenzoyl) thiourea[26], it seems that the intramolecular hydrogen bond was ?inherited? by 1.

Fig. 1. Molecular structure of 1. Thermal ellipsoids are drawn at 30% level. Other hydrogen atoms except for NH are omitted for clarity

Compound 1 represents the rare example of,-disubstituted acylguanidines to bear the intra- molecular hydrogen bond within the solid structure in contrast to the previously known cases[21-24]. Another structural feature of 1 is that the Mes plane is nearly perpendicular to the NCNC quasi-plane (79.51°) due to the steric resistance. Correspondingly, the N(1)–C(1)–N(3) bond angle (123.35°) is more or less larger than those for-mono-substituted acylguani- dines[3,11-18](114.7～120.6°). There was no short contact like intermolecular hydrogen bond found among molecules of 1.

Table 1. Selected Bond Lengths (?) and Bond Angles (°) of Compounds 1～5

Table 2. Hydrogen Bond Lengths (?) and Bond Angles (°) of Compounds 1～5

Symmetry code: #1:–1/2, –+1/2, –+1

Fig. 2. Molecular structure of 2. Thermal ellipsoids are drawn at 30% level. Other hydrogen atoms except for NH are omitted for clarity

The core structure of C(O)N=C[N(H)Ar??]N of 2 owes a conformation similar to that of 1, while the N(1)–C(1)–N(3) bond angle is found to slightly shrink to 121.84° relative to that of 1 (123.35°). In sharp contrast, the Ph plane is almost parallel to the least-squares plane NCNC by 12.80°, which is in line with the observations in those related-mono-subs-tituted acylguanidines involving R1= Ph[3,11-18]. Similarly, no short contact was found among the molecules of 2.

Starting from PhC(O)N=C[N(H)Ar??]NBn2(2), the ?change? of R3substituent from Bn to the further less bulkyPr led to the formation of an analogue PhC(O)N=C[N(H)Ar??]NPr2(3, Scheme 2). It also presents the intramolecular hydrogen bond (molecular structure of 3 not shown here). In the case of 3, the N(1)–C(1)–N(3) bond angle is further decreased to 121.50°. When Ar? = 2,6-Me2C6H3was introduced as R2, another,-disubstituted acy-lguanidine PhC(O)N=C[N(H)Ar?]NCy2(4) (Scheme 2) was obtained. The spectroscopic and structural characterization of 4 (not shown) revealed that it is highly analogous to 1～3.

A closer examination of structures 1～4 indicated that the rough reduction of the steric hindrance of R substitutents of R1C(O)N=C[N(H)R2]NR32(abbre- viated here as R1-R2-R3for comparison purposes) led to the slight enlongation of N(1)–C(1) bond lengthes and mariginal decrease of N(1)–C(1)–N(3) bond angles from Mes–Ar??–Cy (1) to Ph–Ar??–Bn (2), Ph–Ar??–Pr (3) and Ph–Ar?–Cy (4) (Scheme 3). It is therefore suggested that the further modification of R substituents may bring about substantial change in structure.

Scheme 3. C(1)–N(1) bond lengths and N(1)–C(1)–N(3) bond angles of 1～4

To put forward this consideration, PhC(O)N=C[N(H)Ar?]NEt2(5) was prepared by reacting-(2,6-dimethylphenyl)-?-benzoyl thiourea with diethylamine (Scheme 4), where the R3substituent was taken as the less bulky Et group instead of Cy in 4.

Scheme 4. Synthesis of acylguanidine 5

In the FT-IR spectrum of 5, the strong band observed at 3461.34 cm–1is attributable to N–H stretching, and it is found to be greatly blue-shifted relative to those of1～4 (3060.21～3137.64 cm–1). On the other side, resonance for NH proton was observed at=11.85 ppm in the1H NMR spectrum, which is generally high-field shifted when compared to those of 1～4 (=12.04～12.66 ppm). These observations could provide a hint for the existence of possible but different hydrogen bond in 5.

As characterized by the single-crystal X-ray diffraction, 5 crystallizes in orthorhombic system212121space group. The molecular structure of 5 is depicted in Fig. 3, in which no intramolecular hydrogen bond exists.

Fig. 3. Molecular structure of 5. Thermal ellipsoids are drawn at 30% level. Other hydrogen atoms except for NH are omitted for clarity

The torsion angle of N(1)–C(1)–N(2)–C(2) is found to be –108.6(3)°, in sharp contrast to those of the structurally known,-disubstituted acylguani-dines that contain no intramolecular hydrogen bonds either, including PhC(O)N=C[N(H)Ph]NEt2(42.2°)[21], PhC(O)N=C[N(H)Ph]N(Me)Bn (52.2°)[23],and-NO2–C6H4–C(O)N=C[N(H)Fc?]NMe2(122.2°) (Fc? = 2-ethoxycarbonyl-1-ferrocenylethyl)[24], but still somewhat comparable to that for MeC(O)N=C[N(H)Bu]N(Bu)C(O)Me (–168.1°)[22]. These structural differences could be related to the spatial preference of nucleophile amine to attack the thiocarbonyl site during the desulfurization-con- densation reaction[31]. Structural analyses of the those above reported,-disubstituted acylguanidines revealed that they form intermolecular bonds instead[21-24], by which the adjacent molecules of them were linked into dimers[21]or zigzag long chains[22-24]. The packing diagram of 5 molecules in the unit cell viewed down theaxis is illustrated in Fig. 4, showing intermolecular hydrogen bonds N(1)–H(1)···O(1)#1 to generate zigzag chains along theaxis (symmetry operation #1: #1:–1/2, –+1/2, –+1), as shown in Table 2.

Fig. 4. Packing diagram of 5 with intermolecular hydrogen bonds

In a reference reaction of-(2,6-dimethylphenyl)-?-benzoyl thiourea with diisopropylamine, the obtained product (6) turned out to be a new acylurea PhC(O)N(H)C(O)N(H)Ar? other than the expected,-disubstituted acylguanidine PhC(O)N=C[N(H)Ar?]NPr2. It was suggested that under such a condition the above acylthiourea PhC(O)N(H)C(S)N(H)Ar? was much more reactive with the residual water in reaction system to undergo a desulfurization hydrolysis. This finding is in agreement with our previous practices that the acylthioureas show a facile reactivity with water, alcohol, or amine under catalytic conditions[27]. In practical ways, acylureas can be prepared from amides[32]or carboxamides[33].

4 CONCLUSION

In summary, we have synthesized and charac-terized five new,-acylguanidines R1C(O)N=C[N(H)R2]NR32(R1= Mes or Ph; R2= Ar?? or Ar?; R3= Cy, Bn,Pr, or Et) (Mes = 2,4,6-Me3C6H2, Ar?? = 2,6-Pr2C6H3, Ar? = 2,6-Me2C6H3) by the modification of R substituents. The structures of 1～5 were well characterized by single-crystal X-ray diffraction. Compounds 1～4 each contained a single intramolecular hydrogen bond N(1)–H(1)···O(1), while 5 formed an intermolecular hydrogen bond instead. It was suggested that the steric hindrance of R substituents could play a significant role therein.

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25 September 2017;

8 February 2018 (CCDC 1575244～1575249 for compounds 1～6)

This work was supported by the National Natural Science Foundation of China (21771194),and the Special Fund for Agro-scientific Research in the Public Interest (201503108)

. Born in 1974, Ph D, majoring in inorganic chemistry. E-mail: yangy@csu.edu.cn. ORCID: 0000-0003-4531-8349

10.14102/j.cnki.0254-5861.2011-1835