LETTER ▌1657

letterTandem Hydroformylation–Biginelli ReactionTandem Hydroformylation–Biginelli ReactionDaniela Fuchs,a Mahboobeh Nasr-Esfahani,a Lisa Diab,a Tomáš Šmejkal,b Bernhard Breit*a

a Institut für Organische Chemie, Albert-Ludwigs-Universität Freiburg, Albertstrasse 21, 79104 Freiburg i. Bg., GermanyFax +49(761)2038715; E-mail: bernhard.breit@chemie.uni-freiburg.de

b Syngenta Crop Protection AG, Schaffhauserstrasse, 4332 Stein, Switzerland

Received: 24.04.2013; Accepted after revision: 29.05.2013

Abstract: The combination of a tandem process with a multicom-ponent reaction is a new approach to high atom-economic synthesis.A tandem hydroformylation–Biginelli reaction sequence has beendeveloped leading to a variety of functionalized 4-alkyl-substituted3,4-dihydropyrimidin-2(1H)-ones.

Key words: hydroformylation, Biginelli reaction, tandem reaction,multicomponent reaction, rhodium

3,4-Dihydropyrimidones (DHPM) are integral backbonesof various pharmacologically active compounds and ex-hibit a diverse pharmacological profile1 acting as calciumchannel modulators,2,3 αa1-adrenoceptor antagonism,4 andmany others.5 The method of choice for their preparationis the Biginelli reaction that was discovered in 1891 by theItalian chemist P. Biginelli (Scheme 1).6 It is a multicom-ponent reaction that yields 3,4-dihydropyrimidones fromaldehydes, ureas, and β-keto esters in a one-pot operation.The reaction is promoted by Brønsted and Lewis acids,1

organocatalysts,7 ionic liquids,8 or microwave heating,9

and generally works well with nonenolizable aromaticand heteroaromatic aldehydes. Conversely, Biginelli reac-tions with aliphatic aldehydes are more challenging withlower yields due to side reactions of the aldehydes.6b

Scheme 1 Classic Biginelli reaction

In most cases aliphatic aldehydes are prepared either byreduction of a carboxylic acid derivative or by oxidationof the corresponding alcohol. Neither of these methods isdeemed redox economic.10 The most ideal way to preparealdehydes should make use of an atom-economic additionreaction11 such as the hydroformylation of olefins.12 Start-ing from alkenes and synthesis gas (CO/H2) this processreadily furnishes C1-elongated aldehydes in the presenceof a suitable rhodium catalyst under mild and neutral con-ditions. These aldehydes are ideal for further transforma-tions and we and others have demonstrated that this can be

developed into a variety of tandem processes includingthe combination with organocatalysis.13

As part of our ongoing research on the development ofnew synthetic tandem reactions,14 we herein report on anew tandem hydroformylation–Biginelli reaction startingfrom terminal alkenes and its application to synthesizenovel functionalized 3,4-dihydropyrimidin-2(1H)-ones.To the best of our knowledge only substituted benzalde-hydes and aliphatic aldehydes without functional groupshave been reported so far for the Biginelli reaction.

We wondered whether the combination of hydrofor-mylation with the multicomponent Biginelli reaction as atandem process would access DHPM in one step, startingfrom alkenes, urea, and a β-keto ester. We anticipated thatthe in situ generation of aliphatic aldehydes from alkenesthrough hydroformylation might suppress side reactionssuch as oligomerization and aldol reactions by loweringthe effective concentration of aldehydes in the reactionmixture.

We started our investigation with 1-octene (1), urea (2),and ethyl acetoacetate (3) by employing standard Biginel-li conditions (cat. concd HCl, EtOH) with a hydrofor-mylation catalyst and performed the reaction undersyngas pressure. For the hydroformylation catalyst wechose Rh(CO)2acac/Xantphos which has been proven as arobust hydroformylation catalyst for the generation of lin-ear aldehydes with high regioselectivity.15 To our delightthe reaction furnished the desired DHPM 4 in moderateyield. Formation of the product derived from the branchedaldehyde was not observed due to the high regioselectivityof the hydroformylation. Subsequently, the effects ofpressure, temperature, and reaction time were examined(Table 1) and we found that the reaction works best with20 bar syngas pressure at 100 °C in EtOH (0.5 M)16 for 24hours employing two equivalents of the starting alkene,which yields 88% of the desired product 4 (Table 1, entry12).

Interestingly, running the Biginelli reaction starting fromnonanal under classical conditions with HCl as catalystfurnished a significantly lower yield of the correspondingDHPM 4 (Table 2, entry 1). To see whether this differenceis due to a promoting effect of the hydroformylation cata-lyst on the Biginelli reaction, control experiments startingfrom 1-nonanal (5) in the presence of the rhodium catalystwere performed. Indeed, running the reaction under iden-tical conditions as in the tandem process a slight increasein yield (19% to 31%, Table 2, entries 1 and 5) was noted.

Ph

O

H2N NH2

O

OEt

OO+ +

[H+]

EtOH, Δ NH

NH

O

Ph

EtO

O

SYNLETT 2013, 24, 1657–1662Advanced online publication: 12.07.20130 9 3 6 - 5 2 1 4 1 4 3 7 - 2 0 9 6DOI: 10.1055/s-0033-1339298; Art ID: ST-2013-B0382-L© Georg Thieme Verlag Stuttgart · New York

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Synlett 2013, 24, 1657–1662 © Georg Thieme Verlag Stuttgart · New York

A possible explanation for this observation might be thatthe rhodium–Xanthphos complex somehow activates thealdehyde acting as a kind of Lewis acid which also would

explain that the reaction is still proceeding without HCl(Table 2, entry 4). Although the difference to the reactionwithout HCl was rather little, catalytic amounts of HCl

Table 1 Tandem Hydroformylation–Biginelli Reaction of 1-Octene

Entry Time (h) Temp (°C) P (bar) Molar ratio 1/2/3 Yield (%)b

1 24 100 5 1:1.1:1 55

2 24 100 10 1:1.1:1 59

3 24 100 20 1:1.1:1 62

4 24 100 30 1:1.1:1 44

5 24 100 40 1:1.1:1 45

6 24 60 20 1:1.1:1 15

7 24 80 20 1:1.1:1 28

8 24 120 20 1:1.1:1 42

9 16 100 20 1:1.1:1 52

10 48 100 20 1:1.1:1 58

11 24 100 20 1.5:1.1:1c 66

12 24 100 20 2:1.1:1d 88

13 24 100 20 1:1.1:1.5 58

a Based on the amount of alkene.b Determined by NMR by integration against 1,3,5-trimethoxybenzene (0.1 equiv) as internal standard.c Rh(CO)2acac/Xantphos (0.375/3.75 mol%), based on the amount of alkene.d Rh(CO)2acac/Xantphos (0.25/2.5 mol%), based on the amount of alkene.

H2N NH2

O

Me OEt

O O+ +

Rh(CO)2acac (0.5 mol%)a

Xantphos (5 mol%)a

HCl (concd; 40 µL)

1

Me

5NH

NHEtO2C

Me O

Me7

42 3

EtOH (0.5 M)CO/H2 (1:1)

Table 2 Biginelli Reaction with Different Catalysta

Entry Catalystb Concd HCl (μL) Yield (%)c

1 – 40d 19

2 Rh(CO)2acac (0.25 mol%)b 40 19

3 Rh(CO)2acac/Xantphos (0.25/2.5 mol%)b 40 28

4 Rh(CO)2acac/Xantphos (0.25/2.5 mol%)b – 26

5 Rh(CO)2acac/Xantphos (0.25/2.5 mol%),b 20 bar CO/H2 40 31

a Molar ratio aldehyde/urea/keto ester = 2:1.1:1.b Based on the amount of aldehyde.c Determined by NMR by integration against 1,3,5-trimethoxybenzene (0.1 equiv) as internal standard.d In the absence of HCl and any rhodium catalyst under otherwise identical conditions, no conversion into 4 was observed.

OH2N NH2

O

Me OEt

O O+ +

NH

NHEtO2C

Me OEtOH (0.5 M)100 °C, 24 h

Me

7

Me

7

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LETTER Tandem Hydroformylation–Biginelli Reaction 1659

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were added for the tandem process to ensure optimal re-sults. However, the difference between this one and thetandem result (88%) must be caused by a different effect,probably the presence of the aldehyde in a low stationaryconcentration due to the generation by alkene hydrofor-mylation.

With optimized tandem hydroformylation–Biginelli reac-tion conditions in hand the scope of the reaction was ex-plored starting from different functionalized alkenes(Table 3). In all cases the reaction proceeded with com-

plete regioselectivity in favor of the linear aldehyde andthe resulting Biginelli product 6. A range of functionalgroups proved to be compatible with the reaction condi-tions. Good yields were obtained with allylbenzene, 3,3-dimethylbutene, as well as vinylcyclohexene, showingthat internal alkenes are not affected. The reaction is com-patible with free hydroxy functions, a benzyl ether, esters,amides, and the phthaloyl function allowing for the prep-aration of new functionalized DHPM.

Table 3 Scope of the Tandem Hydroformylation–Biginelli Reactiona

Entry Substrate Product 6 NMR yield (%)c Isolated yield (%)

1 6a 88 71

2 6b 80 78

3 6c 77 75

4d 6d 80 65

5 6e 72 68

6 6f 62 57

7 6g 57 52

8 6h 74 71

9 6i 54 52

10 6j 76 73

11d 6k 70 65

12 6l 59 59

a Molar ratio aldehyde/urea/keto ester = 2:1.1:1.b Based on the amount of alkene.c Determined by NMR by integration against 1,3,5-trimethoxybenzene (0.1 equiv) as internal standard. d 28 h.

FGR

H2N NH2

O

Me OEt

O O+ +

Rh(CO)2acac (0.25 mol%)a

Xantphos (2.5 mol%)a

HCl (concd; 40 µL)

NH

NHEtO2C

Me O

RFG

2 3 6

CO/H2 (1:1; 20 bar)EtOH (0.5 M) 100 °C, 24 h

5

HO 4

AcO4

BzO 4

BnO 4

O

MeO8

OPhHN

O

4

NMe

O

Ph

N

O

O

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In summary, a new tandem reaction sequence consistingof a regioselective rhodium–Xantphos-catalyzed hydro-formylation and a multicomponent Biginelli reaction hasbeen developed. The generation of the aldehyde throughan atom economic catalytic carbon–carbon bond-formingreaction is synthetically attractive. Additionally, the re-sulting low stationary concentration of the aldehyde helpsto suppress side reactions thereby allowing the use offunctionalized aliphatic aldehydes in this multicomponentprocess leading to new alkyl-functionalized DHPM.

All solutions were prepared under an argon 5.0 (Südwest-Gas) at-mosphere in dried glassware. Air- and moisture-sensitive liquidsand solutions were transferred via syringe. All solvents were driedand distilled by standard procedures. Solutions were concentratedunder reduced pressure by rotary evaporation. Chromatographic pu-rification of products was accomplished on Merck silica gel Si 60®(200–400 mesh). NMR spectra were acquired on Bruker AMX 400,Bruker DRX 500, and Varian Mercury 300 HFCP. 1H NMR data arereported as follows: chemical shift (δ in ppm), multiplicity (s, sin-glet; br s, broad singlet; d, doublet; t, triplet; q, quartet; m, multi-plet), coupling constant (Hz), integration. 13C NMR data arereported in terms of chemical shift (δ in ppm), multiplicity, and cou-pling constant (Hz). Elemental analyses were performed on an Ele-mentar vario (Elementar Analysensysteme GmbH). Melting pointswere determined using a Dr. Tottoli apparatus (Büchi). All tandemreactions were performed in a Premex stainless steel autoclaveMedimex (100 mL) containing a magnetic stirring bar (700 rpm).For hydroformylation–Biginelli experiments a synthesis gas mix-ture (Messer-Griesheim) was used (CO/H2 = 1:1; CO 3.7, H2 4.3).The following substrates were purchased from commercial sourcesand distilled prior to use: 1-octene (Acros), vinylcyclohexene(Acros), 5-hexen-1-ol (VWR/Merck), allylbenzene (AlfaAesar),3,3-dimethylbutene (AlfaAesar). The following substrateswere prepared according to reported literature procedures:N-allylphthalimide,17 hex-5-enyl acetate,18 hex-5-enyloxymethyl-benzene,19 hex-5-enyl phenylcarbamate,20 hex-5-en-1-yl benzoate,21

N-methyl-N-phenylpent-4-enamide,22 methylundec-10-enoate.23

General Experimental ProcedureThe optimized hydroformylation–Biginelli reactions were per-formed by charging an autoclave with [Rh(CO)2acac] (2.60 mg,10.0 μmol 0.25 mol%), Xantphos (57.9 mg 100 μmol, 2.5 mol%),and urea (2, 132 mg, 2.2 mmol, 1.1 equiv) as solids under an atmo-sphere of argon. Subsequently, a solution of the alkene (4 mmol, 2equiv), ethyl acetoacetate (3, 0.25 mL, 260 mg, 2 mmol, 1 equiv)and concd HCl (40 μL) in EtOH (4 mL) was prepared and thentransferred into the autoclave via syringe. The autoclave was purgedthree times with syngas (CO/H2, 1:1), pressurized at 20 bar, andplaced in a preheated aluminum block at 100 °C. The reactions werestopped after 24 h by cooling the autoclave in a water bath (18 °C),venting and purging with argon. To the crude reaction mixture1,3,5-trimethoxybenzene (33.6 mg, 0.20 mmol, 0.1 equiv) as inter-nal standard was added and the suspension dissolved in CH2Cl2 (5mL). After evaporation of the solvents the crude product was ana-lyzed by NMR spectroscopy and purified via flash chromatographyto yield the pure 3,4-dihydropyrimidin-2(1H)-ones 6a–l as colorlesssolids or foams.

5-Ethoxycarbonyl-6-methyl-4-octyl-3,4-dihydropyrimidin-2(1H)-one (6a)The general procedure was followed starting from 1-octene (623μL, 449 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos, urea, ethyl ace-toacetate, and HCl. Purification via flash chromatography (CH2Cl2

to 1:1 CH2Cl2–EtOAc) furnished 6a as a colorless solid (422 mg,71%); mp 137 °C. 1H NMR (400.131 MHz, DMSO): δ = 0.84 (t,J = 6.9 Hz, 3 H), 1.17 ppm (t, J = 7.1 Hz, 3 H), 1.14–1.31 (m, 12 H),

1.32–1.43 (m, 2 H), 2.14 (s, 3 H), 3.96–4.13 (m, 3 H), 7.28 (dd,J = 2.1, 3.4 Hz, 1 H), 8.89 (d, J = 1.6 Hz, 1 H. 13C NMR (101.620MHz, DMSO): δ = 13.88, 14.16, 17.64, 22.03, 23.60, 28.54, 28.72,28,27, 31.22, 36.64, 49.99, 58.96, 99.38, 148.20, 152.71, 165.40.HRMS [pos. APCI (MeOH)]: m/z [M +H]+ calcd for C16H28N2O3:297.21782; found: 297.21820 (–1.3 ppm). Anal. Calcd forC16H28N2O3: C, 64.83; H, 9.52; N, 9.45. Found: C, 64.85; H, 9.63;N, 9.38.

5-Ethoxycarbonyl-6-methyl-4-(3-phenylpropyl)-3,4-dihydro-pyrimidin-2(1H)-one (6b)The general procedure was followed starting from allylbenzene(531 μL, 473 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos, urea, eth-yl acetoacetate, and HCl. Purification via flash chromatography(CH2Cl2 to 1:1 CH2Cl2–EtOAc) furnished 6b as a colorless solid(473 mg, 78%); mp 167 °C. 1H NMR (400.131 MHz, DMSO): δ =1.13 (t, J = 7.1 Hz, 3 H), 1.33–1.68 (m, 4 H), 2.14 (s, 3 H), 2.51–2.60 (m, 2 H), 3.94–4.11 (m, 3 H), 7.10–7.20 (m, 3 H), 7.21–7.28(m, 2 H), 7.33 (dd, J = 3.5, 2.0 Hz, 1 H), 8.90 (d, J = 1.8 Hz, 1 H).13C NMR (101.630 MHz, DMSO): δ = 14.17, 17.71, 25.92, 34.88,36.36, 50.01, 59.02, 99.32, 125.62, 128.18, 128.25, 142.90, 148.32,152.71, 165.39. HRMS [pos. APCI (MeOH)]: m/z [M + H]+ calcdfor C17H22N2O3: 303.17087; found: 303.17130 (–1.4 ppm). Anal.Calcd for C17H22N2O3: C, 67.53; H, 7.33; N, 9.26. Found: C, 67.85;H, 7.50; N, 9.00.

4-[2-(Cyclohex-3-enyl)-ethyl]-5-ethoxycarbonyl-6-methyl-3,4-dihydropyrimidin-2(1H)-one (6c)The general procedure was followed starting from vinylcyclohex-ene (521 μL, 432 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos, urea,ethyl acetoacetate, and HCl. Purification via flash chromatography(CH2Cl2 to 2:1 CH2Cl2–EtOAc) furnished 6c as a colorless solid(440 mg, 75%); mp 178–180 °C. 1H NMR (499.501 MHz, DMSO,27 °C): δ (mixture of diastereomers) = 1.05–1.32 (m, 3 H), 1.17 (t,J = 7.1 Hz, 3 H), 1.38–1.47 (m, 3 H), 1.48–1.69 (m, 2 H), 1.96 (d,J = 4.1 Hz, 2 H), 2.01–2.09 (m, 1 H), 2.15 (s, 3 H), 3.97–4.13 (m, 3H), 5.60 (s, 2 H), 7.31 (br s, 1 H), 8.90 (br s, 1 H). 13C NMR(125.610 MHz, DMSO, 27 °C): δ (mixture of diastereomers) =14.73, 18.20, 25.08/25.14, 28.66/29.13, 30.90/31.03, 31.70/32.07,32.99/33.08, 34.35/34.43, 50.64/50.66, 59.52, 99.88/99.92,126.83/126.92, 127.22/127.27, 148.81, 153.20, 165.92. HRMS[pos. APCI (MeOH)]: m/z [M + H]+ calcd for C16H24N2O3:293.18652; found: 293.18652 (0.4 ppm). Anal. Calcd forC16H24N2O3: C, 65.73; H, 8.27; N, 9.58. Found: C, 65.82; H, 8.11;N, 9.44.

4-(33-Dimethyl-butyl)-5-ethoxycarbonyl-6-methyl-3,4-dihy-dropyrimidin-2(1H)-one (6d)The general procedure was followed starting from 3,3-dimethylbu-tene (516 μL, 337 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos, urea,ethyl acetoacetate, and HCl. The reaction time was prolonged to 28h. Purification via flash chromatography (CH2Cl2 to 1:1 CH2Cl2–EtOAc) furnished 6d as a colorless solid (350 mg, 65%); mp188 °C. 1H NMR (400.131 MHz, DMSO): δ = 0.81 (s, 9 H), 1.01–1.30 (mc, 2 H), 1.17 (t, J = 7.1 Hz), 1.31–1.41 (m, 2 H), 2.15 (s, 3H), 3.91–4.21 (m, 3 H), 7.26 (dd, J = 3.4, 2.1 Hz, 1 H), 8.87 (d,J = 1.6 Hz, 1 H). 13C NMR (101.630 MHz, DMSO): δ = 14.24,17.68, 29.21, 29.76, 31.89, 37.90, 50.89, 58.94, 99.30, 148.21,152.62, 165.42. HRMS [pos. APCI (MeOH)]: m/z [M + H]+ calcdfor C14H24N2O3: 269.18652; found: 269.18680 (–1.0 ppm). Anal.Calcd for C14H24N2O3: C, 62.66; H, 9.01; N, 10.44. Found: C,62.29; H, 9.13; N, 10.06.

5-Ethoxycarbonyl-4-(6-hydroxy-hexyl)-6-methyl-3,4-dihydro-pyrimidin-2(1H)-one (6e)The general procedure was followed starting from 5-hexen-1-ol(480 μL, 401 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos, urea, eth-yl acetoacetate, and HCl. Purification via flash chromatography(CH2Cl2 to EtOAc) furnished 6e (388 mg, 68%) as a colorless solid;mp 98–99 °C. 1H NMR (400.131 MHz, DMSO): δ = 1.17 (t, J = 7.1Hz, 3 H), 1.20–1.42 (m, 10 H, H-8-11), 2.15 (s, 3 H), 3.35 (dt,

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J = 6.4, 6.4 Hz, 2 H), 3.97–4.13 (m, 3 H), 4.30 (t, J = 5.2 Hz, 1 H),7.28 (dd, J = 3.5, 2.1 Hz, 1 H), 8.89 (d, J = 1.8 Hz, 1 H). 13C NMR(101.630 MHz, DMSO): δ = 14.22, 17.69, 23.76, 25.47, 28.71,32.47, 36.72, 50.05, 59.02, 60.69, 99.43, 148.22, 152.75, 165.44.HRMS [pos. APCI (MeOH)]: m/z [M + H]+ calcd for C14H24N2O4:285.18143; found: 285.18160 (–0.6 ppm). Anal. Calcd forC14H24N2O4: C, 59.14; H, 8.51; N, 9.85. Found: C, 59.17; H, 58.28;N, 9.67.

4-(6-Acetoxy-hexyl)-5-ethoxycarbonyl-6-methyl-3,4-dihydro-pyrimidin-2(1H)-one (6f)The general procedure was followed starting from hex-5-enyl ace-tate (469 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos, urea, ethylacetoacetate, and HCl. Purification via flash chromatography(CH2Cl2 to 1:1 CH2Cl2–EtOAc) furnished 6f as a colorless solid(365 mg, 57%); mp 77 °C. 1H NMR (400.131 MHz, DMSO): δ =1.17 (t, J = 7.1 Hz), 1.19–1.43 (m, 8 H), 1.45–1.59 (m, 2 H), 1.98(s, 3 H), 2.14 (s, 3 H) 3.96 (t, J = 6.6 Hz, 2 H), 3.99–4.12 (m, 3 H),7.29 (dd, J = 3.5, 2.2 Hz, 1 H), 8.89 (d, J = 1.8 Hz, 1 H). 13C NMR(101.630 MHz, DMSO): δ = 14.19, 17.67, 20.68, 23.57, 25.32,28.02, 28.35, 36.58, 49.98, 58.99, 63.74, 99.37, 148.22, 152.71,165.40, 170.34. HRMS [pos. APCI (MeOH)]: m/z [M + H]+ calcdfor C16H26N2O5: 327.19200; found: 327.19240 (–1.2 ppm). Anal.Calcd for C16H26N2O5: C, 58.88; H, 8.03; N, 8.58. Found: C, 58.61;H, 8.31; N, 8.25.

4-(6-Benzoyloxy-hexyl)-5-ethoxycarbonyl-6-methyl-3,4-dihy-dropyrimidin-2(1H)-one (6g)The general procedure was followed starting from hex-5-en-1-ylbenzoate (649 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos, urea,ethyl acetoacetate, and HCl. Purification via flash chromatography(CH2Cl2 to 1:1 CH2Cl2–EtOAc) furnished 6g as a colorless solid(376 mg, 52%); mp 117–118 °C. 1H NMR (400.131 MHz, DMSO):δ = 1.16 (t, J = 7.1 Hz), 1.21–1.47 (m, 8 H), 1.64–1.72 (m, 2 H),2.15 (s, 3 H), 3.94–4.12 (m, 3 H), 4.25 (t, J = 6.6 Hz, 2 H), 7.30 (dd,J = 3.5, 2.1 Hz, 1 H), 7.48–7.55 (m, 2 H), 7.61–7.69 (m, 1 H), 7.91–7.98 (m, 2 H), 8.90 (d, J = 1.9 Hz, 1 H). 13C NMR (101.630 MHz,DMSO): δ = 14.19, 17.69, 23.62, 25.44, 28.10, 28.38, 36.59, 49.99,59.00, 64.64, 99.40, 128.73 (2 C), 129.02 (2 C), 129.85, 133.21,148.24, 152.72, 165.41, 165.71. HRMS [pos. APCI (MeOH)]: m/z[M + H]+ calcd for C21H28N2O5: 389.20765; found: 389.20770 (–0.1ppm).

4-(6-Benzyloxy-hexyl)-5-ethoxycarbonyl-6-methyl-3,4-dihy-dropyrimidin-2(1H)-one (6h)The general procedure was followed starting from hex-5-enyloxy-methylbenzene (593 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos,urea, ethyl acetoacetate, and HCl. Purification via flash chromatog-raphy (CH2Cl2 to 1:1 CH2Cl2–EtOAc) furnished 6h as a colorlesssolid (534 mg, 71%); mp 88–90 °C. 1H NMR (499.500 MHz, DM-SO): δ = 1.16 (t, J = 7.1 Hz, 3 H), 1.19–1.40 (m, 8 H), 1.45–1.54 (m,2 H), 2.15 (s, 3 H), 3.39 (t, J = 6.6 Hz, 2 H), 3.96–4.11 (m, 3 H),4.42 (s, 2 H), 7.22–7.36 (m, 6 H, H-3), 8.91 (d, J = 1.9 Hz, 1 H). 13CNMR (125.610 MHz, DMSO): δ = 14.20, 17.69, 23.66, 25.63,28.55, 29,11, 36.64, 50.02, 59.00, 69.55, 71.75, 99.41, 127.26,127.34 (2 C), 128.17 (2 C), 138.72, 148.24, 152.74, 165.42. HRMS[pos. APCI (MeOH)]: m/z [M + H]+ calcd for C21H30N2O4:374.20798; found: 374.20780 (0.5 ppm). Anal. Calcd forC21H30N2O4: C, 67.35; H, 8.07; N, 7.48. Found: C, 67.71; H, 7.99;N, 7.14.

5-Ethoxycarbonyl-4-(11-methoxycarbonyl-undecyl)-6-methyl-3,4-dihydropyrimidin-2(1H)-one (6i)The general procedure was followed starting from methylundec-10-enoate (793 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos, urea, ethylacetoacetate, and HCl. Purification via flash chromatography(CH2Cl2 to 1:1 CH2Cl2–EtOAc) furnished 6i as a colorless solid(398 mg, 52%); mp 110 °C. 1H NMR (400.131 MHz, DMSO): δ =1.13–1.44 (m, 16 H), 1.17 (t, J = 7.1 Hz, 3 H), 1.45–1.53 (m, 2 H),2.14 (s, 3 H), 2.27 (t, J = 7.5 Hz, 2 H), 3.56 (s, 3 H), 3.97–4.12 (m,3 H), 7.28 (dd, J = 3.5, 2.1 Hz, 1 H), 8.89 (d, J = 1.8 Hz, 1 H). 13C

NMR (101.630 MHz, DMSO): δ = 14.20, 17.67, 23.64, 24.41,28.42, 28.64, 28.73, 28.83, 28.85, 28.91, 33.25, 36.66, 50.02, 51.02,58.99, 99.40, 148.22, 152.72, 165.44, 173.32. HRMS [pos. APCI(MeOH)]: m/z [M + H]+ calcd for C20H34N2O5: 383.25460; found:383.25470 (–0.3 ppm).

5-Ethoxycarbonyl-6-methyl-4-(6-N-phenylcarbamoyloxy-hex-yl)-3,4-dihydropyrimidin-2(1H)-one (6j)The general procedure was followed starting from hex-5-enyl phe-nylcarbamate (709 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos,urea, ethyl acetoacetate, and HCl. Purification via flash chromatog-raphy (CH2Cl2 to 1:1 CH2Cl2–EtOAc) furnished 6j as a colorlessfoam (590 mg, 73%). 1H NMR (400.131 MHz, DMSO): δ = 1.17 (t,J = 7.1 Hz, 3 H), 1.20–1.43 (m, 8 H), 1.53–1.63 (m, 2 H), 2.15 (s, 3H), 3.97–4.12 (m, 5 H), 6.92–6.99 (m, 1 H), 7.21–7.27 (m, 2 H),7.29 (dd, J = 3.5, 2.1 Hz, 1 H), 7.41–7.47 (m, 2 H), 8.90 (d, J = 1.9Hz, 1 H), 9.54 (br s, 1 H). 13C NMR (101.630 MHz, DMSO): δ =14.21, 17.69, 23.67, 25.36, 28.46, 28.50, 36.66, 50.03, 59.03, 64.06,99.39, 118.12, 122.23 (2 C), 128.66 (2 C), 139.20, 148.24, 152.73,153.58, 165.43. HRMS [pos. APCI (MeOH)]: m/z [M + H]+ calcdfor C21H29N3O5: 404.21855; found: 404.21860 (–0.1 ppm).

5-Ethoxycarbonyl-4-[5-(N-methyl-N-phenylcarbamoyl)-pen-tyl]-6-methyl-3,4-dihydropyrimidin-2(1H)-one (6k)The general procedure was followed starting from N-methyl-N-phenylpent-4-enamide (757 mg, 4.00 mmol), [Rh(CO)2acac], Xant-phos, urea, ethyl acetoacetate, and HCl. Purification via flash chro-matography (CH2Cl2 to EtOAc) furnished 6k as a colorless foam(488 mg, 65%). 1H NMR (400.131 MHz, DMSO): δ = 0.96–1.31(m, 4 H), 1.14 (t, J = 7.1 Hz, 3 H), 1.89–2.03 (m, 2 H), 2.13 (s, 3 H),3.13 (s, 3 H), 3.93–4.10 (m, 3 H), 7.19–7.48 (m, 6 H), 8.89 (d,J = 1.8 Hz, 1 H). 13C NMR (101.630 MHz, DMSO): δ = 14.20,17.68, 23.35, 24.64, 33.14, 36.51, 49.94, 59.00, 99.27, 127.27,129.58 (2 C), 144.02 (2 C), 148.23, 152.66, 165.43, 171.44. HRMS[pos. APCI (MeOH)]: m/z [M + H]+ calcd for C20H27N3O4:374.20798; found: 374.20780 (0.5 ppm).

5-Ethoxycarbonyl-6-methyl-4-(3-phtalimido-propyl)-3,4-dihy-dropyrimidin-2(1H)-one (6l)The general procedure was followed starting from N-al-lylphthalimide (749 mg, 4.00 mmol), [Rh(CO)2acac], Xantphos,urea, ethyl acetoacetate, and HCl. Purification via flash chromatog-raphy (CH2Cl2 to EtOAc) furnished 6l as a colorless solid (443 mg,59%); mp 195 °C. 1H NMR (400.131 MHz, DMSO): δ = 1.06 (t,J = 7.1 Hz), 1.33–1.73 (m, 4 H), 2.13 (s, 3 H), 3.46–3.61 (m, 2 H),3.87–4.09 (m, 3 H), 7.26 (dd, J = 3.4, 2.0 Hz, 1 H), 7.77–7.88 (m, 4H), 8.91 (d, J = 1.8 Hz, 1 H). 13C NMR (101.630 MHz, DMSO): δ= 14.05, 17.71, 23.02, 34.10, 37.37, 50.03, 58.96, 98.62, 122.99 (2C), 131.50 (2 C), 134.40 (2 C), 148.59, 152.53, 165.42, 167.89.HRMS [pos. APCI (MeOH)]: m/z [M + H]+ calcd for C19H21N3O5:372.15595; found: 372.15600 (–0.1 ppm). Anal. Calcd forC19H21N3O5: C, 61.45; H, 5.70; N, 11.31. Found: C, 61.67; H, 5.62;N, 11.18.

Acknowledgment

This work was supported by Syngenta Crop Protection.

Supporting Information for this article is available online athttp://www.thieme-connect.com/ejournals/toc/synlett.Supporting InformationSupporting Information

References and Notes

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