SS-2013-N0091-OP.fm, 6/26/13Imprimatur:

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paperExpedient Base-Mediated Desulfitative Dimethylamination, Oxidation, or Etherification of 2-(Methylsulfanyl)-3,5-dihydro-4H-imidazol-4-one ScaffoldsFunctionalization of 3,5-Dihydro-4H-imidazol-4-onesShahnawaz Khan,a Vikas Tyagi,a Rohit Mahar,b Vikas Bajpai,b Brijesh Kumar,b Prem M. S. Chauhan*a

a Medicinal and Process Chemistry Division, CSIR-Central Drug Research Institute, Lucknow, 226 001, IndiaE-mail: premsc58@hotmail.com; E-mail: prem_chauhan_2000@yahoo.com; Fax ??fax number??

b Sophisticated Analytical Instrument Facility, CSIR-Central Drug Research Institute, Lucknow, 226 001, India

Received: 30.01.2013; Accepted after revision: 03.06.2013

Abstract: The dimethylamino functionality is generally introducedonto the 3,5-dihydro-4H-imidazol-4-one skeleton by treatment of ahalogenated derivative with low-boiling dimethylamine at a hightemperature and pressure. The corresponding aliphatic ethers areusually prepared by Williamson ether synthesis, but the availabletransition-metal-catalyzed methods require highly toxic reagents(such as dimethyl sulfate or methyl halides) and expensive metalcatalysts, and they entail harsh reaction conditions and complexworkups. A simple and efficient method is described for base-me-diated desulfitative dimethylamination, oxidation, or etherificationat the C2-position of the 2-(methylsulfanyl)-3,5-dihydro-4H-imid-azol-4-one scaffold by using potassium carbonate and aqueous N,N-dimethylformamide or an aliphatic alcohol.

Key words: heterocycles, aminations, etherifications, oxidations,ketones, amines, ethers

The dimethylamino group is a common functional groupthat is present in a variety of natural products and synthet-ic molecules.1 For example, indole alkaloids isolated fromthe tunicate Dendrodoa grossularia contain dimethylami-no groups (Figure 1); among these, alkaloid 1 shows mod-erate cytotoxicity towards the L1210 leukemia cell lines(4–10 μg/mL) and greater cytotoxicity for the MCF7 andWiDr cell lines (≤10 ng/mL).2 Additionally, the pyrro-lopyrimidine 4 (Figure 1), a lead compound in the devel-opment of potent inhibitors of the interaction of the tumorsuppressor protein p53 with MDMX and MDM2 proteins,contains a dimethylamino group.3 The dimethylaminogroup is also found in a number of important drugs.4

The dimethylamino functionality is generally introducedby treatment of a halogenated compound with low-boilingdimethylamine at high temperature and pressure.5 To

avoid the difficulties of handling low-boiling dimethyl-amine and the low yields of the reaction, N,N-dimethyl-formamide, in the presence of a base, has been used as asource of the dimethylamine functionality.6

Our ongoing research program to develop novel strategiesfor the synthesis of biologically important heterocycles,7

and our previous report on the dimethylamination ofheterocycles8 prompted us to examine the substitution-de-pendent desulfitative dimethylamination and oxidation re-actions of 2-(methylsulfanyl)-3,5-dihydro-4H-imidazol-4-one derivatives (Scheme 1).

Scheme 1 Three approaches towards desulfitative replacement reac-tions

Figure 1 Natural products and bioactive molecule containing a dimethylamino group

NH

NH

NO

NMe2

O

NH

N

NO

NMe2

O

O

NH

N

NO

NMe2

1 2 3

N N

N

NH

Me2N

O

N

H2N

O

4

N

HN

R2

S

O

R1

N

N

R2

NMe2

O

R1

N

N

R2

O

O

R1

N

HN

R2

O

O

R1

R3

dimethylamination

oxidation

etherification

SYNTHESIS 2013, 45, 000A–000HAdvanced online publication: 0 0 3 9 - 7 8 8 11 4 3 7 - 2 1 0 XDOI: 10.1055/s-0033-1338499; Art ID: SS-2013-N091-OP© Georg Thieme Verlag Stuttgart · New York

B S. Khan et al. PAPER

Synthesis 2013, 45, A–H © Georg Thieme Verlag Stuttgart · New York

Scheme 2 Desulfitative dimethylamination of 5-benzylidene-2-thioxoimidazolidin-4-one

Aliphatic etherification is a difficult task in synthetic or-ganic chemistry.9 The conventional method for this reac-tion is the Williamson ether synthesis, which uses highlytoxic reagents, such as dimethyl sulfate and methyl ha-lides, and generates stoichiometric quantities of inorganicsalts.10 In addition, various transition-metal-catalyzedmethods have been reported for the preparation of aliphat-ic ethers.11 Although efficient, these methods require ex-pensive metal catalysts and entail anhydrous and harshreaction conditions and complex workup procedures.Simple and efficient protocols for etherification are there-fore required. In this context, we report an efficient meth-od for the etherification of 2-(methylsulfanyl)-3,5-dihydro-4H-imidazol-4-one derivatives at the C-2 posi-tion by using an aliphatic alcohol in the presence of potas-sium carbonate. A general strategy for base-mediateddesulfitative dimethylamination, oxidation, or etherifica-tion reactions of 2-(methylsulfanyl)-3,5-dihydro-4H-im-

idazol-4-one derivatives by using a base and N,N-dimethylformamide or an aliphatic alcohol is shown inScheme 1.

Initially, we examined the desulfitative dimethylamina-tion of 5-benzylidene-2-thioxoimidazolidin-4-one (6)with N,N-dimethylformamide as the amine source and po-tassium carbonate as the base under the microwave condi-tions, but the yield of product 6 was poor (12%) (Scheme2).

Interestingly, the S-methyl derivative of substrate 5, pre-pared by methylation with iodomethane in acetone, gavea higher yield of the dimethylamino derivative 6. Encour-aged by these results, we used the S-methyl derivative 7ato explore the optimal reaction conditions for dimethyl-amination with N,N-dimethylformamide as the aminesource. The presence of water was found to be essential(Table 1). When anhydrous N,N-dimethylformamide was

NH

NNMe2

ONH

HN

S

O

K2CO3, DMF–H2O

140 °C, MW, 1 h

5 6

Table 1 Optimization of Conditions for the Desulfitative Dimethyl-amination and Oxidation Reactions

Entrya Base Solvent Yieldb (%) of 8a

Yieldb (%) of 9a

1 – DMF – –

2 K2CO3 DMF 34 trace

3 K2CO3 DMF–H2O 81 –

4 K2CO3 H2O 0c –

5 Na2CO3 DMF–H2O 73 –

6 KOH DMF–H2O 57 19

7 K2CO3 1,4-dioxane – 74

8 Na2CO3 1,4-dioxane – 61

a Reaction conditions: 7a (1 equiv), K2CO3 (2 equiv), solvent (2 mL), 140 °C, MW, 40 min.b Yield of isolated product.c The starting material was recovered.

NH

NNMe2

ONH

HN

O

ONH

NSMe

O

+base, solvent

temp, MW, 40 min

7a 8a 9a

Table 2 Scope of the Desulfitative Dimethylamination and Oxida-tion Reactions of 2-(Methylsulfanyl)-3,5-dihydro-4H-imidazol-4-ones

Substratea R1 R2 Yieldb (%) of 8a–o

Yieldb (%) of 9a–o

7a Ph H 81 0c

7b 3,4-(MeO)2C6H3 H 78 12

7c 2-naphthyl H 61 traced

7d 4-MeOC6H4 H 77 –

7e 4-O2NC6H4 H 57 18

7f 3,4,5-(MeO)3C6H2 H 61 Trace

7g 4-BnOC6H4 H 79 0

7h 4-BrC6H4 H 59 14

7i 3,4-(MeO)2C6H3 4-MeOC6H4 0e 74

7j 4-BnOC6H4 Ph – 70

7k Ph Bn – 61

7l 4-PrC6H4 Me – 72

7m 4-FC6H4 Me – 59

7n 3,4-(OCH2O)C6H3 Me – 64

7o Ph Me – 72

a Reaction conditions: Substrate 7a–o (1 equiv), K2CO3 (2 equiv), DMF–H2O (1:1; 2 mL), 140 °C, MW, 40 min.b Yield of isolated product.c Product 9 was not observed.d Product 9 was obtained in a trace amount.e Product 8 was not observed.

N

N

R2

NMe2

O

R1

N

HN

R2

O

O

R1

N

N

R2

SMe

O

R1

+

7a–o 8a–o 9a–o

PAPER Functionalization of 3,5-Dihydro-4H-imidazol-4-ones C

© Georg Thieme Verlag Stuttgart · New York Synthesis 2013, 45, A–H

used at 140 °C, the reaction was incomplete and the di-methylamino product 8a was obtained in low yield (entry2), but when water and N,N-dimethylformamide wereused in a ratio of 1:1, the yield of 8a increased to 81% (en-try 3). However, when water was used as the sole solvent,the diketone product 9a was obtained in trace amounts(entry 4). Various bases gave good to excellent yields inthe dimethylamination reaction with N,N-dimethylfor-mamide (entries 3, 5 and 6). Of these bases, potassiumcarbonate was the base of choice, giving the product 8a in81% yield (entry 3). The reaction failed to proceed in theabsence of a base (entry 1). It is interesting to note thatwhen N,N-dimethylformamide was replaced with 1,4-di-oxane, the reaction was completed in straightforwardmanner to give the diketone 9a exclusively in good yield(entry 7).

Next, we examined the effects of substituents in the 1-po-sition. When a substituent was present in the 1-position,the oxidative product was formed as the major product,whereas in the absence of this substitution, the dimethyl-aminated product was formed exclusively (Table 2). Hav-ing identified the optimal protocol for dimethylamination,we applied it to substrates 7a–o, and we obtained the cor-responding dimethylamino products in good yields.

A plausible mechanism for the oxidation and dimethyl-amination at the C2-position of 2-(methylsulfanyl)-3,5-dihydro-4H-imidazol-4-one moiety by N,N-dimethylfor-mamide–water involves two paths (Scheme 3; paths 1 and2). In path 1, nucleophilic substitution of substrate A bywater molecules at the C2-position gives the desulfitativeoxidized product B, which subsequently tautomerizes toform the stable product C. In path 2, carbonylation of 2-(methylsulfanyl)-3,5-dihydro-4H-imidazol-4-one D pro-ceeds with cleavage of N,N-dimethylformamide to givethe carbonylated intermediate E. Subsequent nucleophilicattack by dimethylamine, formed by the cleavage of N,N-

dimethylformamide, gives intermediate F, which under-goes base-mediated decarbonylation to give product G.12

We have also applied our optimized condition to the Big-inelli multicomponent reaction (MCR) product 1013 andthe pyrazolopyrimidine derivative 12 (Scheme 3). Thereare few reports of direct amination at the C2-position ofBiginelli MCR-type products. Moreover, a dimethylami-no group at the C6-position of pyrazolopyrimidine deriv-atives is generally introduced by reaction of thecorresponding halogenated pyrazolopyrimidine with anamine.14 To our delight, the respective products 11 and 13were obtained in good yields under our optimized condi-tions (Scheme 4).

Scheme 4 Dimethylamination of Biginelli MCR product 10 and pyr-azolopyrimidine derivative 12

We decided to apply the experience that we gained fromthe above study to the etherification of 2-(methylsulfa-nyl)-3,5-dihydro-4H-imidazol-4-ones at the C2-positionby using alcohols. To identify suitable conditions for the

Scheme 3 A plausible mechanism for substituent-dependent desulfitative dimethylamination and oxidation reactions of 2-(methylsulfanyl)-3,5-dihydro-4H-imidazol-4-ones

N

N

O

R

SMe

N

N

O

H

SMe

N

N

O

Me

SMepath 1 path 2

R = Me R = H

O

Me2N H

R1R1

R1

N

N

O SMe

R1 H

O

Me2NH

N

N

O NMe2

R1 H

O

base

– CO

N

N

O NMe2

R1

H

OH

N

N

O

Me

OH

R1

tautomerization

N

NH

O

Me

O

R1

A

B C

E

G

D

F

–

NH

N

NMe2

O

O

Cl

NH

N

SMe

O

O

Cl

MW, 140 °C, 40 min

N

NN

NH

SMe

SMe

K2CO3, DMF–H2O (1:1)

MW, 140 °C, 40 minN

NN

NH

NMe2

10 11, 63%

1213, 57%

SMe

K2CO3, DMF–H2O (1:1)

D S. Khan et al. PAPER

Synthesis 2013, 45, A–H © Georg Thieme Verlag Stuttgart · New York

etherification, we chose the imidazolone 14a and butanolas model coupling partners, and we examined the reactionin the presence of various bases and at various tempera-ture (Table 3). Of the three bases that we examined, potas-sium carbonate was found to be the best, giving ether 15ain 83% yield when butanol was used as the solvent at160 °C (Table 3, entry 2). Sodium carbonate and potassi-um hydroxide gave poor yields of 15a (entries 3 and 4),and the reaction did not proceed in the absence of a base(entry 1). With potassium carbonate as the base, reducingthe reaction temperature to 140 °C or 120 °C gave signif-icantly lower yields of 15a (entries 5 and 6). The reactionproceeded to completion within 45 minutes under micro-wave conditions at 160 °C, whereas in the absence of mi-crowave irradiation, it took 16 to 18 hours to reachcompletion.

Having identified the optimal protocol, we extended it tothe etherification of various substituted 2-(methylsulfa-nyl)-3,5-dihydro-4H-imidazol-4-one scaffolds with vari-ous aliphatic alcohols, and we obtained the correspondingethers in moderate to good yields (Table 4).

In summary, we have developed an efficient method forthe substitution-dependent dimethylamination or oxida-tion of substituted 2-(methylsulfanyl)-3,5-dihydro-4H-imidazol-4-one scaffolds at the C2-position by using amixture of N,N-dimethylformamide and water in the pres-ence of potassium carbonate. This protocol provides astraightforward method for dimethylamination using N,N-dimethylformamide instead of low-boiling dimethyl-

amine. Additionally, etherification of 2-(methylsulfanyl)-3,5-dihydro-4H-imidazol-4-ones at the 2-position wasreadily achieved by using an aliphatic alcohol and potas-sium carbonate under mild conditions, providing access toextra diversity at this position.

All reagents and solvents were purchased from commercial sourcesand used without purification. 1H NMR spectra were recorded at300 or 400 MHz with a ?? spectrometer and 13C NMR spectra wererecorded at 50, 75, or 100 MHz with a ?? spectrometer in deuteratedsolvents with TMS as internal reference. Mass spectra and high-res-olution mass spectra were recorded in the ESI (positive ion) modewith ?? and ?? spectrometers, respectively. Microwave reactionswere conducted by using a Biotage Initiator in 10-mL glass tubessealed with Teflon septa and placed in the cavity of the microwaveoven. The progress of the reaction was routinely monitored by TLCon precoated silica gel plates.

5-Alkylidene-2-(dimethylamino)-3,5-dihydro-4H-imidazol-4-ones (8a–h), 5-alkylideneimidazolidine-2,4-diones (9a,i–o), and Related Compounds (11 and 13); General ProcedureA 10-mL glass reaction vial containing a stirring bar was chargedwith the 2-(methylsulfanyl)-3,5-dihydro-4H-imidazol-4-one 7a–o,Biginelli MCR product 10, or pyrazolopyrimidine derivative 11(100 mg, 1 equiv), followed successively by K2CO3 (2 equiv) and1:1 DMF–H2O (3 mL). The vial was sealed tightly with a Teflonseptum and heated in the cavity of the microwave oven at 140 °C for40 min. When the reaction was complete (TLC), the solvent was

Table 3 Optimization of Reaction Condition for the Desulfitative Etherification

Entrya Base Temp (°C) Yieldb (%)

1 – 160 –c

2 K2CO3 160 83

3 Na2CO3 160 69

4 KOH 160 31

5 K2CO3 140 43

6 K2CO3 120 16

a Reaction conditions: 14a (1 equiv), K2CO3 (2 equiv), BuOH (3 mL), 120–160 °C, MW, 45 min.b Yield of isolated product.c No reaction.

N

N

MeON

N

Me

SMe

O

OBubase, BuOH

temp, MW, 45 min

14a 15a

NO2 NO2

Table 4 Scope of the Desulfitative Etherification of 2-(Methylsulfa-nyl)-3,5-dihydro-4H-imidazol-4-ones

Entrya R1 R2 R3 Temp (°C)

Yieldb (%)

1 4-O2NC6H4 Me Bu 160 89

2 Ph Me Bu 160 88

3 3,4-(OCH2O)C6H3 Me Bu 160 81

4 3,5-(MeO)2C6H3 Ph Bu 160 62

5 4-PrC6H4 Me Bu 160 78

6 3,4-(OCH2O)C6H3 Me Pr 130 69

7 4-O2NC6H4 Me Et 120 67

8 2-naphthyl Me Pr 130 53

9 4-Me2NC6H4 Me Pr 130 62

10 4-O2NC6H4 Me Pr 130 74

11 4-PrC6H4 Me Pr 130 71

12 Ph Me Pr 130 62

a Reaction conditions: 14 (1 equiv), K2CO3 (2 equiv), R3OH (2 mL), 120–160 °C, MW, 45 min.b Yield of isolated product.

N

N

R2O

R1

N

N

R2

SMe

O

R1

OR3

14 15

PAPER Functionalization of 3,5-Dihydro-4H-imidazol-4-ones E

© Georg Thieme Verlag Stuttgart · New York Synthesis 2013, 45, A–H

evaporated under reduced pressure and the residue was purified byflash column chromatography (silica gel, hexane– EtOAc).

5-Benzylidene-2-(dimethylamino)-3,5-dihydro-4H-imidazol-4-one (8a)Yellow solid; yield: 80 mg (81%); mp 160–163 °C.

FTIR (KBr): 3434, 3116, 1706, 1667, 1599, 1447, 898, 769, 693cm–1.1H NMR (300 MHz, CDCl3): δ = 11.35 (br s, 1 H), 8.23 (d, J = 6.0Hz, 2 H), 7.82–7.65 (m, 3 H), 6.28 (s, 1 H), 3.12 (s, 6 H).13C NMR (75 MHz, CDCl3): δ = 172.1, 160.3, 155.7, 143.7, 140.3,129.9, 125.4, 124.9, 107.8, 36.9.

HRMS (ESI): m/z [M + H]+ calcd for C12H14N3O: 216.1137; found:216.1142.

5-(3,4-Dimethoxybenzylidene)-2-(dimethylamino)-3,5-dihydro-4H-imidazol-4-one (8b)Yellow solid; yield: 76 mg (78%); mp 184–186 °C.

FTIR (KBr): 3420, 2934, 1612, 1443, 1262, 1150, 1024, 894 cm–1.1H NMR (400 MHz, CDCl3): δ = 11.1 (s, 1 H), 8.09 (s, 1 H), 7.39(d, J = 7.6 Hz, 1 H), 6.92 (d, J = 8.0 Hz, 1 H), 6.24 (s, 1 H), 3.76 (s,3 H), 3.75 (s, 3 H), 3.05 (s, 6 H).13C NMR (100 MHz, CDCl3): δ = 172.6, 159.0, 148.7, 140.2, 129.6,123.9, 113.4, 112.2, 111.9, 55.8, 55.5, 37.1.

HRMS (ESI): m/z [M + H]+ calcd for C14H18N3O3: 276.1348; found:276.1340.

2-(Dimethylamino)-5-(2-naphthylmethylene)-3,5-dihydro-4H-imidazol-4-one (8c)Yellow solid; yield: 60 mg (61%); mp >200 °C.

FTIR (KBr): 3405, 2934, 1615, 1435, 1277, 1114, 898, 769 cm–1.1H NMR (400 MHz, CDCl3): δ = 11.3 (s, 1 H), 8.97 (br s, 1 H), 8.22(s, 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.81 (d, J = 7.6 Hz, 1 H), 7.59–749 (m, 3 H), 7.02 (s, 1 H), 3.11 (s, 6 H).13C NMR (100 MHz, CDCl3): δ = 173.2, 160.4, 142.9, 133.8, 131.9,131.6, 129.2, 128.6, 127.8, 126.8, 126.2, 123.2, 105.0, 37.3.

HRMS (ESI): m/z [M + H]+ calcd for C16H16N3O: 266.1293; found:266.1286.

2-(Dimethylamino)-5-(4-methoxybenzylidene)-3,5-dihydro-4H-imidazol-4-one (8d)Yellow solid; yield: 75 mg (77%); mp 177–181 °C.

FTIR (KBr): 3424, 1610, 1343, 1262, 1050, 1014, 894 cm–1.1H NMR (300 MHz, CDCl3): δ = 11.1 (s, 1 H), 8.04 (d, J = 8.1 Hz,2 H), 6.94 (d, J = 8.1 Hz, 2 H), 6.43 (s, 1 H), 3.77 (s, 3 H), 3.07 (s,6 H).13C NMR (75 MHz, CDCl3): δ = 172.3, 158.7, 158.5, 139.7, 131.5,128.8, 113.8, 111.4, 55.0, 36.7.

HRMS (ESI): m/z [M + H]+ calcd for C13H16N3O2: 246.1243; found:246.1237.

2-(Dimethylamino)-5-(4-nitrobenzylidene)-3,5-dihydro-4H-im-idazol-4-one (8e)Yellow solid; yield: 57 mg (57%); mp 188–190 °C.

FTIR (KBr): 3446, 1613, 1327, 1100, 887 cm–1.1H NMR (300 MHz, CDCl3): δ = 11.5 (s, 1 H), 8.27–8.15 (m, 4 H),6.29 (s, 1 H), 3.15 (br s, 6 H).13C NMR (75 MHz, CDCl3): δ = 171.9, 160.7, 145.2, 144.7, 143.6,130.0, 123.5, 106.7, 36.9.

HRMS (ESI): m/z [M + H]+ calcd for C12H13N4O3: 261.0988; found:261.0971.

2-(Dimethylamino)-5-(3,4,5-trimethoxybenzylidene)-3,5-di-hydro-4H-imidazol-4-one (8f)Bright-yellow solid; yield: 60 mg (61%); mp 194–197 °C.

FTIR (KBr): 3442, 1649, 1371, 1248, 1125, 894 cm–1.1H NMR (300 MHz, CDCl3): δ = 11.24 (br s, 1 H), 7.50 (s, 2 H),6.26 (s, 1 H), 3.79 (s, 6 H), 3.68 (s, 3 H), 3.09 (s, 6 H).13C NMR (75 MHz, CDCl3): δ = 172.9, 159.7, 153.4, 152.9, 141.0,137.3, 132.1, 111.5, 107.8, 107.4, 60.5, 56.0, 37.1.

HRMS (ESI): m/z [M + H]+ calcd for C15H20N3O4: 306.1454; found:306.1441.

5-[4-(Benzyloxy)benzylidene]-2-(dimethylamino)-3,5-dihydro-4H-imidazol-4-one (8g)Yellow solid; yield: 78 mg (79%); mp 148–150 °C.

FTIR (KBr): 3434, 1653, 1601, 1450, 1238, 999, 894 cm–1.1H NMR (300 MHz, CDCl3): δ = 11.12 (br s, 1 H), 8.00 (d, J = 7.8Hz, 2 H), 7.47–7.33 (m, 5 H), 7.03 (d, J = 8.7 Hz, 2 H), 6.28 (s, 1H), 5.13 (s, 2 H), 3.08 (s, 6 H).13C NMR (75 MHz, CDCl3): δ = 173.1, 158.1, 137.4, 131.9, 129.3,128.8, 128.3, 128.1, 115.2, 111.5, 69.6, 37.2.

HRMS (ESI): m/z [M + H]+ calcd for C19H20N3O2: 322.1556; found:322.1551.

5-(2-Bromobenzylidene)-2-(dimethylamino)-3,5-dihydro-4H-imidazol-4-one (8h)Pale-yellow solid; yield: 58 mg (59%); mp 170–172 °C.

FTIR (KBr): 3120, 1718, 1661, 1597, 1251, 897 cm–1.1H NMR (300 MHz, CDCl3): δ = 11.3 (br s, 1 H), 8.86 (br s, 1 H),7.63 (d, J = 7.8 Hz, 1 H), 7.41 (t, J = 7.2 Hz, 1 H), 7.15 (t, J = 7.2Hz, 1 H), 6.54 (s, 1 H), 3.11 (s, 6 H).13C NMR (75 MHz, CDCl3): δ = 172.8, 160.7, 143.6, 135.5, 133.0,131.7, 128.8, 128.0, 124.4, 107.2, 37.4.

HRMS (ESI): m/z [M + H]+ calcd for C12H12BrN3O: 293.0164;found: 293.0172.

5-Benzylideneimidazolidine-2,4-dione (9a)White solid; yield: 64 mg (72%); mp 164–166 °C.

FTIR (KBr): 3211, 3051, 2368, 1770, 1656, 1450, 1379, 1255, 878,769, 654 cm–1.1H NMR (300 MHz, DMSO-d6): δ = 11.2 (s, 1 H), 10.5 (s, 1 H),7.62 (d, J = 7.2 Hz, 2 H), 7.42–7.32 (m, 3 H), 6.4 (s, 1 H).13C NMR (75 MHz, DMSO-d6): δ = 165.1, 155.2, 132.5, 128.9,128.3, 127.8, 127.5, 107.8.

HRMS (ESI): m/z [M + H]+ calcd for C10H9N2O2: 189.0659; found:189.0657.

5-(3,4-Dimethoxybenzylidene)-3-(4-methoxybenzyl)imidazoli-dine-2,4-dione (9i)White solid; yield: 68 mg (74%); mp 177–180 °C.

FTIR (KBr): 3195, 1761, 1718, 1440, 1248, 1150, 1028 cm–1.1H NMR (400 MHz, CDCl3): δ = 10.7 (s, 1 H), 7.23 (t, J = 8.4 Hz,3 H), 7.14 (s, 1 H), 6.97 (d, J = 8.4 Hz, 1 H), 6.89 (d, J = 8.8 Hz, 2H), 6.52 (s, 1 H), 4.57 (s, 2 H), 3.81 (s, 3 H), 3.77 (s, 3 H), 3.70 (s,3 H).13C NMR (100 MHz, CDCl3): δ = 164.4, 159.1, 155.5, 150.0, 149.2,129.4, 129.1, 125.8, 125.0, 123.7, 114.4, 113.1, 112.2, 111.3, 56.1,56.0, 55.5, 41.2.

HRMS (ESI): m/z [M + H]+ calcd for C20H21N2O5: 369.1450; found:369.1451.

5-[4-(Benzyloxy)benzylidene]-3-phenylimidazolidine-2,4-dione (9j)White solid; yield: 64 mg (70%); mp 167–171 °C.

F S. Khan et al. PAPER

Synthesis 2013, 45, A–H © Georg Thieme Verlag Stuttgart · New York

FTIR (KBr): 3224, 1718, 1414, 1248 cm–1.1H NMR (300 MHz, CDCl3): δ = 10.9 (s, 1 H), 7.70 (d, J = 8.4 Hz,2 H), 7.51–7.35 (m, 10 H), 7.10 (d, J = 8.4 Hz, 2 H), 6.63 (s, 1 H),5.18 (s, 2 H).13C NMR (75 MHz, CDCl3): δ = 163.7, 159.2, 154.4, 137.2, 132.3,131.8, 129.2, 128.9, 128.4, 128.2, 127.3, 125.9, 124.9, 115.6, 110.8,69.8.

HRMS (ESI): m/z [M + H]+ calcd for C23H19N2O3: 371.1396; found:371.1411.

3-Benzyl-5-benzylideneimidazolidine-2,4-dione (9k)White solid; yield: 55 mg (61%); mp 189–192 °C.

FTIR (KBr): 3429, 2927, 1656, 1403, 1006 cm–1.1H NMR (400 MHz, CDCl3): δ = 10.8 (s, 1 H), 7.65 (d, J = 7.6 Hz,2 H), 7.43–7.26 (m, 8 H), 6.58 (s, 1 H), 4.67 (s, 2 H).13C NMR (100 MHz, CDCl3): δ = 163.9, 154.9, 136.4, 132.7, 129.5,128.7, 128.6, 128.5, 127.5, 127.4, 126.4, 109.9, 41.3.

HRMS (ESI): m/z [M + H]+ calcd for C17H15N2O2: 279.1134; found:279.1136.

3-Methyl-5-(4-propylbenzylidene)imidazolidine-2,4-dione (9l)Light-yellow solid; yield: 64 mg (72%); mp 160–164 °C.

FTIR (KBr): 3224, 2929, 1713, 1461, 1161, 1020, 825, 649 cm–1.1H NMR (300 MHz, CDCl3): δ = 10.6 (s, 1 H), 7.54 (d, J = 7.8 Hz,2 H), 7.22 (d, J = 7.5 Hz, 2 H), 6.49 (s, 1 H), 2.94 (s, 3 H), 2.57 (d,J = 7.2 Hz, 2 H), 1.61 (q, J = 1.61 Hz, 2 H), 0.89 (t, J = 7.2 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 164.7, 155.7, 143.4, 130.7, 129.9,129.2, 126.4, 110.0, 37.5, 24.6, 24.3, 14.0.

HRMS (ESI): m/z [M + H]+ calcd for C14H17N2O2: 245.1290; found:245.1285.

5-(2-Fluorobenzylidene)-3-methylimidazolidine-2,4-dione (9m)White solid; yield: 52 mg (59%); mp 172–174 °C.

FTIR (KBr): 3430, 1718, 1657, 1010, 763 cm–1.1H NMR (400 MHz, CDCl3): δ = 10.8 (s, 1 H), 7.46–7.39 (m, 3 H),7.11 (s, 1 H), 6.47 (s, 1 H), 2.91 (s, 3 H).13C NMR (100 MHz, CDCl3): δ = 164.5, 163.9, 161.5, 135.6, 135.6,131.0, 130.9, 128.1, 126.2, 108.1, 24.7.

HRMS (ESI): m/z [M + H]+ calcd for C11H10FN2O2: 221.0726;found: 221.0720.

5-(1,3-Benzodioxol-5-ylmethylene)-3-methylimidazolidine-2,4-dione (9n)White solid; yield: 57 mg (64%); mp 193–196 °C.

FTIR (KBr): 3222, 1757, 1718, 1457, 1254, 1031, 646 cm–1.1H NMR (400 MHz, CDCl3): δ = 10.6 (s, 1 H), 7.26 (s, 1 H), 7.13(t, J = 7.6 Hz, 1 H), 6.94 (d, J = 8.0 Hz, 1 H), 6.45 (s, 1 H), 6.04 (s,2 H), 2.92 (s, 3 H).13C NMR (100 MHz, CDCl3): δ = 164.7, 155.7, 148.2, 148.1, 127.3,125.5, 125.4, 110.2, 109.2, 109.1, 101.9, 24.6.

HRMS (ESI): m/z [M + H]+ calcd for C12H11N2O4: 247.0719; found:247.0720.

5-Benzylidene-3-methylimidazolidine-2,4-dione (9o)White solid; yield: 63 mg (72%); mp 180–184 °C.

FTIR (KBr): 3427, 1658, 1462, 999, 765 cm–1.1H NMR (400 MHz, CDCl3): δ = 10.7 (s, 1 H), 7.62 (d, J = 7.6 Hz,2 H), 7.40–7.29 (m, 3 H), 6.50 (s, 1 H), 2.93 (s, 3 H).13C NMR (100 MHz, CDCl3): δ = 164.7, 155.8, 133.3, 129.9, 129.2,128.9, 127.2, 109.7, 24.7.

HRMS (ESI): m/z [M + H]+ calcd for C11H11N2O2: 203.0821; found:203.0811.

Ethyl 4-(4-Chlorophenyl)-2-(dimethylamino)-6-methyl-1,4-di-hydropyrimidine-5-carboxylate (11)Pale-yellow solid; yield: 62 mg (74%); mp >200 °C.

FTIR (KBr): 3422, 2949, 1658, 1439, 1216, 1088, 702 cm–1.1H NMR (300 MHz, CDCl3): δ = 10.4 (br s, 1 H), 7.43 (t, J = 7.2Hz, 4 H), 5.46 (s, 1 H), 4.11 (d, J = 6.0 Hz, 2 H), 3.15 (s, 6 H), 2.52(s, 3 H), 1.16 (d, J = 6.30 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 164.8, 150.0, 146.7, 140.9, 133.1,129.1, 128.7, 104.0, 60.7, 51.2, 39.8, 17.9, 14.4.

HRMS (ESI): m/z [M + H]+ calcd for C16H21ClN3O2: 322.1322;found: 322.1314.

N,N-Dimethyl-6-(methylsulfanyl)-1H-pyrazolo[3,4-d]pyrimi-din-4-amine (13)Yellow solid; yield: 56 mg (62%); mp 184–186 °C.

FTIR (KBr): 3432, 3115, 1585, 1329, 948, 771 cm–1.1H NMR (400 MHz, CDCl3): δ = 13.2 (s, 1 H), 8.06 (s, 1 H), 3.27(s, 6 H), 2.46 (s, 3 H).13C NMR (100 MHz, CDCl3): δ = 167.2, 156.1, 134.4, 97.6, 13.4.

HRMS (ESI): m/z [M + H]+ calcd for C8H12N5S: 210.0813; found:210.0820.

3-Substituted 2-Alkoxy-5-(alkylidene)-3,5-dihydro-4H-imidaz-ol-4-ones (15a–l); General ProcedureA 10-mL glass reaction vial containing a stirring bar was chargedsuccessively with the substituted imidazolone 14 (100 mg, 1 equiv),K2CO3 (2 equiv), and alcohol R3OH (3 mL). The vial was sealedtightly with a Teflon septum and heated in the cavity of the micro-wave oven at 120–160 °C for 45 min. When the reaction was com-plete (TLC), the solvent was evaporated under reduced pressure andthe residue was purified by flash column chromatography (silicagel, hexane–EtOAc).

2-Butoxy-3-methyl-5-(4-nitrobenzylidene)-3,5-dihydro-4H-im-idazol-4-one (15a)Light-yellow solid; yield: 97 mg (89%); mp 143–146 °C.

FTIR (KBr): 3445, 2942, 1577, 1335, 1100, 814 cm–1.1H NMR (300 MHz, CDCl3): δ = 8.24–8.20 (m, 4 H), 6.87 (s, 1 H),4.63 (t, J = 6.3 Hz, 2 H), 3.12 (s, 3 H), 1.91–1.82 (m, 2 H), 1.53–1.46 (m, 2 H), 1.05 (t, J = 7.2 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 169.3, 164.7, 147.3, 141.6, 141.4,131.7, 123.8, 117.9, 70.5, 30.8, 25.7, 19.2, 13.8.

HRMS (ESI): m/z [M + H]+ calcd for C15H18N3O4: 304.1297; found:304.1285.

5-Benzylidene-2-butoxy-3-methyl-3,5-dihydro-4H-imidazol-4-one (15b)White solid; yield: 99 mg (88%); mp 101–103 °C.

FTIR (KBr): 3424, 2956, 1722, 1579, 1476, 1302, 948, 683 cm–1.1H NMR (300 MHz, CDCl3): δ = 8.09 (d, J = 7.2 Hz, 2 H), 7.42–7.28 (m, 3 H), 6.94 (s, 1 H), 4.60 (t, J = 6.6 Hz, 2 H), 3.10 (s, 3 H),1.89–1.80 (m, 2 H), 1.58–1.46 (m, 2 H), 1.05 (t, J = 7.5 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 169.6, 162.9, 138.4, 134.8, 131.5,129.1, 128.6, 121.6, 69.8, 30.8, 25.4, 19.1, 13.8.

HRMS (ESI): m/z [M + H]+ calcd for C15H19N2O2: 259.1447; found:259.1441.

5-(1,3-Benzodioxol-5-ylmethylene)-2-butoxy-3-methyl-3,5-di-hydro-4H-imidazol-4-one (15c)White solid; yield: 87 mg (81%); mp 107–110 °C.

FTIR (KBr): 3431, 2942, 1585, 1485, 1257, 1028 cm–1.

PAPER Functionalization of 3,5-Dihydro-4H-imidazol-4-ones G

© Georg Thieme Verlag Stuttgart · New York Synthesis 2013, 45, A–H

1H NMR (300 MHz, CDCl3): δ = 7.95 (s, 1 H), 7.35 (d, J = 7.8, 1H), 6.86–6.82 (m, 2 H), 6.01 (s, 2 H), 4.57 (t, J = 6.3, 2 H), 3.10 (s,3 H), 1.86 (t, J = 6.9 Hz, 2 H), 1.55 (q, J = 7.5, 2 H), 1.04 (t, J = 7.2Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 169.4, 162.1, 148.4, 147.8, 136.7,129.2, 127.1, 121.6, 110.5, 108.3, 101.2, 69.6, 30.6, 25.3, 19.0,13.7.

HRMS (ESI): m/z [M + H]+ calcd for C16H19N2O4: 303.1345; found:303.1339.

2-Butoxy-5-(3,4-dimethoxybenzylidene)-3-phenyl-3,5-dihydro-4H-imidazol-4-one (15d)Light-yellow solid; yield: 65 mg (62%); mp 115–117 °C.

FTIR (KBr): 3429, 2925, 1721, 1594, 1267, 1148, 930, 730 cm–1.1H NMR (300 MHz, CDCl3): δ = 8.01 (s, 1 H), 7.40–7.26 (m, 6 H),6.91 (s, 1 H), 6.82 (d, J = 8.4 Hz, 1 H), 4.52 (t, J = 6.6, 2 H), 3.86(s, 3 H), 3.83 (s, 3 H), 1.77–1.68 (m, 2 H), 1.41–1.31 (m, 2 H), 0.89(t, J = 7.5 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 168.1, 160.5, 150.3, 148.8, 135.6,132.3, 129.0, 127.8, 127.7, 125.8, 125.8, 122.7, 113.6, 110.9, 69.7,55.8, 55.6, 30.5, 19.0, 13.6.

HRMS (ESI): m/z [M + H]+ calcd for C22H25N2O4: 381.1814; found:381.1808.

2-Butoxy-3-methyl-5-(4-propylbenzylidene)-3,5-dihydro-4H-imidazol-4-one (15e)White solid; yield: 84 mg (78%); mp 92–94 °C.

FTIR (KBr): 3405, 2929, 1718, 1479, 1302, 1150, 948, 684 cm–1.1H NMR (300 MHz, CDCl3): δ = 7.88 (d, J = 7.8 Hz, 2 H), 7.09 (d,J = 8.1 Hz, 2 H), 6.79 (s, 1 H), 4.44 (t, J = 6.6 Hz, 2 H), 2.94 (s, 3H), 2.50 (t, J = 7.2 Hz, 2 H), 1.74 (q, J = 6.6 Hz, 2 H), 1.65–1.47(m, 2 H), 1.44–1.31 (m, 2 H), 0.91–0.85 (m, 6 H).13C NMR (75 MHz, CDCl3): δ = 169.5, 162.3, 144.0, 137.6, 132.2,131.3, 128.6, 121.6, 69.5, 38.0, 30.6, 25.2, 24.3, 19.0, 13.8, 13.7.

HRMS (ESI): m/z [M + H]+ calcd for C18H25N2O2: 301.1916; found:301.1904.

5-(1,3-Benzodioxol-5-ylmethylene)-3-methyl-2-propoxy-3,5-di-hydro-4H-imidazol-4-one (15f)Yellow solid; yield: 72 mg (69%); mp 131–133 °C.

FTIR (KBr): 2888, 1706, 1586, 1484, 1258, 1037, 941 cm–1.1H NMR (300 MHz, CDCl3): δ = 7.93 (s, 1 H), 7.34 (d, J = 7.8 Hz,1 H), 6.85–6.81 (m, 2 H), 5.99 (s, 2 H), 4.53 (t, J = 6.6 Hz, 2 H),3.09 (s, 3 H), 1.94–1.82 (m, 2 H), 1.09 (t, J = 7.2 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 169.4, 162.1, 148.4, 147.8, 136.7,129.2, 127.0, 121.5, 110.5, 108.3, 101.2, 71.2, 25.2, 22.0, 10.2.

HRMS (ESI): m/z [M + H]+ calcd for C15H17N2O4: 289.1188; found:289.1182.

2-Ethoxy-3-methyl-5-(4-nitrobenzylidene)-3,5-dihydro-4H-im-idazol-4-one (15g)Yellow solid; yield: 67 mg (67%); mp 175–177 °C.

FTIR (KBr): 2998, 1723, 1655, 1568, 1336, 1151, 1015, 688, 572cm–1.1H NMR (300 MHz, CDCl3): δ = 8.18–8.15 (m, 4 H), 6.81 (s, 1 H),4.66 (q, J = 6.9 Hz, 2 H), 3.08 (s, 3 H), 1.51 (t, J = 7.2 Hz, 3 H).13C NMR (75 MHz, CDCl3): δ = 169.0, 164.4, 147.0, 141.3, 141.2,131.5, 123.5, 117.5, 66.5, 25.4, 14.3.

HRMS (ESI): m/z [M + H]+ calcd for C13H14N3O4: 276.0984; found:276.0980.

3-Methyl-5-(2-naphthylmethylene)-2-propoxy-3,5-dihydro-4H-imidazol-4-one (15h)Yellow solid; yield: 55 mg (53%); mp 143–146 °C.

FTIR (KBr): 3427, 2934, 1720, 1575, 1371, 1150, 803 cm–1.1H NMR (400 MHz, CDCl3): δ = 8.83 (d, J = 7.6, 1 H), 8.35 (d,J = 8.4 Hz, 1 H), 7.86–7.79 (m, 3 H), 7.58–7.48 (m, 3 H), 4.53 (t,J = 6.8 Hz, 2 H), 3.12 (s, 3 H), 1.91–1.82 (m, 2 H), 1.07 (t, J = 7.2Hz, 3 H).13C NMR (100 MHz, CDCl3): δ = 169.5, 163.3, 139.0, 133.7, 132.4,130.4, 130.1, 129.6, 128.8, 126.5, 125.7, 125.6, 123.3, 116.8, 71.4,25.4, 22.0, 10.2.

HRMS (ESI): m/z [M + H]+ calcd for C18H19N2O2: 295.1447; found:295.1439.

5-[4-(Dimethylamino)benzylidene]-3-methyl-2-propoxy-3,5-di-hydro-4H-imidazol-4-one (15i)Light-yellow solid; yield: 65 mg (62%); mp 156–159 °C.

FTIR (KBr): 3458, 2924, 1709, 1599, 1360, 1145, 677 cm–1.1H NMR (400 MHz, CDCl3): δ = 7.97 (d, J = 8.4 Hz, 2 H), 6.89 (s,1 H), 6.68 (d, J = 8.0 Hz, 2 H), 4.48 (t, J = 5.6, 2 H), 3.06 (s, 3 H),2.98 (s, 6 H), 1.87–1.82 (m, 2 H), 1.05 (t, J = 6.8 Hz, 3 H).13C NMR (100 MHz, CDCl3): δ = 169.5, 160.7, 150.8, 134.3, 133.0,123.1, 122.7, 111.7, 70.8, 40.0, 25.2, 22.1, 10.3.

HRMS (ESI): m/z [M + H]+ calcd for C16H22N3O2: 288.1712; found:288.1704.

3-Methyl-5-(4-nitrobenzylidene)-2-propoxy-3,5-dihydro-4H-imidazol-4-one (15j)Yellow solid; yield: 77 mg (74%); mp 166–169 °C.

FTIR (KBr): 3442, 2963, 1729, 1577, 1493, 1334, 1154, 923, 692cm–1.1H NMR (400 MHz, CDCl3): δ = 8.20–8.14 (m, 4 H), 6.83 (s, 1 H),4.56 (t, J = 6.4 Hz, 2 H), 3.11 (s, 3 H), 1.94–1.85 (m, 2 H), 1.08 (t,J = 7.6 Hz, 3 H).13C NMR (100 MHz, CDCl3): δ = 169.0, 164.5, 146.9, 141.3, 141.2,131.5, 123.6, 117.6, 72.0, 25.4, 22.0, 10.2.

HRMS (ESI): m/z [M + H]+ calcd for C14H16N3O4: 290.1141; found:290.1135.

3-Methyl-2-propoxy-5-(4-propylbenzylidene)-3,5-dihydro-4H-imidazol-4-one (15k)Yellow solid; yield: 74 mg (71%); mp 113–116 °C.

FTIR (KBr): 2932, 1718, 1578, 1486, 1371, 1150, 948 cm–1.1H NMR (400 MHz, CDCl3): δ = 7.96 (d, J = 8.4 Hz, 2 H), 7.19 (d,J = 8.0 Hz, 2 H), 6.90 (s, 1 H), 4.51 (t, J = 6.8 Hz, 2 H), 3.08 (s, 3H), 2.60–2.53 (m, 2 H), 1.89 (q, J = 7.2 Hz, 2 H), 1.66–1.60 (m, 2H), 1.06 (t, J = 7.2 Hz, 3 H), 0.94 (t, J = 7.6 Hz, 3 H).13C NMR (100 MHz, CDCl3): δ = 169.8, 162.5, 144.3, 137.7, 132.4,131.5, 128.9, 122.1, 71.4, 38.2, 29.9, 24.5, 22.2, 13.9, 10.4.

HRMS (ESI): m/z [M + H]+ calcd for C17H23N2O2: 287.1760; found:287.1756.

5-Benzylidene-3-methyl-2-propoxy-3,5-dihydro-4H-imidazol-4-one (15l)Yellow solid; yield: 65 mg (62%); mp 96–98 °C.

FTIR (KBr): 2927, 1720, 1572, 1370, 1150, 944, 686 cm–1.1H NMR (400 MHz, CDCl3): δ = 8.05 (d, J = 7.6 Hz, 2 H), 7.38–7.28 (m, 3 H), 6.90 (s, 1 H), 4.51 (t, J = 6.8 Hz, 2 H), 3.06 (s, 3 H),1.88–1.82 (m, 2 H), 1.06 (t, J = 7.2 Hz, 3 H).13C NMR (100 MHz, CDCl3): δ = 169.6, 162.8, 138.4, 134.8, 131.4,129.0, 128.6, 121.6, 71.4, 29.8, 22.1, 10.3.

HRMS (ESI): m/z [M + H]+ calcd for C14H17N2O2: 245.1290; found:245.1285.

H S. Khan et al. PAPER

Synthesis 2013, 45, A–H © Georg Thieme Verlag Stuttgart · New York

Acknowledgment

S.K., V.T., and R.M. are grateful to the University Grant Commis-sion, New Delhi, for financial support. The authors also thank Dr.Sanjeev K. Shukla, SAIF-CDRI, for providing spectral and analyti-cal data. The CDRI communication number is 8441.

Supporting Information for this article is available online athttp://www.thieme-connect.com/ejournals/toc/synthesis. Includedare copies of 1H and 13C NMR spectra of all the compounds.Supporting InformationSupporting Information

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N

N

R2

N

O

R1

N

HN

R2

O

O

R1N

NO

R3

R2O

R1

R2 = Me, Ph, Bn

R2 = H

R2 = Me, PhR3 = Et, Pr, Bu

N

N

R1

OR2

SMe

K 2C

O3

DMF–H2O (1

:1)

MW, 1

40 °C, 4

0 min

K2CO

3 DMF–H2O (1:1)

MW, 140 °C, 40 min

K2CO3 R3OH, MW120–160 °C, 45 min

graphic abstract