[3+3] Annulation via Ring Opening/Cyclization of Donor–Acceptor Cyclopropanes with (Un)symmetrical Ureas: A Quick Access to Highly Functionalized Tetrahydropyrimidinones

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Accepted Article

Title: [3+3] Annulation via Ring Opening/Cyclization of Donor-Acceptor

Cyclopropanes with (un)symmetrical ureas: A Quick Access to

Highly Functionalized Tetrahydropyrimidinones

Authors: Irshad Maajid Taily, Debarshi Saha, and Prabal Banerjee

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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201901400

Link to VoR: http://dx.doi.org/10.1002/ejoc.201901400

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[3+3] Annulation via Ring Opening/Cyclization of Donor-Acceptor

Cyclopropanes with (un)symmetrical ureas: A Quick Access to

Highly Functionalized Tetrahydropyrimidinones

Irshad Maajid Taily, Debarshi Saha, and Prabal Banerjee*

Dedicated to Professor Ganesh Pandey on the occasion of his 65^thbirthday.

Abstract: A mild and straight-forward access to pharmacologically

privileged tetrahydropyrimidinones exploiting readily available Donor-

Acceptor cyclopropanes (DACs) is reported. This methodology

involves the Lewis acid catalyzed synthesis of uriedo-malonates from

(un)symmetrical ureas and DACs followed by I₂-base mediated

cyclization to their corresponding tetrahydropyrimidinones. The

cyclization protocol involves nucleophilic attack of the nitrogen of urea

on the newly generated electrophilic acceptor end of DAC. The post

functionalization offered potential biologically active molecules.

Introduction

Nitrogen heterocycles constitute the pharmacophore of about

fifty-eight percent of U.S. FDA approved small molecule drugs.¹

Among them, tetrahydropyrimidinone nucleus is of particular

interest due to its wide range of pharmacological applications.^2,3

The peculiarity is that it is one of the four pharmaceutically known

nitrogen containing heterocycles that contain carbonyl group as

part of their primary ring systems along with cephems, penams

and quinolinones.⁴Tetrahydropyrimidinones constitute the pivotal

components of various important bioactive molecules because of

Scheme

Tetrahydropyrimidinones.

1. Exploitation of Urea Moieties Towards the Synthesis of

their broad pharmacological spectrum (Figure 1).⁵

Recently tetrahydropyrimidinones were exploited as

precursors for pseudo natural chromopynones in biology-oriented

synthesis (BIOS) approach. These chromopynones are novel

glucose uptake inhibitors that selectively inhibit glucose

transporters Glut-1 and -3. These have also shown the anti-

proliferative effect and thus paves the way for novel, structurally

unprecedented promising anti-tumor drugs.⁶

properties, a number of synthetic methodologies of simple

pyrimidinones has been reported till date. Pietro Biginelli in 1891

for the first time described the synthesis of pyrimidinones and

pyrimidines.⁷Martin et al. in 2000 described dialkylation of O-

benzylhydroxylurea with 1,3-dibromopropane to produce simple

tetrahydropyrimidinones (Scheme 1, eq 1).⁸Obushak et al.

Because of their versatile therapeutic and pharmacological

reported

FeCl₂.H₂O

catalyzed

synthesis

of

tetra-

hydropyrimidinones from furfuraldehyde, ethyl acetoacetate, and

ureas.⁹Chen et al. disclosed an organocatalytic synthesis of

pyrimidinones from ureas and aldehydes.¹⁰Though all the

methods available till date for the synthesis of

tetrahydropyrimidinones are appreciable both in versatility and

efficiency, but most of them suffer in terms of substrate scope and

reaction conditions employed.¹¹

Figure 1. Tetrahydropyrimidinone nucleus present in various pharmacologically

active molecules.

Inspired by the mechanistic insight of these works and the

knowledge of DAC reactivity, we got interested in the dialkylation

of dibenzyloxyurea moiety by DAC to produce highly

functionalized tetrahydropyrimidinones. To the best of our

knowledge, tetrahydropyrimidinones have not been synthesized

from readily available DACs so far. Traditionally, DACs undergo

formal cycloaddition reaction with dipolarophile due to its inherent

zwitterionic nature (Scheme 1, eq 2) and thus are highly

acknowledged versatile building blocks for diverse carbocycles

Mr. Irshad Maajid Taily, Mr. Debarshi Saha, and Dr. Prabal Banerjee^*

Department of Chemistry, Indian Institute of Technology Ropar, Nangal

Road, Rupnagar, Punjab 140001, India

E-mail: prabal@iitrpr.ac.in .

http://www.iitrpr.ac.in/PBGroup/

Supporting information and ORCID(s) from the author(s) for this article

areavailable on on the WWW under

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Table 1. Optimization of Reaction Conditions.^a

and heterocycles.^12,13,14In a typical heterolytic cleavage, the

cyclopropane diesters produce a malonate center at their

acceptor end.^{15, 16}From the very onset, the malonate centers

have proved excellent targets for various transformations.^{17, 18}

The malonate center so produced can be exploited to reverse the

reactivity at the acceptor end of DAC. A bi-nucleophilic species

can directly undergo annulation reaction with DACs instead of a

dipolarophile (Scheme 1, eq 3). This makes an attractive aspect

in the utilization of DACs towards the synthesis of various carbo

and heterocycles.

Entry

Lewis

acid

mol %

solvent

time

(h)

yield

(%)^b

The idea was that one of the diamide nitrogens of urea would

attack the donor end of DAC to produce uriedo-malonate moiety.

The reactivity of the acceptor end of DAC will then be reversed by

I₂-base system, and nucleophilic attack by other nitrogen of urea

at this center will furnish the tetrahydropyrimidinones (Scheme 1,

eq 4).

Herein, we report a Lewis acid catalyzed synthesis of ureido-

malonates from DACs and substituted ureas that is followed by

iodine mediated cyclization to afford highly functionalized

tetrahydropyrimidinones in moderate to excellent yield.

1

2.

3

-

DCM

24

5

n.r^c

n.r

c.m^d

25

MgI₂

10

20

10

20

30

20

30

20

30

MgI₂

4.

5.

6.

7

MgBr₂

BF₃.OEt₂

Cu(OTf)₂

Sc(OTf)₃

InCl₃

24

8

32

8

48

Results and Discussion

9

62

Based on the knowledge of reactivity of DACs¹⁹, we

commenced the screening of optimized reaction condition

considering p-methoxyphenyl substituted cyclopropane diester 1a

and dibenzyloxyurea 2a as model substrates, using 20 mol% of

the catalyst in DCM. Initially, we screened Lewis acids like MgI₂,

MgBr₂, but failed to get the expected product in both the cases

(Table 1, entries 2, 3, 4). A complex mixture was formed in the

case of BF₃.OEt₂catalyzed reaction (Table 1, entry 5). However,

the desired product was formed in Cu(OTf)₂catalyzed reaction

but the yield (25%) was not satisfactory as much of the both

starting materials remain unconsumed (Table 1, entry 6). There

was an improvement of the yield (48%) in the case of Sc(OTf)₃

catalyzed reaction, but the conversion of starting materials to the

desired product was not fully achieved even upon increasing the

catalyst loading to 30 mol% (62% yield) in 24 h (Table 1, entries

8, 9). The expectations were met in the case of InCl₃catalyzed

reaction where the yield obtained was 78% and 90% with 20

mol% and 30 mol% catalyst loading respectively with a reduced

reaction time of 8 h (Table 1, entries 10, 11).

10

11

78

InCl₃

8

90

^aReactions were carried out with 1 equiv. of 1a and 1 equiv. of 2a. ^bIsolated

yields. ^cn.r. = no reaction. ^dc.m. = complex mixture. DCM = dichloromethane.

double bond and thus C–C bond rotation is possible across this

bond. The double bond returns to its original position once the

nucleophile attacks the donor end of DAC. The rotation in the

meanwhile results in the formation of both E and Z isomers of 3j.

The DACs with different ester groups were also investigated to

check the effect of the bulkiness of ester groups (Table 2, 3g, 3h).

All of them proved viable substrates, and no profound effect on

the transformation was observed.

To get further insight into the reaction and due to the effect of

symmetry on the pharmacokinetic and pharmacodynamic profile²⁰

of various biologically active scaffolds containing them, we

explored the viability of various unsymmetrical ureas (Table 2, 2c,

2d, 2e). To our delight, various types of unsymmetrical ureas

participated in the reaction giving moderate to an excellent yield

of the adduct. Firstly, we screened bis N- alkyloxy urea 2c and

found that it participated in the reaction very well. The chemo-

selective attack of the N-benzyloxy group and not N-(p-

nitrobenzyloxy) group is probably due to its higher electron

density. This is in agreement with the single crystal X-ray structure

of 4k (Figure 2). Then we evaluated N-alkyloxy N-alkyl

unsymmetrical urea 2d and found that this also took part in the

reaction efficiently. The regioselective attack of N-alkyloxy

nitrogen of urea at the donor side of DAC in 3l is due to the higher

electron density at nitrogen because of the vicinal oxygen atom.²¹

This was proved by ¹H-NMR spectrum. The triplet of characteristic

N-H proton at 6.00 ppm confirmed the participation of N-

benzyloxy group and not N-benzyl group. The ambiguity of

formation of both the isomers and crystallizing of only one isomer

With the optimized reaction conditions in hand substrate

scope and limitation of the reaction both with respect to various

phenyl substituted DACs and ureas were probed next (Table 2).

It was found that the reaction displayed a broad scope with

electron rich DACs like dimethoxy, trimethoxy, N-dimethyl phenyl

substituted ones (Table 2). The reaction showed compromised

result in the case of less activated p-methylphenyl substituted

DAC (Table 2, 3d). However, this was achieved smoothly at 45-

0

50 C in DCE, but the reaction time got extended to about 24 h.

Also, the p-fluoro and p-chlorophenyl substituted DACs remained

intact due to their less reactivity. A mixture of trans and cis

isomers was obtained in the case of styryl cyclopropane diester

(E: Z = 74: 26, Table 2, 3j). This could be due to the temporary

stabilization of positive charge by the double bond at the donor

end of DAC. It brings a single bond character in the otherwise

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Table 2. Reaction of DACs 1 with Ureas 2.

Entry

3a

1

2

Ar

R¹

C₂H₅

CH3

R²

R³

C₆H₅CH₂O

4-NO₂C₆H₄CH₂O

C₆H₅CH₂

time (h)

yield (%)^a

90

1a

1b

1c

1d

1e

1f

2a

2c

2d

2e

4-OMeC₆H₄

C₆H₅CH₂O

8

7.5

8

3b

3c

3, 4-(OMe)₂C₆H₃

4-N(Me)₂C₆H₄

4-MeC₆H₄

87

86

3d^b

3e

24

10

1.5

12

10

12

9

78

3, 4-(CH₂O₂)C₆H₃

2, 4, 6-(OMe)₃C₆H₂

4-OMe C₆H₄

87

3f^c

3g

3h

3i

94

1g

1h

1i

89

3, 4-(OMe)₂C₆H₃

C₄H₃O (furfuryl)

C₆H₅CH=CH

CH(CH₃)₂

C₂H₅

95

73

3j^d

3k

1j

80

1a

4-OMe C₆H₄

12

8

85

3l

4-OMe C₆H₄

91

3m

4-OMe C₆H₄

C₆H₅

8

91

^aIsolated yields and reaction time are illustrated. ^bThe reaction in the case of 3d was carried out in DCE at 45-50 ⁰C. ^cWith 0.1 equiv. of InCl₃. ^dIn the case of 3j the

ratio of isomers obtained is E: Z = 74: 26 (for details, see Supporting Information).

was ruled out on the basis of chromatographic data and NMR

spectra of both the acyclic compounds 3k, 3l and their

corresponding tetrahydropyrimidinones 4k, 4m respectively (for

details, see Supporting Information). Since N, N–biarylureas and

N, N–dialkylureas are not good nucleophiles as such, the

nucleophilicity at the nitrogen center can be increased by

attaching an alkyloxy group.²¹Hence, N, N–dialkylurea 2b and

biarylurea 2f proved non-viable substrates for this transformation.

Next, we investigated N- aryl N-alkyloxy urea 2e where we got the

product 3m in moderate yield. These results imply a wide scope

of this methodology.

isomers of 3j were converted to trans product 4j only. This could

be attributed to the iodine mediated isomerization of substituted

alkenes²²and the steric hindrance from N- benzyloxy group. The

bulky N- benzyloxy group makes cis-configuration unfavorable.

Hence, only the product with trans geometry was formed. The

trans geometry of the product is confirmed by its COSY and

NOESY NMR (for details, see Supporting Information). I₂-DBU

system failed to cyclize N- alkyl uriedo-malonates (Table 3, 4l).

This proves that the N-alkyloxy oxygen, which is vicinal to nitrogen

center assists the cyclization. The use of strong base NaH did not

only make this transformation happen but also completed the

reaction within 15 minutes. Due to the resonance effect of both

phenyl and urea carbonyl on the nitrogen center, N- aryl uriedo-

malonate failed to cyclize (Table 2, 3m). The structure of 4c

(CCDC 1898265) and 4k (CCDC 1898880) were also ascertained

Keeping in view the acidity of malonate and urea hydrogens, the

synthesized uriedo-malonates were transformed to their

corresponding tetrahydropyrimidinones by I₂-base system. I₂-

Na₂CO₃proved inferior while I₂-DBU afforded the desired product

in excellent yields. In the case of bis N- alkyloxy uriedo-malonates, by single-crystal X-ray analysis (Figure 2).

there was a complete conversion of the starting material to

tetrahydropyrimidinones within 1-2 h. Both the geometrical

With the optimized reaction conditions in hand, we attempted

a sequential one-pot synthesis of 4a, and to our delight we could

procure the desired product in moderate yield (scheme 2).

Figure 2. X- ray crystal structures of 4c and 4k.

Scheme 2. Sequential one pot synthesis.

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Table 3. Transformation of uriedo-malonates to tetrahydropyrimidinone.

compound

3

Ar

R¹

C₂H₅

CH3

R²

R³

time (h)

yield(%)^a

92

4a

4b

4c

4d

4e

4f

3a

3b

3c

3d

3e

3f

4-OMeC₆H₄

C₆H₅CH₂O

4-NO₂C₆H₄CH₂O

C₆H₅CH₂

2

3, 4-(OMe)₂C₆H₃

4-N(Me)₂C₆H₄

4-MeC₆H₄

2

91

2

94

2

95

3, 4-(CH₂O₂)C₆H₃

2, 4, 6-(OMe)₃C₆H₂

4-OMe C₆H₄

3, 4-(OMe)₂C₆H₃

C₄H₃O

2

90

2

82

4g

4h

4i

3g

3h

3i

2

90

CH(CH₃)₂

C₂H₅

2

90

92

4j

3j

C₆H₅CH=CH

4-OMe C₆H₄

0.5

2

85

4k

4l^b

3k

3l

87

15 min

89

^aIsolated yields and reaction time are illustrated. ^bNaH was used instead of DBU (for details, see Supporting Information)

groups (MBG) in metalloenzyme inhibitors like Zileuton (5-LOX

Scheme 4. Derivatization of 4a.

Scheme 3. Plausible Mechanism.

inhibitor and marketed as Zyflo), SAHA (HDAC inhibitor and

marketed under the trade name Zolinza). ^{8, 23}In another aspect,

the Krapcho mono-decarboxylation of 4a is followed by the

elimination of vicinal N-benzyloxy group and further

rearrangement of imine to enamine gave the dihydropyrimidinone

6 (scheme 4, eq. 2) which resembles various biologically active

molecules.²⁴

Based on the experimental results and the literature reports a

plausible mechanism of both uriedo-malonate moiety formation

and cyclization step is proposed in Scheme 3. The nitrogen center

of urea 2 attacks the donor end of Lewis acid activated DAC 1 to

form an acyclic uriedo-malonate moiety 3 which upon treatment

with I₂-base undergoes cyclization to the corresponding

tetrahydropyrimidinone 4.

The synthesized tetrahydropyrimidinones can be easily

debenzylated by H₂/Pd-C to N-hydroxytetrahydropyrimidinones

(scheme 4, eq. 1). The N-hydroxyurea groups form metal binding

Conclusions

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¹H-NMR (400 MHz, CDCl₃): δ 7.09-7.06 (m, 4H), 4.25-4.20 (m, 2H), 3.86-

3.85 (m, 2H), 3.19-3.15 (m, 1H), 2.29 (s, 3H), 2.15-2.13 (m, 1H), 1.69-1.67

(m, 1H), 1.28 (t, J = 7.1 Hz, 3H), 0.89 (t, J = 7.1 Hz, 3H)

The developed methodology exploited the readily available DACs

towards

the

synthesis

of

highly

functionalized

tetrahydropyrimidinones. This methodology worked efficiently for

the synthesis of both symmetrical and unsymmetrical urea

containing tetrahydropyrimidinones. The sequential one pot

approach for this transformation was also developed. Electron

rich DACs and (di)alkyloxy ureas proved viable substrates.

However, dialkylurea and electron deficient DACs showed

compromised results. The post functionalization of synthesized

tetrahydropyrimidinones offered potential biologically active

scaffolds.

Diethyl 2-(benzo[d][1,3]dioxol-5-yl)cyclopropane-1,1-dicarboxylate

(1e): ^{12b 1}H-NMR (400 MHz, CDCl₃): δ 6.72–6.64 (m, 3 H), 5.91 (s, 2 H),

4.28-4.17 (m, 2 H), 3.95-3.88 (m, 2 H), 3.14 (t, J = 7.5 Hz, 1 H), 2.09-2.07

(m, 1 H), 1.67-1.65 (m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H), 0.97 (t, J = 7.1 Hz,

3 H)

Diethyl

2-(2,4,6-trimethoxyphenyl)cyclopropane-1,1-dicarboxylate

(1f):^{30 1}H-NMR (400 MHz, CDCl₃): δ 6.05 (s, 2H), 4.13-4.18 (m, 2H), 3.91-

3.83 (m, 2H), 3.78(s, 3H), 3.75 (s, 6H), 2.85-2.83 (m, 1H), 2.41-2.39 (m,

1H), 1.80-1.78 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H)

Dimethyl 2-(4-methoxyphenyl)cyclopropane-1,1-dicarboxylate (1g):³⁰

¹H-NMR (400 MHz, CDCl₃): δ 7.11 (d, J = 8.5 Hz, 2H), 6.80 (d, J = 8.5 Hz,

2H), 3.77 (s, 6H), 3.38 (s, 3H), 3.18 (t, J = 8.5 Hz, 1H), 2.15 (dd, J = 8.0,

5.5 Hz, 1H), 1.72 (dd, J = 8.0, 5.5 Hz, 1H)

Experimental Section

All reactions were carried out under an inert atmosphere with oven-dried

glassware. All solvents and reagents were obtained from commercial

sources and were purified following the standard procedure before use.

The developed chromatogram was analyzed by UV lamp (254 nm) or p-

anisaldehyde solution. Products were purified by silica gel (mesh size 230–

400) column chromatography. The ¹H NMR and ¹³C NMR spectra were

recorded in CDCl₃and DMSO as per requirement. Chemical shifts of 1H

and ¹³C NMR spectra are expressed in parts per million (ppm). All coupling

constants are absolute values and are expressed in Hertz. The description

of the signals includes the following: s = singlet, d = doublet, dd = doublet

of doublet, t = triplet, dt = doublet of triplet, q = quartet, dq = doublet of

quartet, br = broad, and m = multiplet.

Diisopropyl

2-(3,4-dimethoxyphenyl)cyclopropane-1,1-

dicarboxylate: (1h):^{25f 1}H-NMR (400 MHz, CDCl₃): δ 6.77-6.70 (m, 3H),

5.08 (septet, J = 5.8 Hz, 1H), 4.73 (septet, J = 5.8 Hz, 1H), 3.86 (s, 3H),

3.83 (s, 3H), 3.14 (t, J = 8.4 Hz, 1H), 2.08 (dd, J = 8.2, 5.0 Hz, 1H), 1.61

(dd, J = 10.1, 5.0 Hz, 1H), 1.27 (m, 6H), 1.07 (d, J = 6.2 Hz, 3H), 0.75 (d,

J = 6.5 Hz, 3H)

Diethyl 2-(furan-2-yl)cyclopropane-1,1-dicarboxylate (1i): ^{12d 1}H-NMR

(400 MHz, CDCl₃): δ 7.28 (s, 1H), 6.27 (dd, J = 3.2, 1.9 Hz, 1H), 6.12 (d, J

= 3.2 Hz, 1H), 4.22−4.20 (m, 2H), 4.02 (q, J = 7.1 Hz, 2H), 3.08 (t, J = 8.6

Hz, 1H), 2.05 (dd, J = 7.7, 5.0 Hz, 1H), 1.77 (dd, J = 9.5, 5.0 Hz, 1H), 1.28

(t, J = 7.2 Hz, 3H), 1.07 (t, J = 7.1 Hz, 3H)

Diethyl (E)-2-styrylcyclopropane-1,1-dicarboxylate: (1j):^{30 1}H-NMR

(CDCl3, 400 MHz): δ 7.30-7.27 (m, 4H), 7.23(s, 1H), 6.63 (d, J = 15.6 Hz,

1H), 5.81 (dd, J = 15.6, 8.4 Hz, 1H), 4.27-4.14 (m, 4H), 2.73 (q, J = 8.4 Hz,

1H), 1.81 (dd, J = 7.4, 5 Hz, 1H), 1.66 (dd, J = 9, 5 Hz, 1H), 1.28 (t, J = 7

Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H)

General procedure for the preparation of Donor-Acceptor

Cyclopropanes (DACs)²⁵Sodium hydride (1.5 equiv.) was taken in three-

neck R.B flask and washed 3 to 4 times with dry hexane under N₂

atmosphere. 100 mL of DMSO was added. The solution of trimethyl

sulfoxonium iodide (1.5 equiv.) in DMSO (20 mL) was added to the flask

at 0 °C. After 12 min. diethylbenzylidenemalonate (1 equiv.) in 10 mL

DMSO was added to the stirred solution, and the reaction mixture was

allowed to stir for 2 h at room temperature. Upon completion of the reaction

(as monitored by TLC), the reaction mixture was quenched with ice-cold

water, and the organic solution was extracted with diethyl ether. Further

organic solution was dried over anhydrous Na₂SO₄. The solution was

concentrated in vacuo. The crude mixture was further purified by silica gel

column chromatography taking EtOAc/hexane as eluent.

Diethyl-2-(4-fluorophenyl)cyclopropane-1,1-dicarboxylate:

(1k):^12b

¹H-NMR (400 MHz, CDCl₃): δ 7.15-7.14 (m, 2H), 6.93 (t, J = 8.7 Hz, 2H),

4.24-4.19 (m, 2H), 3.86-3.83 (m, 2H), 3.16 (t, J = 8.6 Hz, 1H), 2.11 (dd, J

= 5.0, 3.6 Hz, 1H), 1.68 (dd, J = 5.3, 3.7 Hz, 1H), 1.27 (t, J = 7.0 Hz, 3H),

0.89 (t, J = 7.1 Hz, 3H)

Diethyl-2-(4-chlorophenyl)cyclopropane-1,1-dicarboxylate: (1l):^{25d 1}H-

NMR (400 MHz, CDCl₃): δ 7.26-7.21 (m, 2H), 7.14 (d, J = 9.5 Hz, 2H),

4.31-4.17 (m, 2H), 3.92-3.83 (m, 2H), 3.19-3.18-3.16 (m, 1H), 2.13-2.11

(m, 1H), 1.71-1.69 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H)

General procedure for the synthesis symmetrical urea^26,27

12d

Diethyl 2-(4-Methoxyphenyl)cyclopropane-1,1-dicarboxylate (1a):

¹H-NMR (400 MHz, CDCl₃): δ 7.10 (d, J = 8.6 Hz, 2H), 6.79 (d, J = 8.6 Hz,

2H), 4.22 (m, 2H), 3.84 (m, 2H), 3.75 (s, 3H), 3.15 (t, J = 8.3 Hz, 1H), 2.12-

2.19 (m, 1H), 1.68-1.65 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.1

Hz, 3H)

Diethyl 2-(3,4-dimethoxyphenyl)cyclopropane-1,1-dicarboxylate (1b):

^12d1H-NMR (400 MHz, CDCl₃): δ 6.75-6.73 (m, 3H), 4.24-4.21 (m, 2H),

3.85-3.84 (m, 8H), 3.17 (t, J = 7.1 Hz, 1H), 2.12-2.11 (m, 1H), 1.69-1.67

(m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H)

(i) To a mixed solution of 2-hydroxyisoindoline-1,3-dione (10 mmol, 1.63

g) in DMSO (15 mL) and anhydrous potassium carbonate (8 mmol, 1.2 g)

benzyl bromide (20 mmol, 3.42 g) was added and the resulting mixture

was stirred for 24 h at room temperature. After that, 30 mL of cool water

was added and the resulting mixture was allowed to stand for 30 minutes.

The obtained precipitate was filtered and washed with water (3×5 mL).

Then the precipitate was recrystallized from ethanol and give the product

N-benzyloxyphthalimide as white needle like crystals.

Diethyl 2-(4-(dimethylamino)phenyl)cyclopropane-1,1-dicarboxylate

(1c):^{30 1}H-NMR (400 MHz, CDCl₃): δ7.06 (d, J = 8.8 Hz, 1H), 6.62 (d, J =

8.6 Hz, 1H), 4.27-4.15 (m, 2H), 3.90-3.83 (m, 2H), 3.14 (t, J = 9.0 Hz, 1H),

2.90 (s, 6H),2.12 (dd, J = 5.0, 3.2 Hz, 1H), 1.66 (dd, J = 5.0, 4.1 Hz,

1H),1.28 (t, J = 6.9 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H)

Diethyl 2-p-tolylcyclopropane-1,1-dicarboxylate (1d): ^12d

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(ii) A mixture of N-benzyloxyphthalimide (4 mmol, 1.0 g), acetic acid (4 mL)

and hydrochloric acid (aq. 37 %) (1.5 mL) was refluxed for 1.5 hours. The

reaction mixture was cooled to room temperature and concentrated. Then

cold water (10 mL) was added to the solid residue, and the suspension

was adjusted to alkaline by addition of 10% sodium hydroxide solution.

The obtained solution was subsequently extracted with CH₂Cl₂(3×15 mL),

and the combined organic phases were dried over anhydrous Na₂SO₄and

column chromatography (4:1 to 3:2, hexanes: ethyl acetate) to provide the

colorless solid product.

1-(benzyloxy)-3-(4-nitrobenzyl)oxy)urea (2c): Reaction time: 12 h, 4-

nitrophenylchloroformate (0.10 g, 0.35 mmol), Amine Hcl (0.07 g, 0.34

mmol), 2c (0.06 g, 0.21 mmol), Yield: 60 %, Nature: Yellow solid, R_f= 0.55

(ethyl acetate/hexane 40:60, ¹H-NMR (400 MHz, CDCl₃): δ 8.21 (d, J = 8.9

Hz, 2H), 7.79 (s, 1H), 7.50 (d, J = 8.6, 2H), 7.43-7.29 (m, 6H), 4.90 (s, 2H),

4.79 (s, 2H), ¹³C-NMR (100 MHz, CDCl₃): δ 159.8, 148.0, 142.5, 134.8,

129.4, 129.3, 129.1, 128.8, 123.8, 78.9, IR (neat): 3226, 2918, 2848, 1670,

1591, 1496, 1334, 1288, 1109, 848, 738, 696 cm^-1, HRMS (ESI, Q-TOF)

m/z: [M + H]+ Calculated for C₁₅H₁₆N₃O₅318.1090, found 318.1102

1-benzyl-3-(benzyloxy)urea (2d): ^{29b 1}H-NMR (400 MHz, CDCl₃): δ 7.35

– 7.26 (m, 8H), 7.20 – 7.18 (m, 2H), 7.04 (s, 1H), 5.89 (brs, 1H), 4.78 (s,

2H), and 4.39 (d, J = 6.0 Hz, 2H)

1-(benzyloxy)-3-phenylurea (2e): ^{28 1}H-NMR (400 MHz, CDCl₃): δ 7.45-

7.39 (m, 6H), 7.35-7.27 (m, 5H), 7.07 (dt, J = 8.4, 1.2 Hz, 1H), 4.89 (s, 2H).

1,3 bis(4-methoxyphenyl)urea (2f): In a round bottom flask, 1.0 equiv of

triphosgene was dissolved in dry dichloromethane (C = 0.1 mol/L) under

argon and cooled at 0 °C. A dichloromethane solution (C = 0.1 mol/L) of

the corresponding primary amine or aniline (6.0 equiv) and triethylamine

(6.0 equiv) was added slowly to the solution of triphosgene. The reaction

mixture was stirred for 15 h at room temperature. The volatiles were then

removed under reduced pressure. The resulting solid was washed with

cold water (310 mL) and filtrated to furnish the desired urea without

further purification. ¹H NMR (DMSO, 400 MHz, ppm) δ 8.45 (brd, J = 13.0

Hz, 2H), 7.33 (d, J = 8.4 Hz, 4H), 6.85 (d, J = 9.0 Hz, 4H), 3.71 (s, 6H)

Representative procedure and Substrate scope for the synthesis of

substituted ureido-malonates: A round-bottom flask equipped with a

magnetic stir bar was charged with donor-acceptor cyclopropane 1,

substituted urea 2 and Lewis acid (0.3 equiv) under nitrogen atmosphere.

DCM (2 mL) was added as a solvent to the reaction mixture and stirred at

room temperature until completion of the reaction (as monitored by TLC).

The solvent was evaporated on a rotary evaporator and further purified by

silica gel column chromatography with ethyl acetate/hexane (2:8 v/v) as

eluent.

concentrated to a final volume of 10 mL.

(iii) To the final concentrate obtained above 6M HCl (5 mL) was added to

it under stirring at 0-5 °C. After further stirring for another 1 hour at room

temperature, the solid was filtered, washed with CH₂Cl₂(10 mL) and dried

extensively in vacuo at 45 °C. The product was obtained as a white solid.

(iv) To a solution of O-Benzylhydroxylamine hydrochloride (20.0 g, 125.30

mmol) in dichloromethane (313 mL) was added triethylamine (17.264 mL,

125.30 mmol) at 0 °C and stirred for 10 minutes before the addition of 1,1′-

Carbonyldiimidazole (10.16 g, 62.65 mmol) over a period of 15 minutes in

3 portions. The reaction mixture was stirred at room temperature for 24

hours. The reaction was quenched with water (100 mL) and extracted with

dichloromethane (3 x 400 mL). The combined organic phases were dried

over anhydrous Na₂SO₄and concentrated under reduced pressure. The

crude product was purified via column chromatography (4:1 to 3:2,

hexanes: ethyl acetate) to provide the white solid product (14.1 g, 51.78

mmol, 82 %). R_f= 0.25 (3:2, hexanes: ethyl acetate)

1,3-bis(benzyloxy)urea (2a):^{27 1}H NMR (500 MHz, CDCl₃): ¹H NMR (400

MHz, CDCl₃): δ 7.59 (brs, 2H), 7.41–7.27 (m, 10H), 4.78 (s, 4H)

1, 3-dibenzylurea (2b):²⁸To a solution of amine (1.0 equiv.) in CH₂Cl₂was

added successively DABCO (0.1 equiv.) and a solution of (Boc)₂O (0.5

equiv.). After the completion of the reaction as detected by TLC, the

reaction mixture was cooled to 0 °C, n-hexane was then added, the

resulting solid was collected and further washed with cold water and diethyl

1

ether to afford the corresponding product. H NMR (400 MHz, DMSO-d₆)

δ 7.33-7.20 (m, 10H), 6.43 (t, J = 5.8 Hz, 2H), 4.23 (d, J = 6.4 Hz, 4H)

General procedure for the synthesis of unsymmetrical ureas^29a

:

(i) Amine hydrochloride was suspended in dry dichloromethane (DCM)

(200 mL) and pyridine (7.9 g, 10 mmol). 4-Nitrophenylchloroformate (20.16

g, 10 mmol) dissolved in DCM (100 mL) was added dropwise while stirring

at room temperature for 45 min. After the addition was completed, the

reaction mixture was refluxed for 6 h and then cooled to RT, diluted with

DCM (200 mL), washed sequentially with 1N HCl, H₂O, 1M sodium

bicarbonate solution, water, and brine. The DCM layer was dried over

sodium sulfate and evaporated under vacuum. The crude product was

purified by flash chromatography using a mixture of ethyl acetate/hexane.

(ii) To a solution of O-Benzylhydroxylamine hydrochloride (20.0 g, 125.30

mmol) in dichloromethane (313 mL) was added triethylamine (17.264 mL,

125.30 mmol) at 0 °C and stirred for 10 minutes before the addition of 4-

nitrophenyl (benzyloxy)carbamate over a period of 15 minutes in 3 portions.

The reaction mixture was stirred at room temperature for 24 hours. The

reaction mixture was extracted with dichloromethane (3 x 400 mL). The

combined organic phase was dried over anhydrous Na₂SO₄and

concentrated under reduced pressure. The crude product was purified via

The detailed procedure for the synthesis of 3a: A round-bottom flask

equipped with a magnetic stir bar was charged with 1a (0.05 g, 0.18 mmol),

2a (0.05 g, 0.18 mmol) and InCl₃(0.01 g, 0.54 mmol) under nitrogen

atmosphere. DCM (2 mL) was added as a solvent to the reaction mixture

and stirred at room temperature until completion of the reaction (as

monitored by TLC). The solvent was evaporated on a rotary evaporator

and further purified by silica gel column chromatography taking ethyl

acetate/hexane (2:8 v/v) as eluent to afford 3a (0.09 g, 90% yield).

Diethyl

2-(2-(1,3-bis(benzyloxy)ureido)-2-(4-

methoxyphenyl)ethyl)malonate (3a): Reaction time: 8 h, 1a (0.05 g, 0.18

mmol), 2a (0.05 g, 0.18 mmol), 3a (0.09 g, 0.16 mmol), Yield: 90 %, Nature:

White viscous liquid, R_f= 0.55 (ethyl acetate/hexane 30:70)

¹H-NMR (400 MHz, CDCl₃): δ 8.00 (s, 1H), 7.40-7.22 (m, 10H), 7.02 (d, J

= 7.2 Hz, 2H), 6.84 (d, J = 8.7 Hz, 2H), 5.16 (t, J = 7.8 Hz, 1H), 4.85-4.74

(m, 2H), 4.60 (brs, 1H), 4.39 (brd, J = 9.4 Hz, 1H), 4.24-4.08 (m, 4H), 3.78

(s, 3H), 3.42 (t, J = 7.1 Hz, 1H), 2.72-2.59 (m, 2H), 1.26 (t, J = 7.4 Hz, 3H),

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1.24 (t, J = 7.3 Hz, 3H), ¹³C-NMR (100 MHz, CDCl3): δ 169.2, 169.0, 160.3,

159.5, 135.7, 134.3, 130.0, 129.3, 129.1, 128.8, 128.6, 113.8, 79.0, 78.2,

61.8, 61.7, 60.9, 55.3, 49.4, 30.1, 14.1, 14.1, IR (neat): 3053, 1726, 1514,

1263, 1178, 1029

Hz, 2H), 6.89-6.80 (m, 2H), 6.71 (d, J = 8.0 Hz, 1H), 5.90 (s, 2H), 5.09 (t,

J = 8.0 Hz, 1H), 4.78 (s,2H), 4.62 (brs,1H), 4.42 (brd, J =9.4 Hz, 1H), 4.22-

4.06 (m, 4H), 3.40 (t, J = 7.4 Hz, 1H), 2.67-2.54 (m, 2H), 1.27-1.20 (m, 6H),

¹³C-NMR (100 MHz, CDCl3): δ 169.16, 168.9, 160.1, 147.7, 147.5, 135.7,

134.2, 131.1, 129.3, 129.3, 129.1, 128.8, 128.6, 122.4, 109.0, 108.2, 101.1,

79.1, 78.2, 61.7, 61.2, 49.3, 30.3, 14.1, 14.1, IR (neat): 2981, 1727, 1442,

1236, 1035, 746, 699 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated

for C₃₁H₃₄N₂O₉579.2328, found 579.2343

cm^-1, HRMS (ESI, Q-TOF) m/z: [M + Na]+ Calculated for C₃₁H₃₆N₂O₈

587.2369, found 587.2376

Diethyl

2-(2-(1,3-bis(benzyloxy)ureido)-2-(3,4-

dimethoxyphenyl)ethyl)malonate (3b): Reaction time: 7.5 h, 1b (0.10 g,

0.31 mmol), 2a (0.08 g, 0.31 mmol), 3b (0.16 g, 0.27 mmol), Yield: 87 %,

Diethyl

2-(2-(1,3-bis(benzyloxy)ureido)-2-(2,4,6-

1

Nature: White viscous liquid, R_f= 0.50 (ethyl acetate/hexane 40:60), H-

trimethoxyphenyl)ethyl)malonate (3f): Reaction time: 1.5 h, 1f (0.13 g,

0.37 mmol), 2a (0.10 g, 0.37 mmol), 3f (0.21 g, 0.34 mmol), Yield: 94 %,

Nature: White viscous liquid, R_f= 0.55 (ethyl acetate/hexane 35:65)

¹H-NMR (400 MHz, CDCl₃): δ 8.04 (s, 1H), 7.45-7.33 (m, 5H), 7.31-7.22

(m, 3H), 7.00 (d, J = 8.0 Hz, 2H), 6.14 (s, 2H), 5.88 (t, J = 8.2 Hz, 1H),

4.94-4.80 (m,2H), 4.64 (brs,1H), 4.48 (brd, J = 9.6 Hz, 1H), 4.29-4.10 (m,

4H), 3.83 (s, 3H), 3.79 (s, 6H), 3.44 (t, J = 7.1 Hz, 1H), 2.97-2.77 (m, 2H),

1.34-1.24(m, 6H), ¹³C-NMR (100 MHz, CDCl₃): δ 169.6, 169.5, 161.2,

160.5, 159.8, 136.2, 134.9, 129.1, 129.0, 128.6, 128.5, 128.5, 128.3, 105.5,

90.7, 78.7, 78.6, 78.0, 61.3, 61.3, 55.6, 55.3, 53.5, 50.1, 14.1, IR (neat):

2918, 1727, 1605, 1454, 1204, 1151, 1122, 733, 698 cm^-1, HRMS (ESI, Q-

TOF) m/z: [M + Na]+ Calculated for C₃₃H₄₀N₂O₁₀, 647.2581 found

647.2586

NMR (400 MHz, CDCl₃): δ 7.99 (s, 1H), 7.38-7.20 (m, 8H), 7.00 (d, J = 6.8

Hz, 2H), 6.94 (d, J = 8.3 Hz, 1H), 6.89 (s, 1H), 6.78 (d, J = 8.1 Hz, 1H),

5.15 (t, J = 7.8 Hz, 1H), 4.86-4.74 (m, 2H), 4.60 (brs, 1H), 4.37 (brd, J =

8.9 Hz 1H), 4.24-4.06 (m, 4H), 3.84 (s, 3H), 3.78 (s, 3H), 3.42 (t, J = 7.4

Hz, 1H), 2.65 (t, J = 7.8 Hz, 2H), 1.25 (t, J = 7.2 Hz, 3H), 1.23 (t, J = 7.3

Hz, 3H),¹³C-NMR (100 MHz, CDCl₃): δ 169.2, 169.0, 160.2, 159.7, 148.9,

148.7, 135.6, 135.1, 134.3, 129.7, 129.3, 129.1, 128.8, 128.7, 128.6, 121.0,

111.9, 110.7, 78.8, 78.2, 61.7, 61.1, 55.9, 49.3, 30.1, 14.1, 14.1, IR (neat):

3332, 2958, 1726, 1697, 1514, 1444, 1369, 912, 856 cm^-1, HRMS (ESI, Q-

TOF) m/z: [M + Na]+ Calculated for C₃₂H₃₈N₂O₉617.2475, found 617.2498

Diethyl

2-(2-(1,3-bis(benzyloxy)ureido)-2-(4-

(dimethylamino)phenyl)ethyl)malonate (3c): Reaction time: 8 h, 1c

(0.22 g, 0.73 mmol), 2a (0.20 g, 0.73 mmol), 3c (0.36 g, 0.63 mmol), Yield:

86 %, Nature: White viscous liquid, R_f= 0.55 (ethyl acetate/hexane 30:70),

¹H-NMR (400 MHz, CDCl₃): δ 7.98 (s, 1H), 7.36-7.22 (m, 10H), 7.01 (d, J

=7.5 Hz, 2H), 6.65 (d, J = 7.5 Hz, 2H), 5.12 (t, J = 7.9 Hz, 1H), 4.83-4.73

(m, 2H), 4.56 (brs, 1H), 4.37 (brd, J =8.9 Hz, 1H), 4.23-4.07 (m, 4H), 3.41

(t, J = 7.3 Hz, 1H), 2.91 (s, 6H), 2.64 (t, J = 7.6 Hz, 2H), 1.28-1.20 (m, 6H),

¹³C-NMR (100 MHz, CDCl3): δ 169.3, 169.2, 160.4, 150.4, 135.9, 134.5,

129.7, 129.3, 129.0, 128.8, 128.6, 128.6, 112.3, 78.9, 78.2, 61.7, 61.7,

61.0, 49.5, 40.6, 30.12, 14.2, 14.1, IR (neat): 2981, 1729, 1613, 1281,

1162, 750 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated for

C₃₂H₃₉N₃O₇578.2869, found 578.2866

Dimethyl

2-(2-(1,3-bis(benzyloxy)ureido)-2-(4-

methoxyphenyl)ethyl)malonate (3g): Reaction time: 12 h, 1g (0.09 g,

0.36 mmol), 2a (0.10 g, 0.36 mmol), 3g (0.17 g, 0.36 mmol), Yield: 89 %,

Nature: White viscous liquid, R_f= 0.55 (ethyl acetate/hexane 30:70)

¹H-NMR (400 MHz, CDCl₃): δ 7.98 (s, 1H), 7.39-7.25 (m, 10H), 7.01 (d, J

= 7.0 Hz, 2H), 6.84 (d, J = 8.5 Hz, 2H), 5.14 (t, J = 7.9 Hz, 1H), 4.83-4.75

(m,2H), 4.57 (brs,1H), 4.37 (brd, J = 9.5 Hz, 1H), 3.78 (s, 3H), 3.74 (s, 3H),

3.70 (s, 3H), 3.46 (t, J = 7.8 Hz, 1H), 2.74-2.59(m, 2H), ¹³C-NMR (100 MHz,

CDCl₃): δ 169.6, 169.4, 160.2, 159.6, 135.7, 135.1, 134.3, 130.0, 129.3,

129.1, 129.0, 128.8, 128.7, 113.9, 79.0, 78.9, 78.2, 60.8, 55.3, 52.9, 52.8,

49.1, 30.2, IR (neat): 2928, 1732, 1513, 1453, 1250, 1028, 748, 699 cm^-1

HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated for C₂₉H₃₂N₂O₈, 537.2237

found 537.2242

Diethyl 2-(2-(1,3-bis(benzyloxy)ureido)-2-(p-tolyl)ethyl)malonate (3d):

Reaction time: 24 h, 1d (0.10 g, 0.37 mmol), 2a (0.10 g, 0.37 mmol), 3d

(0.15 g, 0.28 mmol), Yield: 78 %, Nature: White viscous liquid, R_f= 0.55

Diisopropyl

2-(2-(1,3-bis(benzyloxy)ureido)-2-(3,4-

1

(ethyl acetate/hexane 30:70), H-NMR (400 MHz, CDCl₃): δ 8.00 (s, 1H),

dimethoxyphenyl)ethyl)malonate (3h): Reaction time: 10 h, 1h (0.19 g,

0.55 mmol), 2a (0.15 g, 0.55 mmol), 3h (0.32 g, 0.52 mmol), Yield: 94.8 %,

7.36-7.24 (m, 10H), 7.12 (d, J = 7.8 Hz, 2H), 7.01 (d, J = 6.7 Hz, 2H), 5.18

(t, J = 7.9 Hz, 1H), 4.83-4.75 (m, 2H), 4.60 (brs,1H), 4.39 (brd, J = 9.5 Hz

1H), 4.23-4.08 (m, 4H), 3.44 (t, J = 7.4 Hz, 1H), 2.70-2.63 (m, 2H), 2.31 (s,

3H), 1.26 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.2 Hz, 3H), ¹³C-NMR (100 MHz,

CDCl3): δ 169.2, 169.0, 160.2, 138.1, 135.7, 134.3, 134.3, 129.3, 129.2,

129.0, 128.8, 128.7, 128.6, 78.9, 78.2, 61.7, 61.1, 49.3, 29.9, 21.2, 14.1,

14.1, IR (neat): 2980, 1727, 1451, 1200, 1152, 1025, 741, 698 cm^-1, HRMS

(ESI, Q-TOF) m/z: [M + H]+ Calculated for C₃₁H₃₆N₂O₇549.2602, found

549.2601

1

Nature: White viscous liquid, R_f= 0.55 (ethyl acetate/hexane 20:80), H-

NMR (400 MHz, CDCl₃): δ 8.02 (s, 1H), 7.37-7.24 (m, 8H), 7.02 (d, J =7.0

Hz, 2H), 6.96 (d, J =8.2 Hz, 1H), 6.91 (s, 1H), 6.80 (d, J = 8.2 Hz, 1H), 5.17

(t, J = 7.8 Hz, 1H), 5.10-4.98 (m, 2H), 4.85-4.76 (m, 2H), 4.63 (brs, 1H),

4.40 (brd, J = 8.5 Hz, 1H), 3.85 (s, 3H), 3.79 (s, 3H), 3.36 (t, J = 7.2 Hz,

1H), 2.65 (t, J = 7.6 Hz, 2H), 1.26-1.21 (m, 12H), ¹³C-NMR (100 MHz,

CDCl₃): δ 168.7, 168.6, 160.1, 148.9, 148.7, 135.6, 134.3, 129.7, 129.2,

129.1, 129.0, 128.7, 128.6, 121.0, 111.9, 110.7, 78.8, 78.1, 69.2, 61.1,

55.9, 55.8, 49.6, 21.7,21.6, 21.6, 21.6, IR (neat): 2980, 1720, 1516, 1454,

1373, 1257, 1238, 1143, 1099, 1026, 736, 698 cm^-1, HRMS (ESI, Q-TOF)

m/z: [M + H]+ Calculated for C₃₄H₄₂N₂O₉623.2969, found 623.2986

Diethyl 2-(2-(1,3-bis(benzyloxy)ureido)-2-(furan-3-yl)ethyl)malonate

(3i): Reaction time: 12 h, 1i (0.10 g, 0.39 mmol), 2a (0.11 g, 0.39 mmol),

Diethyl

2-(2-(benzo[d][1,3]dioxol-5-yl)-2-(1,3-

bis(benzyloxy)ureido)ethyl)malonate (3e): Reaction time: 10 h, 1e (0.11

g, 0.37 mmol), 2a (0.10, 0.37 mmol), 3e (0.18 g, 0.32 mmol), Yield: 87 %,

1

Nature: White viscous liquid, R_f= 0.55 (ethyl acetate/hexane 40:60), H-

NMR (400 MHz, CDCl₃): δ 8.00 (s, 1H), 7.36-7.21 (m, 8H), 7.01 (d, J = 7.4

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3i (0.15 g, 0.29 mmol) , Yield: 73 %, Nature: White viscous liquid, R_f= 0.55

(ethyl acetate/hexane 30:70), ¹H-NMR (400 MHz, CDCl₃): δ 8.06 (s,

1H),7.42-7.35 (m, 6H), 7.33-7.27 (m, 3H), 7.04 (d, J = 7.6 Hz, 2H), 6.37-

6.33 (m, 2H), 5.38 (t, J = 7.7 Hz, 1H), 4.89-4.80 (m, 2H), 4.53 (brd, J = 9.5

Hz,1H), 4.36(brd, J = 9.9 Hz,1H), 4.27-4.12 (m, 4H), 3.47 (t, J = 7.2 Hz,1H),

2.75-2.65 (m, 1H), 2.62-2.52 (m, 1H), 1.27 (t, J = 6.9 Hz, 3H), 1.26 (t, J =

7.0 Hz, 3H), ¹³C-NMR (100 MHz, CDCl₃): δ 169.0, 168.8, 151.4, 142.4,

135.8, 134.2, 129.3, 129.2, 129.0, 128.7, 128.6, 110.5, 108.9, 78.8, 78.3,

61.8, 54.8, 49.0, 28.7, 14.1, IR (neat): 3358, 2980, 2924, 2364, 1730, 1456,

1371, 12671151, 1028, 742, 700 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+

Calculated for C₂₈H₃₂N₂O₈525.2237, found 525.2232

1467, 1178, 1028, 734 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated

for C₃₁H₃₆N₂O₇, 549.2601 found 549.2608

Diethyl

2-(2-(1-(benzyloxy)-3-phenylureido)-2-(4-

methoxyphenyl)ethyl)malonate (3m): Reaction time: 8 h, 1a (0.05 g,

0.18 mmol), 2e (0.04 g, 0.18 mmol), 3m (0.09 g, 0.16 mmol), Yield: 91 %,

Nature: White viscous liquid, R_f= 0.55 (ethyl acetate/hexane 30:70)

¹H-NMR (400 MHz, CDCl₃): δ 7.54 (s, 1H), 7.44-7.32 (m, 7H), 7.24-7.16

(m, 3H), 7.06-6.97 (m, 1H), 6.86 (d, J = 8.6 Hz, 2H), 5.32 (t, J = 7.8 Hz,

1H), 4.79(brs, 1H), 4.66 (brd, J = 9.5 Hz, 1H), 4.26-4.08 (m, 4H), 3.78 (s,

3H), 3.49 (t, J = 7.2 Hz, 1H), 2.75 (dt, J = 7.6, 2.7 Hz, 2H), 1.26 (t, J = 7.1

Hz, 3H), 1.24 (t, J = 7.3 Hz, 3H), ¹³C-NMR (100 MHz, CDCl₃): δ 169.3,

169.1, 159.4, 157.2, 137.7, 134.8, 130.0, 129.8, 129.4, 129.3, 129.1, 128.9,

123.6, 119.2, 113.9, 79.6, 61.8, 61.7, 60.6, 55.3, 49.4, 30.3, 14.1, 14.1, IR

(neat): 2916, 2848, 1728, 1685, 1514, 1263, 1178 cm^-1, HRMS (ESI, Q-

TOF) m/z: [M + H]+ Calculated for C₃₀H₃₄N₂O₇, 535.2444 found 535.2454

Representative procedure and Substrate scope for the synthesis of

Diethyl

2-(2-(1,3-bis(benzyloxy)ureido)-4-phenylbut-3-en-1-

yl)malonate (3j): Reaction time: 12 h, 1j (0.11 g, 0.36 mmol), 2a (0.10 g,

0.36 mmol), 3j (0.16 g, 0.28 mmol) , Yield: 78 %, Nature: White viscous

liquid, R_f= 0.55 (ethyl acetate/hexane 30:70), ¹H-NMR (400 MHz, CDCl₃)

(only for trans isomer) 8.04 (s, 1H), 7.38-7.12 (m, 13H), 7.04 (d, J = 7.4 Hz,

2H), 6.53 (d, J = 15.7 Hz , 1H), 6.14 (q, J = 8.6 Hz, 1H), 5.69-5.59 (m, 1H),

4.76 (s, 2H), 4.62-4.59 (m, 2H), 4.17-3.96 (m, 4H), 3.45 (t, J = 7.4 Hz, 1H),

2.40 (t, J = 7.8 Hz, 2H), 1.22-1.07 (m, 6H), ¹³C-NMR (100 MHz, CDCl₃):

169.2, 169.1, 168.9, 168.8, 160.4, 160.2, 138.3, 136.3, 135.8, 135.7, 134.3,

130.9, 129.3, 129.2, 129.1, 129.0, 128.8, 128.6, 128.4, 128.1, 128.0, 126.7,

125.1, 79.1, 79.0, 78.2, 64.6, 61.7, 61.6, 51.6, 49.2, 31.7, 30.9, 25.4, 14.1,

14.0, IR (neat): 3325, 3030, 1726, 1454, 1369, 1224, 1151, 1028, 970, 748,

696 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated for C₃₂H₃₇N₂O₇

561.2601, found 561.2607,(E: Z = 74: 26)

substituted Tetrahydropyrimidinones: To

a round-bottom flask

equipped with a magnetic stirring bar was charged uredo-malonate 3 (1

equiv), Iodine (1.2 equiv) and DBU (2.5 equiv). DCM was added as a

solvent and stirred at room temperature in open air until completion of the

reaction (as monitored by TLC). The solvent was evaporated on a rotary

evaporator and further purified by silica gel column chromatography with

ethyl acetate/hexane as eluent.

Detailed procedure for the synthesis of 4a: To a round-bottom flask

equipped with a magnetic stir bar was charged 3a (0.070 g, 0.12 mmol),

Iodine (0.018 g, 0.14 mmol) and DBU (0.045 g, 0.29 mmol). DCM (2 mL)

was added as a solvent and stirred at room temperature in the open air

until completion of the reaction (as monitored by TLC). The solvent was

evaporated on a rotary evaporator and further purified by silica gel column

chromatography taking ethyl acetate/hexane as eluent to afford 4a (0.064

g, 92 % yield).

Diethyl

2-(2-(1-(benzyloxy)-3-((4-nitrobenzyl)oxy)ureido)-2-(4-

methoxyphenyl)ethyl)malonate (3k): Reaction time: 12 h, 1a (0.03 g,

0.15 mmol), 2c (0.05 g, 0.15 mmol), 3k (0.08 g, 0.13 mmol), Yield: 85 %,

Nature: White viscous liquid, R_f= 0.55 (ethyl acetate/hexane 20:80)

¹H-NMR (400 MHz, CDCl₃): δ 8.18 (d, J = 8.7 Hz, 2H), 8.01 (s, 1H),7.46

(d, J = 8.7 Hz, 2H), 7.35-7.28 (m, 5H), 7.12 (d, J = 7.1 Hz, 2H), 6.85 (d, J

= 8.6 Hz, 2H), 5.16 (t, J = 7.7 Hz, 1H), 4.85 (s,2H), 4.63 (brs,1H), 4.45 (brd,

J = 9.5 Hz, 1H), 4.24-4.06 (m, 4H), 3.79 (s, 3H), 3.40 (t, J = 7.2 Hz, 1H),

2.67 (dt, J = 7.8, 2.4 Hz, 2H), 1.26 (t, J = 7.2 Hz, 3H), 1.24 (t, J = 7.3 Hz,

3H), ¹³C-NMR (100 MHz, CDCl3): δ 169.1, 168.9, 160.5, 159.6, 143.1,

134.3, 133.3, 133.2, 129.9, 129.4, 129.2, 129.1, 128.9, 123.7, 113.9, 79.1,

61.8, 61.7, 61.0, 55.3, 49.3, 30.1, 14.1, 14.1, IR (neat): 2925, 1728, 1519,

1454, 1345, 1251, 1030, 852, 741, 700 cm^-1, HRMS (ESI, Q-TOF) m/z: [M

+ H]+ Calculated for C₃₁H₃₅N₃O₁₀610.2408, found 610.2401

Diethyl

1,3-bis(benzyloxy)-6-(4-methoxyphenyl)-2-

oxotetrahydropyrimidine-4,4(1H)-dicarboxylate (4a): Reaction time: 2

h, 3a (0.07 g, 0.12 mmol), 4a (0.06 g, 0.11 mmol), Yield: 92 %, Nature:

White solid, Melting point: 109 °C, R_f= 0.55 (ethyl acetate/hexane 20:80),

¹H-NMR (400 MHz, CDCl₃): δ 7.42 (d, J = 7.8 Hz, 2H), 7.36-7.28 (m, 5H),

7.24-7.18 (m, 3H), 7.01(d, J = 7.6 Hz, 2H), 6.92 (d, J = 8.7 Hz, 2H), 5.28

(d, J = 9.5 Hz, 1H), 5.04 (dd, J = 9.5, 2.7 Hz, 2H), 4.46-4.37 (m, 2H), 4.31

(q, J= 7.0 Hz, 2H), 4.22-4.14 (m, 2H), 3.84 (s, 3H), 2.86 (dd, J =14.1, 2.5

Hz, 1H), 2.67 (dd, J =14.2, 4.6 Hz, 1H), 1.27 (t, J = 6.8 Hz, 3H), 1.22 (t, J

= 6.9 Hz, 3H), ¹³C-NMR (100 MHz, CDCl₃): δ 167.7, 166.3, 159.9, 158.9,

135.6, 135.2, 130.2, 129.6, 129.1, 128.9, 128.5, 128.3, 128.3, 114.1, 78.4,

78.0, 73.1, 62.9, 62.8, 61.1, 55.5, 37.1, 14.2, 13.9, IR (neat): 2907, 1726,

1511, 1244, 1172, 1004, 836, 649 cm^-1, HRMS (ESI, Q-TOF) m/z: [M +

H]+ Calculated for C₃₁H₃₄N₂O₈, 563.2393 found 563.2403

Diethyl

2-(2-(3-benzyl-1-(benzyloxy)ureido)-2-(4-

methoxyphenyl)ethyl)malonate (3l): Reaction time: 8 h, 1a (0.09 g, 0.36

mmol), 2d (0.10 g, 0.36 mmol), 3l (0.18 g, 0.33 mmol), Yield: 91 %, Nature:

White viscous liquid, R_f= 0.55 (ethyl acetate/hexane 20:80)

¹H-NMR (400 MHz, CDCl₃): δ 7.38-7.16 (m, 10H), 6.96 (brs, 2H), 6.83 (d,

J = 8.5 Hz, 2H), 5.99 (t, J = 5.9 Hz, 1H), 5.17 (t, J = 7.9 Hz, 1H), 4.74

(brs,1H), 4.59 (brs,1H), 4.30 (dd, J = 15.1, 5.4 Hz, 1H), 4.24-4.07 (m, 5H),

3.78 (s, 3H), 3.48 (t, J = 7.4 Hz, 1H), 2.77-2.63 (m, 2H),1.24 (q, J= 7.3 Hz,

6H), ¹³C-NMR (100 MHz, CDCl₃): δ 169.4, 169.2, 159.4, 138.5, 135.0,

130.1, 129.9, 129.3, 129.0, 128.9, 128.5, 127.3, 127.3, 113.7, 78.9, 61.7,

61.7, 55.3, 49.5, 43.9, 30.5, 14.2, 14.1, IR (neat): 3298, 2914, 2848, 1728,

Diethyl

1,3-bis(benzyloxy)-6-(3,4-dimethoxyphenyl)-2-

oxotetrahydropyrimidine-4,4(1H)-dicarboxylate (4b): Reaction time: 2

h, 3b (0.07 g, 0. 11 mmol), 4b (0.064 g, 0.10 mmol), Yield: 91 %, Nature:

White solid, Melting point: 115 °C, R_f= 0.55 (ethyl acetate/hexane 30:70),

¹H-NMR (400 MHz, CDCl₃): δ 7.43 (d, J = 7.3 Hz, 2H), 7.36-7.28 (m, 3H),

7.24-7.16 (m, 3H), 7.02 (d, J = 6.9 Hz, 2H), 6.94 (d, J = 8.7 Hz, 2H), 6.88

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European Journal of Organic Chemistry

FULL PAPER

(s, 3H), 5.29 (d, J = 9.7 Hz, 1H), 5.05 (d, J = 9.7 Hz, 2H), 4.48-4.39 (m,

2H), 4.31 (q, J = 7.1 Hz, 2H), 4.19 (q, J = 7.9 Hz, 2H), 3.91 (s, 3H), 3.89

(s, 3H), 2.86 (dd, J = 14.1, 11.6 Hz, 1H), 2.69 (dd, J = 14.2, 4.4 Hz, 1H),

1.27 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.0 Hz, 3H), ¹³C-NMR (100 MHz,

CDCl₃): δ 167.7, 166.3, 158.9, 149.2, 149.1, 135.5, 135.1, 130.5, 129.5,

129.0, 128.5, 128.3, 128.2, 120.1, 111.0, 110.5, 78.3, 78.0, 73.1, 62.9,

62.8, 61.4, 56.1, 56.1, 37.1, 14.1, 13.9, IR (neat): 2958, 1734, 1516, 1454,

1367, 1257, 1234, 1139, 1082, 1022, 912, 729, cm-1, HRMS (ESI, Q-TOF)

m/z: [M + H]+ Calculated for C₃₂H₃₆N₂O₉, 593.2499 found 593.2500

1080, 1004, 732, 697 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated

for C₃₁H₃₂N₂O₉, 577.2186 found 577.2192

Diethyl

1,3-bis(benzyloxy)-2-oxo-6-(2,4,6-

trimethoxyphenyl)tetrahydropyrimidine-4,4(1H)-dicarboxylate (4f):

Reaction time: 2 h, 3f (0.17 g, 0.28 mmol), 4f (0.14 g, 0.23 mmol), Yield:

82 %, Nature: Colourless liquid, R_f= 0.55 (ethyl acetate/hexane 25:75),

¹H-NMR (400 MHz, CDCl₃): δ 7.40 (d, J = 8.0 Hz, 2H), 7.33-7.16 (m, 6H),

7.11-7.05 (m, 2H), 6.15-6.03 (m, 2H), 5.30 (d, J = 9.5 Hz, 1H), 5.18 (dd, J

= 10.8, 4.9 Hz, 1H), 5.00 (d, J = 9.7 Hz, 1H), 4.89 (d, J = 10.0 Hz, 1H),

4.58 (d, J = 10.1 Hz, 1H), 4.32-4.20 (m, 2H), 4.19-4.07 (m, 2H), 3.89-3.74

(m, 6H), 3.68 (s, 3H), 3.13 (t, J = 11.9 Hz, 1H), 2.54 (dd, J = 13.5, 6.7 Hz,

1H), 1.24 (t, J = 7.2 Hz, 3H), 1.18 (t, J = 7.1 Hz, 3H), ¹³C-NMR (100 MHz,

CDCl₃): δ 167.9, 166.3, 161.3, 160.2, 159.4, 158.5, 136.0, 129.4, 129.1,

128.2, 128.1, 128.1, 106.0, 91.1, 90.8, 90.5, 78.8, 73.1, 62.6, 62.2, 55.9,

55.7, 55.4, 50.7, 33.5, 14.2, 13.9, IR (neat): 2923, 1756, 1589, 1556, 1193,

1118, 1018, 744, 698 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated

for C₃₃H₃₈N₂O₁₀, 623.2605 found 623.2620

Diethyl

1,3-bis(benzyloxy)-6-(4-(dimethylamino)phenyl)-2-

oxotetrahydropyrimidine-4,4(1H)-dicarboxylate (4c): Reaction time: 2

h, 3c (0.06 g, 0.10 mmol), 4c (0.05 g, 0.09 mmol), Yield: 94 %, Nature:

White solid, Melting point: 108 °C, R_f= 0.55 (ethyl acetate/hexane 30:70),

¹H-NMR (400 MHz, CDCl₃): δ 7.35 (d, J = 7.8 Hz, 2H), 7.28-7.21 (m, 3H),

7.21-7.16 (m, 2H), 7.15-7.10(m, 3H), 6.95 (d, J = 7.5 Hz, 2H), 6.66 (d, J =

8.7 Hz, 2H), 5.22 (d, J = 9.6 Hz, 1H), 4.96 (t, J = 10.5 Hz, 2H), 4.35-4.28

(m, 2H), 4.23 (q, J = 7.1 Hz, 2H), 4.15-4.06(m, 2H), 3.89 (s, 3H), 4.15-4.06

(m, 2H), 2.90 (s, 6H), 2.82 (dd, J = 14.6, 11.7 Hz, 1H), 2.58 (dd, J = 14.0,

4.5 Hz, 1H), 1.19 (t, J = 7.0 Hz, 3H), 1.14 (t, J = 7.2 Hz, 3H), ¹³C-NMR (100

MHz, CDCl₃): δ 167.8, 166.3, 159.0, 150.9, 135.7, 135.3, 129.6, 129.1,

128.6, 128.3, 128.2, 125.4, 112.4, 78.3, 78.0, 73.2, 62.8, 62.7, 61.1, 40.7,

37.1, 14.2, 13.9, IR (neat): 2980, 2935, 1734, 1614, 1523, 1452, 1355,

1261, 1217, 1008, 931 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated

for C₃₂H₃₇N₃O₇, 576.2710 found 576.2706

Dimethyl

1,3-bis(benzyloxy)-6-(4-methoxyphenyl)-2-

oxotetrahydropyrimidine-4,4(1H)-dicarboxylate (4g): Reaction time: 2

h, 3g (0.12 g, 0.21 mmol), 4g (0.10 g, 0.19 mmol), Yield: 90 %, Nature:

White solid, Melting point: 120 °C, R_f= 0.55 (ethyl acetate/hexane 30:70),

¹H-NMR (400 MHz, CDCl₃): δ 7.42 (d, J = 7.8 Hz, 2H), 7.37-7.30 (m, 5H),

7.25-7.18 (m, 3H), 7.02 (d, J = 7.6 Hz, 2H), 6.92 (d, J = 8.6 Hz, 2H), 5.26

(d, J = 9.6 Hz, 1H), 5.00 (dd, J = 17.5, 8.0 Hz, 2H), 4.44-4.32 (m, 2H), 3.84

(d, J = 1.8 Hz, 6H), 3.73 (s, 3H), 2.90 (dd, J = 15.0, 11.7 Hz, 1H), 2.67

(dd, J = 14.0, 4.6 Hz, 1H), ¹³C-NMR (100 MHz, CDCl₃): δ 168.3, 166.6,

159.9, 158.7, 135.4, 135.1, 130.0, 129.6, 129.3, 128.9, 128.5, 128.5, 128.4,

128.3, 114.1, 78.5,78.0, 73.1, 61.1, 55.5, 53.7, 53.6, 37.3, IR (neat): 2954,

1741, 1612, 1513, 1454, 1246, 1218, 1028, 733, 698 cm^-1, HRMS (ESI, Q-

TOF) m/z: [M + H]+ Calculated for C₂₉H₃₀N₂O₈, 535.2080 found 535.2090

Diethyl

1,3-bis(benzyloxy)-2-oxo-6-(p-tolyl)tetrahydropyrimidine-

4,4(1H)-dicarboxylate (4d): Reaction time: 2 h, 3d (0.05 g, 0.08 mmol),

4d (0.04 g, 0.82 mmol), Yield: 95 %, Nature: White solid, Melting point:

101 °C, R_f= 0.55 (ethyl acetate/hexane 20:80), ¹H-NMR (400 MHz,

CDCl₃): δ 7.39 (d, J = 7.9 Hz, 2H), 7.32-7.22 (m, 5H), 7.21-7.12 (m, 5H),

6.95 (d, J = 7.6 Hz, 2H), 5.25 (d, J = 9.5 Hz, 1H), 5.01 (d, J = 9.4 Hz, 1H),

4.45-4.35 (m, 2H), 4.26 (q, J = 6.9 Hz, 2H), 4.17-4.04 (m, 2H), 2.84 (dd, J

= 14.4, 11.4 Hz, 1H), 2.64 (dd, J = 14.0, 4.6 Hz, 1H), 2.35 (s, 3H) 1.23 (t,

J = 7.2 Hz, 3H), 1.17 (t, J = 7.0 Hz, 3H), ¹³C-NMR (100 MHz, CDCl₃): δ

167.6, 166.2, 158.9, 138.5, 135.6, 135.2, 135.2, 129.5, 129.4, 129.0, 128.4,

128.3, 128.2, 127.6, 78.3, 77.9, 73.1, 62.8, 61.4, 37.1, 21.3, 14.1, 13.9, IR

(neat): 3001, 2981, 1733, 1453, 1367, 1215, 1009, 733, 697 cm^-1, HRMS

(ESI, Q-TOF) m/z: [M + H]+ Calculated for C₃₁H₃₄N₂O₇, 547.2444 found

547.2419

Diisopropyl

1,3-bis(benzyloxy)-6-(3,4-dimethoxyphenyl)-2-

oxotetrahydropyrimidine-4,4(1H)-dicarboxylate (4h): Reaction time: 2

h, 3h (0.10 g, 0.16 mmol), 4h (0.09 g, 0.14 mmol), Yield: 90 %, Nature:

White solid, Melting point: 105 °C, R_f= 0.55 (ethyl acetate/hexane 30:70),

¹H-NMR (400 MHz, CDCl₃): δ 7.45 (d, J = 7.8 Hz, 2H), 7.35-7.27 (m, 3H),

7.24-7.17 (m, 3H), 7.02 (d, J = 7.7 Hz, 2H), 6.95-6.84 (m, 3H), 5.31 (d, J =

9.4 Hz, 1H), 5.20-4.98 (m, 4H), 4.50-4.41 (m, 2H), 3.91 (s, 3H), 3.89 (s,

3H), 3.84 (s, 3H), 2.81 (dd, J = 14.8, 11.3 Hz, 1H), 2.66 (dd, J = 14.1, 4.5

Hz, 1H), 1.28-1.15 (m, 12H), ¹³C-NMR (100 MHz, CDCl₃): δ 167.2, 166.0,

159.1, 149.3, 149.2, 135.7, 135.3, 130.8, 129.5, 129.0, 128.5, 128.3, 128.2,

120.1, 111.0, 110.4, 78.2, 78.0, 73.2, 71.0, 70.7, 61.4, 56.1, 37.1, 21.7,

21.7, 21.6, 21.5, IR (neat): 2982, 1729, 1516, 1455, 1373, 1263, 1236,

1104, 750, 699 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated for

C₃₄H₄₀N₂O₉, 621.2812 found 621.2786

Diethyl

6-(benzo[d][1,3]dioxol-5-yl)-1,3-bis(benzyloxy)-2-

oxotetrahydropyrimidine-4,4(1H)-dicarboxylate (4e): Reaction time: 2

h, 3e (0.09 g, 0.16 mmol), 4e (0.08 g, 0.14 mmol), Yield: 90 %, Nature:

White solid, Melting point: 112 °C, R_f= 0.55 (ethyl acetate/hexane 30:70),

¹H-NMR (400 MHz, CDCl₃): δ 7.42 (d, J = 7.7 Hz, 2H), 7.36-7.28 (m, 3H),

7.26-7.19 (m, 3H), 7.08 (dd, J = 7.1, 1.9 Hz, 2H), 6.90 (s, 1H), 6.80 (s, 2H),

5.98 (s, 2H), 5.28 (d, J = 9.6 Hz, 1H), 5.04 (t, J = 9.1 Hz, 2H), 4.50 (d, J =

9.3 Hz, 1H), 4.40 (dd, J = 11.3, 4.6 Hz, 1H), 4.34-4.26 (m, 2H), 4.23-4.14

(m, 2H), 2.81 (dd, J = 14.8, 11.4 Hz, 1H), 2.66 (dd, J = 14.0, 4.4 Hz, 1H),

1.27 (t, J = 7.2 Hz, 3H), 1.22 (t, J = 7.2 Hz, 3H), ¹³C-NMR (100 MHz,

CDCl₃): δ 167.6, 166.1, 158.9, 148.0, 147.9, 135.5, 135.2, 132.0, 129.5,

129.1, 128.4, 128.3, 121.5, 108.2, 107.5, 101.4, 78.3, 77.9, 73.0, 62.9,

62.8, 61.4, 37.2, 14.1, 13.9, IR (neat): 1962, 2888, 1734, 1489, 1446, 1203,

Diethyl 1,3-bis(benzyloxy)-6-(furan-3-yl)-2-oxotetrahydropyrimidine-

4,4(1H)-dicarboxylate (4i): Reaction time: 2 h, 3i (0.06 g, 0.11 mmol), 4i

(0.04 g, 0.09 mmol), Yield: 82 %, Nature: Colourless liquid, R_f= 0.55 (ethyl

1

acetate/hexane 20:80), H-NMR (400 MHz, CDCl₃): δ 7.47-7.41 (m, 1H),

7.38 (dd, J = 7.7, 2.0 Hz, 2H), 7.33-7.21 (m, 5H), 7.21-7.13 (m, 2H), 6.42-

6.32 (m, 2H), 5.22 (d, J = 9.6 Hz, 1H), 5.01 (dd, J = 14.4, 9.1 Hz, 2H), 4.57

(dd, J = 11.0, 4.6 Hz, 1H), 4.35-4.09 (m, 5H), 3.08 (dd, J = 14.6, 11.0 Hz,

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FULL PAPER

1H), 2.68 (dd, J = 14.1, 4.5 Hz, 1H), 1.21 (dt, J = 7.0, 3.2 Hz, 6H), ¹³C-

NMR (100 MHz, CDCl₃): δ 167.5, 166.2, 158.1, 150.0, 142.7, 135.6, 135.0,

129.7, 129.0, 128.6, 128.3, 128.2, 110.7, 109.9, 78.3, 78.1, 72.7, 62.9,

62.9, 54.7, 33.6, 14.1, 13.9, IR (neat): 2981, 2337, 1720, 1369, 1265, 1192,

1091 1014 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated for

C₂₈H₃₀N₂O₈, 523.2080 found 523.2051

1a (0.10 g, 0.34 mmol), 2a (0.09 g, 0.34 mmol) and InCl₃(0.02 g, 0.10

mmol) under nitrogen atmosphere. DCM (3 mL) was added as a solvent

to the reaction mixture and stirred at room temperature until completion of

the reaction (as monitored by TLC). Iodine (0.05 g, 0.40 mmol) and DBU

(0.15 g, 1.02 mmol) were charged and allowed to stir until completion of

the reaction (as monitored by TLC). The solvent was evaporated on a

rotary evaporator and further purified by silica gel column chromatography

taking ethyl acetate/hexane (2:8 v/v) as eluent to afford 4a (0.13 g, 71 %

yield).

Procedure for the debenzylation of 4a³⁰To the solution of 4a (0.10 g, 0.18

mmol) in methanol (3 mL) was added 10% Pd/C and then hydrogenated at 45 psi.

The reaction was monitored by TLC. After completion of the reaction, the mixture

was filtered over a bed of celite, washed with methanol (5 mL) and concentrated

in vacuo. The crude product was further purified by column chromatography on

silica gel (60–120 mesh) using 30% methanol/chloroform (1:9 v/v) as eluent to

afford 5 (0.05 g, 82 % yield).

Diethyl

(E)-1,3-bis(benzyloxy)-2-oxo-6-styryltetrahydropyrimidine-

4,4(1H)-dicarboxylate (4j): Reaction time: 0.5 h, 3j (0.04 g, 0.07 mmol),

4j (0.03 g, 0.05 mmol), Yield: 80 %, Nature: Yellowish viscous liquid, R_f=

0.55 (ethyl acetate/hexane 20:80), ¹H-NMR (400 MHz, CDCl₃): δ 7.39 (d,

J = 7.7 Hz, 2H), 7.35-7.18 (m, 13H), 6.52 (d, J = 15.7 Hz, 1H), 5.93 (dd, J

=16.0, 8.2 Hz, 1H), 5.22 (d, J = 9.6 Hz, 1H), 5.05 (q, J = 9.7 Hz, 2H), 4.83

(d, J = 9.8 Hz, 1H), 4.32-4.12 (m, 4H), 4.11-4.03 (m, 1H), 2.69-2.57 (m,

2H), 1.24 (t, J =7.2 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H), ¹³C-NMR (100 MHz,

CDCl₃): δ 167.5, 166.5, 158.0, 135.8, 135.6, 135.3, 134.4, 129.9, 129.1,

128.7, 128.6, 128.4, 128.2, 126.7, 126.2, 78.4, 78.1, 72.7, 62.8, 59.9, 35.2,

14.1, 13.9, IR (neat): 2980, 1732, 1367, 1261, 1211, 1195, 1006, 746, 694

cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated for C₃₂H₃₅N₂O₇,

559.2444 found 559.2455

Diethyl

1,3-dihydroxy-6-(4-methoxyphenyl)-2

oxotetrahydropyrimidine-4,4(1H)-dicarboxylate (5): Reaction time: 3 h,

4a (0.10 g, 0.17 mmol), 5 (0.05 g, 0.14 mmol), Yield: 82 %, Nature: White

solid, Melting point: 315 °C, R_f= 0.55 (ethyl acetate/hexane 65:35), ¹H-

NMR (400 MHz, DMSO): δ 9.48 (s, 1H), 9.22 (s, 1H), 7.18 (d, J = 8.7 Hz,

2H), 6.90 (d, J = 8.6 Hz, 2H), 4.36 (q, J = 5.2 Hz, 1H), 4.27 (q, J = 7.0 Hz,

2H), 4.15-4.00 (m, 2H), 2.60-2.52 (m, 1H), 2.52-2.44 (m, 1H), 1.25 (t, J =

7.0 Hz, 3H), 1.15 (t, J = 7.0 Hz, 3H) ,¹³C-NMR (100 MHz, DMSO): δ 167.2,

165.5, 158.7, 158.3, 131.3, 127.3, 113.3, 78.8, 72.1, 61.6, 60.1, 54.7, 36.6,

28.6, 13.5, 13.3, IR (neat): 3322, 2916, 2848, 1735, 1664, 1514, 1246,

1174, 1078, 1026, 947, 732 cm^-1, HRMS (ESI, Q-TOF) m/z: [M + H]+

Calculated for C₁₇H₂₂N₂O₈, 383.1454 found 383.1440

Procedure for the Krapcho decarboxylation of 4a^12aTo the solution of

4a (0.10 g, 0.18 mmol) in DMSO (3 mL) were added LiCl (6 equiv.) and

H₂O (1 drop), and the reaction mixture was heated at 160 °C until

consumption of starting material (as monitored by TLC). Three mL of water

was added to the mixture and then the mixture was extracted with diethyl

ether, dried over Na₂SO₄, and purified by column chromatography using a

10−20% ethyl-acetate/ hexane solvent system to afford 6 (0.053 g, 0.14

mmol).

Diethyl 1-(benzyloxy)-6-(4-methoxyphenyl)-3-((4-nitrobenzyl)oxy)-2-

oxotetrahydropyrimidine-4,4(1H)-dicarboxylate (4k): Reaction time: 2

h, 3k (0.03 g, 0.04 mmol), 4k (0.02 g, 0.04 mmol), Yield: 87 %, Nature:

White solid, Melting point: 98 °C, R_f= 0.55 (ethyl acetate/hexane 30:70),

¹H-NMR (400 MHz, CDCl₃): δ 8.19 (d, J = 8.7 Hz, 2H), 7.60 (d, J = 8.6 Hz,

2H), 7.31 (d, J = 8.7 Hz, 2H), 7.25-7.17 (m, 3H), 7.01 (d, J = 7.7 Hz, 2H),

6.93 (d, J = 8.6 Hz, 2H), 5.39 (d, J = 11.1 Hz, 1H), 5.20 (d, J = 10.9 Hz,

1H), 5.00 (d, J = 9.0 Hz, 1H), 4.51 (dd, J = 11.1, 4.5 Hz, 1H), 4.39 (d, J =

9.2 Hz, 1H), 4.32 (q, J = 6.9 Hz, 2H), 4.20 (q, J = 7.2 Hz, 2H), 3.84 (s, 3H),

2.82 (dd, J = 14.8, 11.3 Hz, 1H), 2.70 (dd, J = 14.0, 4.5 Hz, 1H), 1.28 (t, J

= 6.8 Hz, 3H), 1.23 (t, J = 6.8Hz, 3H), ¹³C-NMR (100 MHz, CDCl₃): δ 167.4,

166.3,160.0, 159.0, 147.8, 143.1, 135.0, 129.8, 129.5, 129.1, 128.9, 128.6,

128.3, 123.6, 114.1, 78.0, 73.2, 63.0, 61.0, 55.5, 36.9, 14.2, 14.0, IR

(neat): 2924, 2853, 1737, 1610, 1518, 1346, 1247, 1218, 1020, 698 cm^-1,

HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated for C₃₁H₃₃N₃O₁₀, 608.2244

found 608.2238

Diethyl

3-benzyl-1-(benzyloxy)-6-(4-methoxyphenyl)-2-

oxotetrahydropyrimidine-4,4(1H)-dicarboxylate (4l): Reaction time: 15

min., 3l (0.06 g, 0.10 mmol), 4l (0.05 g, 0.09 mmol), Yield: 89 %, Nature:

Colourless liquid, R_f= 0.55 (ethyl acetate/hexane 30:70), ¹H-NMR (400

MHz, CDCl₃): δ 7.37-7.25 (m, 6H), 7.23-7.17 (m, 4H), 7.00 (d, J = 7.4 Hz,

2H), 6.93 (d, J = 8.6 Hz, 2H), 5.25 (d, J = 16.9 Hz, 1H), 5.05 (d, J = 9.2 Hz,

1H), 4.47 (dd, J = 11.2, 3.8 Hz, 1H), 4.38 (t, J = 12.6 Hz, 2H), 4.24-4.10

(m, 2H), 3.89-3.80 (m, 4H), 3.70-3.62 (m, 1H), 2.93 (dd, J =15.1, 11.1 Hz,

1H), 2.73 (dd, J =14.0, 3.7, 1H), 1.25 (t, J = 7.3 Hz, 3H), 0.99 (t, J = 7.3

Hz, 3H), ¹³C-NMR (100 MHz, CDCl₃): δ 168.8, 167.2, 159.8, 158.5, 138.3,

135.4, 130.7, 129.6, 128.9, 128.4, 128.2, 126.8, 126.7, 114.0, 78.1, 70.0,

62.8, 60.6, 55.5, 50.2, 37.5, 14.1, 13.5, IR (neat): 2981, 1737, 1681, 1514,

1441, 1249, 1080, 1029, 736, 698 cm^-1, HRMS (ESI, Q-TOF) m/z: [M +

H]+ Calculated for C₃₁H₃₄N₂O₇, 547.2444 found 547.2451

Ethyl

1-(benzyloxy)-6-(4-methoxyphenyl)-2-oxo-1,2,3,6-

tetrahydropyrimidine-4-carboxylate (6): Reaction time: 12 h, 4a (0.10 g,

0.17 mmol), 6 (0.05 g, 0.14 mmol), Yield: 78 %, Nature: Colourless liquid,

R_f= 0.55 (ethyl acetate/hexane 30:70), ¹H-NMR (400 MHz, CDCl₃): δ 7.27-

7.22 (m, 3H), 7.21-7.14 (m, 4H), 6.83 (d, J = 8.6 Hz, 2H), 6.78 (brs, 1H),

5.78 (dd, J = 4.3, 2.5 Hz, 1H), 4.99 (d, J = 4.2 Hz, 1H), 4.89 (d, J = 10.0

Hz, 1H), 4.43 (d, J = 10.2 Hz, 1H), 4.26-4.14 (m, 2H), 3.74 (s, 3H), 1.23

(t, J = 6.8 Hz, 3H), ¹³C-NMR (100 MHz, CDCl₃): δ 161.2, 160.0, 152.2,

135.4, 131.2, 129.6, 129.2, 128.7, 128.5, 126.3, 114.3, 110.3, 77.7, 63.8,

62.3, 55.5, 14.2, IR (neat): 2980, 1689, 1664, 1602, 1510, 1172, 1026 cm^-

¹, HRMS (ESI, Q-TOF) m/z: [M + H]+ Calculated for C₂₁H₂₂N₂O₅, 383.1607

found 383.1611

Representative procedure for the sequential one pot synthesis of 4a

A round-bottom flask equipped with a magnetic stir bar was charged with

Conflict of interest

The authors declare no conflict of interest.

10.1002/ejoc.201901400

European Journal of Organic Chemistry

FULL PAPER

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Acknowledgment

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We gratefully acknowledge the financial support from Department

of Science & Technology, India. We also thank IIT Ropar for

providing infrastructure and other facilities related to this work.

Keywords: Donor Acceptor Cyclopropane • (un)symmetrical

urea • Malonate • Tetrahydropyrimidinone

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10.1002/ejoc.201901400

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Layout 2:

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Umpolung reactivity

Irshad Maajid Taily, Debarshi Saha, and

Prabal Banerjee*

Page No. – Page No.

Title: [3+3] Annulation via Ring

Opening/Cyclization

Acceptor Cyclopropanes

(un)symmetrical ureas:

of

Donor-

with

Quick

A

Access to Highly Functionalized

Tetrahydropyrimidinones



Exploitation of DACs towards the synthesis of highly functionalized

tetrahydropyrimidinones.



Both symmetrical and unsymmetrical ureas are viable substrates.

Moderate to excellent yield.

Article Doi

[3+3] Annulation via Ring Opening/Cyclization of Donor–Acceptor Cyclopropanes with (Un)symmetrical Ureas: A Quick Access to Highly Functionalized Tetrahydropyrimidinones

DOI: 10.1002/ejoc.201901400

Source and publish data:

Authors:

Article abstract of DOI:10.1002/ejoc.201901400

Full text of DOI:10.1002/ejoc.201901400

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