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Proceeding Paper

A New Approach to 5-Functionalized 1,2-Dihydropyrimidin-2-ones/imines via Base-Induced Chloroform Elimination from 4-Trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones/imines †

by
Pavel A. Solovyev
1,
Anastasia A. Fesenko
2 and
Anatoly D. Shutalev
2,*
1
Russian Technological University, 86 Vernadsky Avenue, 119571 Moscow, Russia
2
N. D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, 47 Leninsky Ave., 119991 Moscow, Russia
*
Author to whom correspondence should be addressed.
†
Presented at the 22nd International Electronic Conference on Synthetic Organic Chemistry, 15 November–15 December 2018; Available Online: https://sciforum.net/conference/ecsoc-22.
Proceedings 2019, 9(1), 15; https://doi.org/10.3390/ecsoc-22-05678
Published: 14 November 2018
(This article belongs to the Proceedings of 22nd International Electronic Conference on Synthetic Organic Chemistry)
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Abstract

:
A novel four-step methodology for the synthesis of 5-acyl- and 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones has been developed. The reaction of readily available N-[(1-acetoxy-2,2,2-trichloro)ethyl]-ureas with Na-enolates of 1,3-diketones, β-oxoesters, or α-arylsulfonylketones followed by heterocyclization–dehydration of the oxoalkylureas formed gave 5-acyl- or 5-arylsulfonyl-4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones. The latter, in the presence of strong bases, eliminates CHCl3 to give the target compounds. The above methodology was also used in the synthesis of 5-acyl-1,2-dihydropyrimidin-2-imines starting from N-[(1-acetoxy-2,2,2-trichloro)ethyl]-N′-guanidine.

1. Introduction

5-Non-functionalized 1,2-dihydropyrimidin-2-ones (1a R1 = H, alkyl, aryl) (Figure 1) are of considerable interest due to their wide range of biological activities [1,2,3,4,5]. These compounds have been extensively studied, and effective methods for their synthesis have been developed [6,7,8]. In contrast, 5-acyl-1,2-dihydropyrimidin-2-ones (1b R3 = alkyl, aryl, alkoxy, etc.) have been studied less widely. A number of methods, including condensations of (С-С-С-N-C-N)- [9,10,11], (C-C-C-N + C-N)- [12], and (C-C-C + N-C-N)-types [10,13,14], dehydrogenation [15] and oxidation [16,17,18,19,20,21,22,23] of the corresponding 1,2,3,4-tetrahydropyrimidin-2-ones, catalytic acylation of 5-trialkylstannylpyrimidines [24], and hydrolysis of appropriate 2-functionalized pyrimidines [24,25,26,27,28,29,30], have been reported for the synthesis of pyrimidines 1b. However, the synthetic methods generally efficient in the preparation of 1a tend to give poor yields in the specific case of 1b.
Other 5-functionalized 1,2-dihydropyrimidin-2-ones remain hitherto practically inaccessible. For example, there are only a few reports on the synthesis of 5-arylsulfonyl-1,2-dihydropyrimidin- 2-ones (1c R4 = aryl) [31,32]. Thus, the development of a general approach to the synthesis of 5-functionalized 1,2-dihydropyrimidin-2-ones is important.
Taking into consideration the reported formation of imines from α-trichloromethyl-substituted secondary amines and amides by elimination of chloroform in the presence of bases [33,34,35,36], we hypothesized that 5-functionalized 1,2-dihydropyrimidin-2-ones (1b,c R2 = H) could be obtained starting from the corresponding 4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones. Synthesis of the latter is presented in our retrosynthetic plan (Scheme 1) and includes ureidoalkylation of enolates of α-functionalized ketones [37,38,39,40,41].
Here, we describe a novel convenient approach to 5-acyl-1,2-dihydropyrimidin-2-ones 1b and 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones 1c via 4-trichloromethyl-1,2,3,4-tetrahydropyrimidin- 2-ones as key intermediates. The application of this approach to the synthesis of 5-acyl-1,2-dihydropyrimidin-2-imines are also reported.

2. Results and Discussion

In our previous experience, α-tosyl-substituted N-alkylureas proved very useful starting materials for the preparation of various 5-functionalized 1,2,3,4-tetrahydropyrimidin-2-ones by ureidoalkylation of α-functionalized ketones [37,38,39,40,41]. However, the synthesis of tosyl derivative 3 bearing a trichloromethyl group failed (Scheme 2), while acetoxy derivatives 4 and 5 [42] were conveniently prepared by treatment of the readily available 2 [43] with Ac2O in pyridine and Ac2O in the presence of H2SO4, respectively. Based on the ability of the acetoxy group to serve as a good leaving group in various reactions of ureidoalkylation [44,45,46,47,48,49], we hypothesized that compounds 4 and 5 might also be used in the synthesis of compounds 7 under the conditions similar to those applicable for ureidoalkylation of α-substituted ketones with α-tosyl-substituted N-alkylureas [37,38,39,40,41].
Sodium enolates of 1,3-dicarbonyl compounds 6a,b and β-oxoesters 6c,d generated in situ by treating the corresponding CH-acids with an equivalent amount of NaH reacted with urea 4 for 2.7–4.3 h at room temperature to give the products of acetoxy group substitution, N-oxoalkylureas 7a–d, in 70–95% yield (Scheme 3, Table 1).
Anhydrous MeCN was used as a solvent for preparation of compounds 7a,c–d; however, for compound 7b anhydrous THF was used because the solubility of the enolate of 6b in MeCN was very low and the resulting extremely dense suspension hampered the completion of reaction of NaH with 6b.
Following the same procedure, urea 5 reacted with the sodium enolate of 6a and 6c in MeCN (rt, 4.2–4.4 h) to give oxoalkylureas 7e and 7f in 82 and 69% yield, respectively (Scheme 3, Table 1).
IR-, 1H-, and 13C-NMR spectra indicated that compounds 7a–f only existed in acyclic form both in solid state and in DMSO-d6 solution. Their cyclic isomers 8a–f (Scheme 3) were not detected by any spectroscopic methods.
Compounds 7c,d,f were formed as mixtures of two diastereomers (Table 1). The diastereoselectivity of the product formation depended on the structures of both reagents and was higher with 5 than with 4 (entry 3 vs. entry 8) and with 6d than with 6c (entry 3 vs. entry 4). The reaction time did not affect the ratio of diastereomers (entry 5 vs. entry 6). The use of a greater excess of a nucleophile slightly reduced the stereoselectivity (entry 5 vs. entry 4), which indicated that these reactions were controlled by both kinetic and thermodynamic factors.
Sodium enolates of ketones bearing the arylsulfonyl group at the α-position generated in situ by treating the corresponding CH-acids 9a–d with an equivalent amount of NaH reacted with ureas 4 and 5 (MeCN or THF, rt, 4–9 h) to give products of nucleophilic substitution of the acetoxy group, sulfones 10a–e, in a 76–90% yield (Scheme 4, Table 2).
Reactions of 9a–d with 4 and 5 proceeded with high diastereoselectivity to give sulfones 10a–e in 70–94% diastereomeric excesses (Table 2). The polarity of the solvent had a slight effect on diastereoselectivity (Entry 1 vs. Entry 2; Entry 6 vs. Entry 7). N-Acyl-substituted urea 5 reacted with enolate of 9b with higher diastereoselectivity compared with urea 4 (Entry 3 vs. Entry 4).
Based on the values of vicinal couplings of protons in the NH-CH-CH moiety, we have concluded that the minor diastereomers of 10a–e in DMSO-d6 solution exist in a conformation with an anti–anti orientation of the named protons (3JNH,CH = 10.1–10.8 Hz, 3JCH,CH = 8.8–9.0 Hz), while the orientation of the protons for major diastereomers is anti for NH-CH and gauche for СH–CH moieties (3JNH,CH = 9.5–9.6 Hz, 3JCH,CH = 1.5–1.8 Hz).
Next, refluxing solutions of ureas 7a–f in the presence of TsOH (Scheme 5) led to 4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones 12a–d. The dependence of the yields of 12a–d on the reaction conditions is outlined in Table 3.
Heterocyclization–dehydration of 7a–d proceeded smoothly in MeCN as a solvent to give 12a–d in high yields (75–95%, Table 3, entries 1, 7–11). Reaction of 7a,c was complete after 0.5–1 h in the presence of TsOH (0.3 equiv, entries 1, 8). By comparison with compounds 7a,c, their counterparts 7b,d, which possess a less electrophilic carbonyl group, were converted into 12b,d (entries 7, 10–11) using a greater amount of catalyst or/and longer reaction time. Pyrimidine 12c was also readily synthesized from 7c using toluene as a solvent (entry 9).
In contrast to the smooth conversion of 7a into 12a in MeCN, refluxing 7a in EtOH, MeOH, or toluene in the presence of TsOH led to the formation of 12a plus the product of its deacetylation, pyrimidine 13 (entries 2–6). Presumably, 13 was obtained as a result of the acid-promoted deacylation of 7a followed by heterocyclization and dehydration of the intermediate formed. The data listed in Table 3 indicates that the formation of 13 was favored in more polar solvents (entry 4 vs. entry 6), at higher reaction temperature (entry 2 vs. entry 3), and in protic solvents (entry 1 vs. entry 5). The amount of catalyst had no appreciable effect on the ratio of 12a to 13 (entry 3 vs. entry 4 vs. entry 5).
5-Arylsulfonyl-substituted tetrahydropyrimidines 14a–d were obtained by the reflux of sulfones 10a–e in alcohols (EtOH, n-BuOH) in the presence of TsOH (1–4 equiv) (Scheme 6, Table 4).
Formation of compounds 14a,b from 10a,b proceeds via heterocyclization of intermediate hydroxypyrimidines 11a,b followed by dehydration. In case of N-acetylureas 10c–e, the first step is N-deacylation into corresponding ureas 10b,f,g followed by cyclization into hydroxypyrimidines 11b,f,g and fast dehydration into tetrahydropyrimidines 14b–d. The data presented in Table 4 shows that the result of the reaction depends on the structure of the starting compounds and reaction conditions. The rate of pyrimidine 14 formation increases with increasing reaction temperature (Entry 7 vs. Entry 8) and quantity of TsOH (Entry 3 vs. Entry 4; Entry 6 vs. Entry 7). N-deacylation of 10c–e proceeds much faster than subsequent transformation of obtained 10b,f,g into в 14b–d (Entry 2 vs. Entry 4; Entries 3, 6, and 7). Benzoyl-containing ureas 10a–c react significantly slower comparing with acetyl-containing ureas 10d,e (Entries 1, 2, and 4 vs. Entries 5 and 8). Apparently, cyclization of N-deacylated ureas 10a,b,f,g into the corresponding hydroxypyrimidines (11), which is affected by electrophilicity of carbonyl group and steric bulk of R1, is the rate-determining step of compounds 14a–d formation.
Thus, under optimal conditions, reflux of 10a–e in BuOH in the presence of 2–4 equiv of TsOH led to the smooth formation of pyrimidines 14a–d in 63–93% yields.
Finally, aromatization of tetrahydropyrimidines 12a–d by NaH (1.2–1.25 equiv) in an aprotic solvent at room temperature led to formation of the corresponding 5-acyl-1,2-dihydropyrimidin-2-ones 15a–d in good yields (Scheme 7). The reaction proceeded best in THF (for 15a,c,d) and, for 15b, in DME while the more polar MeCN failed to give satisfactory yields even with a prolonged reaction time (24 h) and a greater excess of NaH (up to 1.5 equiv).
Analogously, treatment of tetrahydropyrimidines 14a–d with strong bases in aprotic solvents resulted in the formation of the corresponding 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones 16a–d (Scheme 7). Target pyrimidines (16a–d) were obtained by the reaction of 14a–d (rt, MeCN, 1.2–3.3 h) with NaH (1.1 equiv) in 80–98% yields. The rate of elimination decreased with a decrease in the base strength. When compound 14d was treated with DBU (2.1 equiv) in MeCN, aromatization was completed in five days and led to the formation of 16d in 96% yield. Reaction of 14с with sodium malonate in MeCN did not proceed at rt and was complete only after reflux for 1 h, resulting in 16c in 85% yield. Compound 14d being treated with NaH (1.1 equiv) in THF (rt, 2 h) gave compound 16d in 90% yield.
Transformation of 12a–d into 15a–d and 14a–d into 16a–d proceeds via elimination of chloroform. Proton abstraction from the more acidic N(1)-H group in 12a–d, 14a–d followed by CCl3-anion elimination leads to formation of 15a–d, 16a–d (Scheme 8).
The above methodology was also used in the synthesis of 5-acyl-1,2-dihydropyrimidin-2-imines starting from N-[(1-acetoxy-2,2,2-trichloro)ethyl]-N′-guanidine 19 (Scheme 9). The latter was prepared by heating N-tosylguanidine with excess chloral without solvent, followed by treatment of the obtained methylol derivative 18 with Ac2O in pyridine.
Acetate 19 reacted with the Na-enolates of CH-acids 6a,c–d to give the corresponding products of the acetyl group substitution, compounds 20a–d, which, under reaction conditions, completely (for R = Me) or partly (for R = Ph) cyclized into 4-hydroxypyrimidin-2-imines 21a–d. Dehydration of the compounds obtained was readily carried out by boiling in EtOH in the presence of TsOH to afford the corresponding tetrahydropyrimidin-2-imines 22 in high yields. The treatment of carboxylates 22b,c with NaH in THF proceeded with the elimination of chloroform to give the target alkyl 2-tosylimino-1,2-dihydropyrimidine-5-carboxylates 23a,b.

3. Conclusions

We have developed a novel general approach to 5-acyl- and 5-arylsulfonyl-substituted 1,2-dihydropyrimidin-2-ones/imines that involved base-induced elimination of CHCl3 from the corresponding 4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones/imines. The latter were prepared using the reaction of readily available N-[(1-acetoxy-2,2,2-trichloro)ethyl]ureas and guanidines with Na-enolates of 1,3-diketones, β-oxoesters, or α-arylsulfonylketones, followed by acid-catalyzed heterocyclization–dehydration of the products formed.

Acknowledgments

This work was supported by the Russian Foundation for Basic Research (grant No. 18-33-00374).

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Proceedings 09 00015 g001
Figure 1. Structures of 1,2-dihydropyrimidin-2-ones 1a, 5-acyl-1,2-dihydropyrimidin-2-ones 1b, and 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones 1c.
Figure 1. Structures of 1,2-dihydropyrimidin-2-ones 1a, 5-acyl-1,2-dihydropyrimidin-2-ones 1b, and 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones 1c.
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Scheme 1. Retrosynthesis of 5-functionalized 1,2-dihydropyrimidin-2-ones.
Scheme 1. Retrosynthesis of 5-functionalized 1,2-dihydropyrimidin-2-ones.
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Scheme 2. Synthesis of ureidoalkylating agents 4 and 5. Reagents and conditions: (a) H2O, rt; (b) 4-MeC6H4S(O)OH, H2O, rt or heating; (c) Ac2O, py, rt, 75%; and (d) Ac2O, H2SO4, rt, 79%.
Scheme 2. Synthesis of ureidoalkylating agents 4 and 5. Reagents and conditions: (a) H2O, rt; (b) 4-MeC6H4S(O)OH, H2O, rt or heating; (c) Ac2O, py, rt, 75%; and (d) Ac2O, H2SO4, rt, 79%.
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Scheme 3. Synthesis of ureas 7a–f by reaction of sodium enolates of 1,3-diketones 6a,b and β-oxoesters 6c,d with 4 and 5.
Scheme 3. Synthesis of ureas 7a–f by reaction of sodium enolates of 1,3-diketones 6a,b and β-oxoesters 6c,d with 4 and 5.
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Scheme 4. Synthesis of oxoalkylureas 10a–e.
Scheme 4. Synthesis of oxoalkylureas 10a–e.
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Scheme 5. Synthesis of 5-acyl-4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones 12a–d.
Scheme 5. Synthesis of 5-acyl-4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones 12a–d.
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Scheme 6. Synthesis of 5-arylsulfonyl-4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones 14a–d.
Scheme 6. Synthesis of 5-arylsulfonyl-4-trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones 14a–d.
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Scheme 7. Synthesis of 5-acyl-1,2-dihydropyrimidin-2-ones 15a–d and 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones 16a–d.
Scheme 7. Synthesis of 5-acyl-1,2-dihydropyrimidin-2-ones 15a–d and 5-arylsulfonyl-1,2-dihydropyrimidin-2-ones 16a–d.
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Scheme 8. Base-induced transformation of 12a–d and 14a–d into 15a–d and 16a–d, respectively.
Scheme 8. Base-induced transformation of 12a–d and 14a–d into 15a–d and 16a–d, respectively.
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Scheme 9. Synthesis of 5-acyl-1,2-dihydropyrimidin-2-imines 23.
Scheme 9. Synthesis of 5-acyl-1,2-dihydropyrimidin-2-imines 23.
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Table 1. Reaction of ureas 4 and 5 with sodium enolates of 6a–d a.
Table 1. Reaction of ureas 4 and 5 with sodium enolates of 6a–d a.
EntryStarting MaterialSolvent Reaction Time, hMolar Ratio
(4/6 or 5/6)		ProductDiastereomeric Ratio bYield, c
%
16a4MeCN3.31:17a-70
26b4THF4.31:17b-89
36c4MeCN41.1:17c57:4386
46d4MeCN2.71.1:17d72:2895
56d4MeCN5.751:17d83:1791
66d4MeCN9.31:17d84:1690
76a5MeCN4.41:17e-82
86c5MeCN4.21.1:17f75:2569
a At room temperature. b Established by 1H NMR data of crude product. c All yields refer to isolated material homogeneous spectroscopically and by thin-layer chromatography (TLC).
Table 2. Reaction of ureas 4 and 5 with sodium enolates of 9a–d at rt.
Table 2. Reaction of ureas 4 and 5 with sodium enolates of 9a–d at rt.
EntryStarting MaterialSolventReaction Time, hProductDiastereomeric Ratio a
(R*,S*)-10/(R*,R*)-10		Yield, b
%
149aMeCN410a95:588
249aTHF4.510a88:1276
349bMeCN510b91:985
459bMeCN810c97:388
559cMeCN410d85:1585
659dMeCN910e85:1586
759dTHF6.510e86:1490
a According to 1H NMR data of crude products. b For isolated compounds.
Table 3. Synthesis of pyrimidinones 12a–d from ureas 7a–f a.
Table 3. Synthesis of pyrimidinones 12a–d from ureas 7a–f a.
EntryStarting MaterialSolventMolar Ratio of 7:TsOHReaction Time, hProduct(s)Molar Ratio of 12a:13 bYield of 12, %
17aMeCN1:0.30.612a-95
27aPhMe1:1.131.012a + 1373:27-
37aEtOH1:1.131.012a + 1394:6-
47aEtOH1:0.51.2512a + 1394:6-
57aEtOH1:0.30.6312a + 1390:10-
67aMeOH1:0.51.7512a + 1362:38-
77bMeCN1:12.212b-91
87cMeCN1:0.31.012c-93
97cPhMe1:1.11.012c-84
107dMeCN1:0.53312d-81
117dMeCN1:3.014.212d-75
127eEtOH1:1.52.012a + 1379:21-
137fEtOH1:2.03.012c-77
a Boiling in the presence of TsOH. b Based on 1H NMR spectrum of crude product.
Table 4. Transformation of 10a–e into 14a–d a.
Table 4. Transformation of 10a–e into 14a–d a.
EntryStarting MaterialSolventMolar Ratio of 10:TsOHReaction Time, hProduct(s)Molar ratio of Products, 14:10 bIsolated Yield of 14, %
110an-BuOH1:4.03114a-63
210bn-BuOH1:4.02514b-75
310cn-BuOH1:3.1514b + 10b c28:72-
410cn-BuOH1:4.01814b-72
510dn-BuOH1:2.0214c-93
610eEtOH1:1.12614d + 10g d68:32-
710eEtOH1:2.116.514d + 10g d80:20-
810en-BuOH1:2.0214d-92
a Reflux in alcohols in the presence of TsOH. b According to 1H NMR data. с Diastereomer mixture, 85:15. d Diastereomer mixture, 84:16.

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Solovyev, P.A.; Fesenko, A.A.; Shutalev, A.D. A New Approach to 5-Functionalized 1,2-Dihydropyrimidin-2-ones/imines via Base-Induced Chloroform Elimination from 4-Trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones/imines. Proceedings 2019, 9, 15. https://doi.org/10.3390/ecsoc-22-05678

AMA Style

Solovyev PA, Fesenko AA, Shutalev AD. A New Approach to 5-Functionalized 1,2-Dihydropyrimidin-2-ones/imines via Base-Induced Chloroform Elimination from 4-Trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones/imines. Proceedings. 2019; 9(1):15. https://doi.org/10.3390/ecsoc-22-05678

Chicago/Turabian Style

Solovyev, Pavel A., Anastasia A. Fesenko, and Anatoly D. Shutalev. 2019. "A New Approach to 5-Functionalized 1,2-Dihydropyrimidin-2-ones/imines via Base-Induced Chloroform Elimination from 4-Trichloromethyl-1,2,3,4-tetrahydropyrimidin-2-ones/imines" Proceedings 9, no. 1: 15. https://doi.org/10.3390/ecsoc-22-05678

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