Enantioselective N-Acylation of Biginelli Dihydropyrimidines by Oxidative NHC Catalysis

Article abstract of DOI:10.1002/ejoc.202000151

The oxidative N-acylation reaction of 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs) with enals and N-heterocyclic carbene (NHC) catalysts is described. The reaction proceeds in the presence of quinone oxidant without additional acyl transfer agents and in the

Full text of DOI:10.1002/ejoc.202000151

A Journal of
Accepted Article
Title: Enantioselective N-Acylation of Biginelli Dihydropyrimidines by
Oxidative NHC Catalysis
Authors: Arianna Brandolese, Daniele Ragno, Costanza Leonardi,
Graziano Di Carmine, Olga Bortolini, Carmela De Risi, and
Alessandro Massi
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000151
Link to VoR: http://dx.doi.org/10.1002/ejoc.202000151
Supported by

10.1002/ejoc.202000151
European Journal of Organic Chemistry
FULL PAPER
Enantioselective N-Acylation of Biginelli Dihydropyrimidines by
Oxidative NHC Catalysis
Arianna Brandolese,[a] Daniele Ragno,[a] Costanza Leonardi,[a] Graziano Di Carmine,[b] Olga Bortolini,[a]
Carmela De Risi,[a] and Alessandro Massi*[a]
In memory of Professor Cinzia Chiappe
[a]
[b]
A. Brandolese, Dr. D. Ragno, C. Leonardi, Prof. C. De Risi, Prof. O. Bortolini, Prof. A. Massi
Department of Chemical and Pharmaceutical Sciences
University of Ferrara
Via L. Borsari, 46, I-44121 Ferrara (Italy)
E-mail: alessandro.massi@unife.it
http://docente.unife.it/alessandro.massi?set_language=it
Dr. G. Di Carmine
School of Chemical Engineering and Analytical Science
The University of Manchester
The Mill, Sackville Street, Manchester, M13 9PL, UK
Supporting information for this article is given via a link at the end of the document.
Abstract: The oxidative N-acylation reaction of 3,4-dihydropyrimidin-
2-(1H)-ones (DHPMs) with enals and N-heterocyclic carbene (NHC)
catalysts is described. The reaction proceeds in the presence of
quinone oxidant without additional acyl transfer agents and in the
asymmetric variant produces pharmaceutically relevant N3-acylated
products with good-to-moderate enantioselectivity.
intermediates.[7d,g] Of note, oxidative NHC catalysis has been
fruitfully employed as synthetic platform for the acylative KR of
secondary amines,[7,8] sulfoximines,[10] and azomethine imines[11]
delivering optically active molecules with high stereoselectivities
(Scheme 1b).
O
X
OH
O
OH
X
X
X
X
X
X
X
Introduction
N
N
N
Y
N
Y
Y
Y
Breslow
intermediate
azolium
enolate
azolium
dienolate
Organocatalytic strategies by N-heterocyclic carbene (NHC)
homoenolate
(a)
catalysis represent a useful tool for the execution of a broad range
O
R
of
asymmetric
transformations
including
benzoin-type
[O]
X
condensations, Stetter reactions, hydroacylations, annulations,
and cycloadditions.[1] These processes proceed by normal
polarity or umpolung reactivity through well-established activation
modes involving key reactive species, namely the Breslow
N
Y
N-nucleophile
Kinetic Resolution (KR)
acyl azolium
(R = X or XC2H2)
O
O
O
O
intermediate,
homoenolate,
and
azolium
(di)enolate
O
intermediates (Scheme 1a).[1] Additionally, the synthetic
opportunities given by NHC organocatalysts are further expanded
by the application of redox protocols (internal and external
oxidation strategies)[2] leading to the acyl azolium intermediate for
the acylation of oxygen-, sulphur-, and nitrogen-nucleophiles in
challenging kinetic resolution (KR),[3] macrolactonization,[4]
desymmetrization,[3,5] and polymerization[6] processes. In
particular, the N-acylation reaction using aldehydes as acylating
agents in place of carboxylic acids/derivatives has proven to
possess some practical advantages (mild reaction conditions,
chemoselectivity, no need of coupling reagents) and it has been
successfully applied to the functionalization of alkyl amines,[7]
anilines,[8] amides,[9] sulfoximines,[10] azomethine imines,[11] and
several nitrogen-containing heterocycles.[7c,e,i-12] In several
occasions, the direct oxidative N-acylation with aldehydes has
been precluded by the competing imine formation,[7] thus
requiring the addition of oxygen nucleophiles as additives[7a,b] or
the execution of a two-step procedure with activated ester
N
R
N
N
R
S
(b)
(c)
N
R1
R2
Ph
R1
R2
R1
R2
R2
O
[O]
NHC*
R3O2C
R3O2C
R4
O
N
R
NH
+
R
this work
R4
N
O
N
O
R1
R1
Scheme 1. (a) Common intermediates in NHC catalysis and generation of acyl
azolium; (b) NHC-catalyzed N-acylation of nitrogen nucleophiles and kinetic
resolutions; (c) this work.
The ureido functionality is an additional structural feature common
to chiral compounds of synthetic and biological relevance,[13] as
exemplified by the Biginelli dihydropyrimidines (3,4-
dihydropyrimidin-2-(1H)-ones, DHPMs).[14] According to the
Evans definition,[15] DHPMs are ‘privileged’ structures in medicinal
1
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10.1002/ejoc.202000151
European Journal of Organic Chemistry
FULL PAPER
chemistry displaying a plethora of pharmacological properties.[14]
Since enantiomeric DHPMs typically exhibit different or even
opposite biological activity, enantioenriched DHPMs have been
addressed by chemical resolution, chromatography on chiral
stationary phases as well as by asymmetric metal/organo/bio-
catalytic approaches.[16] Enzymatic kinetic resolution has also
been applied in a few cases through hydrolysis of activated ester
derivatives of racemic DHPMs.[17] Within the class of Biginelli
products, of particular relevance are the N3-acyl substituted
compounds such as the potent calcium channel blockers SQ-
32926[18] and SQ-32547[18] or the a1a receptor antagonist agent L-
771688.[19] These derivatives are close structural analogs of
pharmaceutically active Hantzsch 1,4-dihydropyridines like
Nifedipine displaying ester groups at C3 and C5 positions of the
heterocyclic nucleus (Figure 1). Indeed, it has been observed that
the substitution of DHPMs with carbonyl groups at the N3 position
often leads to an increase of their biological activity and
stability.[20] Optically active N3-acylated DHPMs are typically
obtained from the corresponding enantioenriched substrate by
treatment with stoichiometric, highly reactive acid chlorides or
anhydrides at elevated temperatures in the presence of a base.[20]
As part of our studies on oxidative NHC catalysis,[5,6,21] we herein
present the direct asymmetric N-acylation of racemic DHPMs with
aldehydes through catalytically generated acyl azolium as a mild
reaction protocol, tolerant to substitutional variation around the
DHPM scaffold (Scheme 1c).
aromatic 4-chlorobenzaldehyde 3a resulted in marked decrease
of reaction efficiency affording the acyl derivative (rac)-6aa in
poor 10% yield (entry 5). As expected, utilization of the aliphatic
n-butyraldehyde 4a delivered a complex reaction mixture due to
the competing aldol reaction with no evidence of product (rac)-
7aa formation (entry 6). In conclusion of this explorative study, an
improved reaction output was finally achieved with
cinnamaldehyde 2a using an excess (2 equiv.) of DHPM 1a, being
the acylated derivative (rac)-5aa recovered in 74% isolated yield
(entry 7).
Table 1. Preliminary study on the achiral N-acylation of DHPM 1a with model
unsaturated-, aromatic-, and aliphatic aldehydes 2a-4a.[a]
O2N
F3C
O
O
N
O
O
i-PrO2C
i-PrO2C
Entry
1
2
3
4[c]
5
Aldehyde
Base
DBU
NaH
NaH
NaH
NaH
NaH
NaH
Time (h)
24
1
24
24
24
24
16
Product (%)[b]
(rac)-5aa (-)
(rac)-5aa (41)
(rac)-5aa (47)
(rac)-5aa (50)
(rac)-6aa (10)
(rac)-7aa (-)
N
O
F
N
NH2
2a
2a
2a
2a
3a
4a
2a
Me
N
Me
N
H
H
SQ-32926
F
SQ-32547
F
6
7[d]
O2N
O
O
(rac)-5aa (74)
MeO2C
MeO
MeO2C
CO2Me
Me
N
N
N
H
[a] Conditions: 1a (0.2 mmol), aldehyde (0.2 mmol), C1 (10 mol%), base (0.4
mmol), 8 (0.2 mmol), anhydrous THF (2 mL), 4 Å MS, RT. [b] Isolated yield. [c]
Reaction run with 0.4 mmol of 2a and 8. [d] Reaction run with 0.4 mmol of 1a
and 0.46 mmol of NaH.
N
Me
N
H
H
N
L-771688
Nifedipine
Figure 1. Biologically active N3-acylated DHPMs and Nifedipine.
The asymmetric version of the model N-acylation of DHPM 1a
was next investigated with cinnamaldehyde 2a as the limiting
reagent using the set of chiral pre-catalysts C2-C7 (Table 2).
Under the conditions of the disclosed racemic process, the amino-
indanol-derived triazolium salts C2-C4 provided unsatisfactory
results even at higher catalytic loading (20 mol%; entries 1-3).
Indeed, only C3 could promote the formation of 5aa in very low
yield (8%) but with an encouraging enantiomeric ratio (er = 78:22,
entry 2). The pyrrole-derived triazolium pre-catalyst C5 proved to
be ineffective (entry 4), while the analogue C6 gave 5aa in 50%
isolated yield and 80:20 er after 16 h (entry 5). These results
seemed to confirm a diminished efficiency of the asymmetric N-
acylation probably due to the higher steric hindrance of chiral pre-
catalysts C5-C6 compared to that of achiral C1. A similar yield of
5aa (55%) accompanied, however, by a lower value of er (60:40)
was detected with the morpholine-based triazolium salt C7 (entry
6). The solvent and base screening with C6 indicated THF as the
optimal reaction medium (entries 5, 7-8) and n-BuLi (2.3 equiv.)
as the preferred base (entries 9-11), thus allowing to slightly
Results and Discussion
Our study started evaluating the influence of the aldehyde
reaction partner on the efficiency of the N-acylation of DHPM 1a
with the achiral triazolium pre-catalyst C1 (10 mol%) and quinone
8 (1 equiv.) as the oxidant (Table 1). Under degassed conditions
(Argon), the use of equimolar cinnamaldehyde 2a and DBU (2
equiv.) in anhydrous THF with 4 Å molecular sieves at room
temperature resulted in no formation of the corresponding N3-
acylated DHPM (rac)-5aa (entry 1). The replacement of DBU with
the stronger base NaH (2 equiv.) gave (rac)-5aa in 41% yield after
one hour along with unreacted 1a (48%; entry 2). Extension of the
reaction time to 24 h as well as the use of excess aldehyde 2a (2
equiv.) only led to a moderate increase of yield (47-50%) because
of the consumption of 2a into the corresponding acid (entries 3-
4). Substitution of the a,b-unsaturated aldehyde 2a with the
2
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10.1002/ejoc.202000151
European Journal of Organic Chemistry
FULL PAPER
increase the yield (55%) and the enantioselectivity of the process
(er = 83:17, entry 11. See the Supporting Information for the full
screening of solvents and bases). The addition of LiCl or LiBF4
(25 mol%) as cooperative Lewis catalysts[22] left the enantiomeric
ratio of 5aa almost unaffected (entries 12-13).
reaction mixture at 0 °C produced a drastic reduction of yield
(25%) and only a little enhancement of er (85:15, entry 15). As
expected on the basis of the results of the racemic process, the
use of an excess (2 equiv.) of aldehyde 1a resulted in a lower
efficiency of the acylation procedure because of the side-
oxidation to cinnamic acid (entry 16). The replacement of quinone
8 with different oxidants such as phenazine 9 and azobenzene 10
had little effect on the reaction outcome in terms of both chemical
yield (45-48%) and enantiomeric ratio (er = 80:20, entries 17-18).
Moreover, the possible use of air as the terminal oxidant was
verified by applying the biomimetic system of electron-transfer
mediators (ETMs) developed by Bäckvall[23] and Sundeń[12,24]
groups. In brief, a catalytic amount (25 mol%) of quinone 8 (ETM’)
was employed in combination with iron(II) phthalocyanine 11 (5
mol%, ETM’’) under air atmosphere affording 5aa in poor yield
(20%) and comparable enantioselectivity (er = 78:22, entry 19).
The modest efficiency of C6 in promoting the kinetic resolution of
DHPM 1a was finally confirmed by reacting 1a and 2a in
equimolar amounts using 8 as the preferred oxidant (entry 20).
Under these conditions, 5aa (er = 81:19) was isolated in 35% yield,
while unreacted 1a (59%) was recovered with low
enantioselectivity (er = 61:39) and (4S)-configuration (see below
for stereochemical assignment). Finally, the occurrence of a
partial racemization at the C4 position of DHPM 5aa was excluded
by a control experiment, which showed the maintenance of the
stereochemical integrity of an authentic sample of 5aa in the
presence of excess n-BuLi (Supporting Information).
Table 2. Optimization of the reaction conditions.[a]
At this stage of the study, the NHC/hydroxamic acid co-catalysis
approach developed by Bode and co-workers for the KR of cyclic
secondary amines[7e] was also attempted with the aim to improve
the enantioselectivity of the model N-acylation reaction.
Accordingly, the achiral triazolium pre-catalyst C1 (10 mol%) and
the chiral hydroxamic acid co-catalyst A (10 mol%) were loaded
into the reaction mixture (equimolar 1a/2a/8, THF) to generate,
after the addition of n-BuLi (1.5 equiv.), the key acylating agent I
susceptible to nucleophilic attack by the deprotonated DHPM 1a
(Scheme 2). Unfortunately, while this strategy afforded 5aa in
higher yield (69%), this compound was recovered in almost
racemic form (er = 53:47) likely because of the major incidence of
the competitive achiral pathway directly promoted by C1.
Entry
NHC.
HX
C2
C3
C4
C5
C6
C7
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
C6
Solvent
Base
Ox.
5aa
(%)[b]
-
8
-
er[c]
1
2
3
4
5
6
7
8
9
10
11
12[d]
13[e]
14[f]
15[g]
16[h]
17
18
19[i]
20[j]
THF
THF
THF
THF
THF
THF
DCM
DMF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
NaH
NaH
NaH
NaH
NaH
NaH
NaH
NaH
KHMDS
t-BuOK
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
n-BuLi
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
8
9
-
78:22
-
-
-
50
55
21
16
20
18
55
30
42
60
25
32
45
48
20
35
80:20
60:40
64:36
62:38
61:39
63:37
83:17
72:18
80:20
75:25
85:15
82:18
80:20
80:20
78:22
81:19
N
C1 (10 mol%)
n-BuLi (1.5 equiv.)
8 (1 equiv.)
N
N
O
O
MeO2C
Me
Cl
A (10 mol%)
N
Ph
1a + 2a
THF, 4 Å MS, RT
C1
N
10
air
8
Me
O
5aa, 69%, 53:47 er
Br
N
OH
O
[a] Conditions: 1a (0.4 mmol), 2a (0.2 mmol), NHC.HX (0.04 mmol), base (0.46
mmol), oxidant (0.2 mmol), anhydrous THF (4 mL), 4 Å MS, RT, 16 h. [b]
Isolated yield. [c] Determined by chiral HPLC. [d] Addition of LiCl (0.05 mmol).
[e] Addition of LiBF4 (0.05 mmol). [f] Temperature: 45 °C. [g] Temperature: 0 °C,
32 h. [h] Conditions: 1a (0.2 mmol), 2a (0.4 mmol), C6 (0.08 mmol), n-BuLi (0.25
mmol), 8 (0.4 mmol), 24 h. [i] Addition of 8 (0.05 mmol) and 11 (0.01 mmol). [j]
Conditions: 1a (0.2 mmol), 2a (0.2 mmol), 24 h. Recovered 1a (59%; er = 61:39)
with (4S)-configuration.
O
A
Br
O
N
O
O
I
Ph
Scheme 2. NHC/hydroxamic acid co-catalysis approach for the synthesis of 5aa.
The study of the temperature effect showed a small improvement
of the reaction yield (60%) at 45 °C together with a partial loss of
enantioselectivity (er = 75:25, entry 14), whereas cooling the
To verify the scope and limitation of the present N-acylation
method, the set of racemic DHPMs 1a-j were examined under the
optimized conditions with pre-catalyst C6 (Table 3). The presence
3
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10.1002/ejoc.202000151
European Journal of Organic Chemistry
FULL PAPER
of electron-withdrawing groups in meta- and para position of the
C4 aromatic ring determined an increase of reactivity (5ba, 68%;
5ca, 72%) with little effect on enantioselectivity compared to the
model 5aa. The ortho-chloro substituent, instead, led to a lower
yield of product 5da (41%) without inducing the enantiomeric
enrichment (er = 81:19) that could be expected on the basis of the
higher steric hindrance around the C4 stereocenter. A little
improvement in terms of er was registered in DHPM 5ea (er =
84:16) displaying the aromatic para-methoxy group, while a much
lower enantiomeric ratio (er = 62:38) was detected in the furyl-
functionalized compound 5fa.
with model 5aa, apart from the marked drop of enantiomeric ratio
shown by 5ha (er = 57:43) bearing an aromatic N1 group. Also,
the introduction of an aliphatic chain at the C4 position resulted in
a diminished enantioselectivity (5ja; er = 71:29) compared to 5ia
with the same substitution pattern. Electron-rich and electron-
poor cinnamaldehydes 2b,c furnished the corresponding N3-
acylated DHPMs 5ab and 5ac with low enantioselectivities, being
5ab an almost racemic product (er = 53:47). Surprisingly, the
same lack of enantiocontrol exerted by C6 was detected moving
from the model DHPM 1a to the thio-analogue 12 as the
substrate; the corresponding N3-acylated product 13, in fact, was
produced in good yield (79%) but negligible enantioselectivity (er
= 58:42). It is important to stress that the stoichiometric oxidant 8
could be easily regenerated with air (see the Experimental
section) and re-used in different runs.
The absolute configuration of products 5 was assigned through a
dedicated experiment where the known DHPM 1g was reacted
with equimolar cinnamaldehyde 2a (30% conversion). The
recovery of DHPM 1g (er = 60:40) with (4S)-configuration (optical
rotation analysis)[25] allowed to deduce the opposite (4R)-
configuration for the acylated counterpart 5ga (er = 77:23). This
assignment was then extended to all DHPMs 5 by analogy (see
the Supporting Information for details).
Table 3. Reaction scope of the enantioselective N-acylation of DHPMs.[a]
C6 (20 mol%)
R2
R2
O
n-BuLi (2.3 equiv.)
8 (1 equiv.)
O
R3O2C
R3O2C
R5
NH
N
+
R5
THF, 4
Å
MS, RT
R4
R4
N
X
N
X
2a-c
R1
R1
1a-j (X = O)
12 ( X = S)
5 (X = O)
13 (X = S)
Cl
Br
O
O
O
O
A proposed mechanism for the disclosed asymmetric N-acylation
of DHPMs is shown in Scheme 3. The NHC II generated by
deprotonation of triazolium salt C6 reacts with aldehyde 2 to give
the homoenolate intermediate III, which in turn is oxidized to the
acyl azolium IV by the external oxidant 8. Subsequent interception
of IV by the deprotonated DHPM 1’ then leads to the product 5
MeO2C
Me
MeO2C
Me
MeO2C
Me
N
Ph
N
Ph
N
Ph
N
O
N
N
O
Me
Me
Me
5aa, 55%, 83:17 er
5ba, 68%, 72:28 er
5ca, 72%, 73:27 er
OMe
and catalyst turnover through the intermediate V.
O
C6
Cl
O
O
O
R2
O
O
MeO2C
MeO2C
n-BuLi
MeO2C
R3O2C
R4
N
Ph
N
Ph
N
Ph
N
R5
Me
N
Me
N
O
Me
N
O
O
N
R1
O
N
Me
Me
Me
R5
N
N
Ar
5da, 41%, 81:19 er
5ea, 50%, 84:16 er
5fa, 52%, 62:38 er
2
5
II
R1
N
O
O
O
R4
R3O2C
O
EtO2C
MeO2C
MeO2C
N
Ph
N
Ph
N
Ph
Ar
Ar
OH
N
O
Me
N
O
Me
N
O
N
Me
N
O
N
R5
R2
R5
N
N
Me
Ph
Bn
N
N
5ga, 57%, 77:23 er
5ha, 58%, 57:43 er
5ia, 62%, 78:22 er
V
III
- 2e
- H
1,2
addition
8
O
Ar
O
O
oxidation
MeO2C
MeO2C
N
Ph
R2
N
R5
N
N
R3O2C
R4
N
Me
N
O
N
Me
N
O
OMe
Bn
Me
N
R1
O
IV
5ja, 58%, 71:29 er
5ab, 60%, 53:47 er
1'
R2
R3O2C
NH
n-BuLi
O
O
R4
N
R1
O
MeO2C
MeO2C
N
N
Ph
1
Me
N
O
Cl
Me
N
S
Me
Me
Scheme 3. Proposed reaction mechanism.
5ac, 55%, 63:37 er
13, 79%, 58:42 er
The acylated DHPMs 5 display an a,b-unsaturated functionality
amenable to synthetic elaborations for the introduction of
additional elements of diversity on the DHPM scaffold. As a proof
of concept study, enantioenriched 5aa (er = 83:17) was subjected
to alkene hydroarylation[26] with benzene and triflic acid (TfOH)
[a] Conditions: 1a (0.4 mmol), aldehyde (0.2 mmol), C6 (0.04 mmol), base (0.46
mmol), 8 (0.2 mmol), anhydrous THF (4 mL), 4 Å MS, RT, 16 h.
The effect of variation of the C5 ester group (5ga) and N1-
substituent (5ha, 5ia) was also investigated and no appreciable
modification of reaction efficiency was observed in comparison
4
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10.1002/ejoc.202000151
European Journal of Organic Chemistry
FULL PAPER
eluted from a column of silica gel with the suitable elution system to give
the 3,4-dihydropyrimidin-2(1H)-one 1.
affording the diaryl derivative 14 in satisfactory yield (55%) and
almost unchanged enantiomeric purity (er = 80:20; Scheme 4)
Methyl 1,6-dimethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (1a)
O
O
Ph
O
O
C6H6 (1.2 equiv.)
TfOH
MeO2C
Me
MeO2C
Me
N
Ph
N
Ph
RT, 2 h
N
N
The product readily precipitated from MeOH cooled at 0 °C. Filtration
followed by washing with cold MeOH and drying under vacuum afforded
the product 1a as a white powder (0.93 g, 90%); m. p. 190-191 °C (Lit.[30]
190-192 °C). 1H NMR (300 MHz, CDCl3) δ= 7.40 - 7.14 (m, 5H, ArH), 5.44
(s, 1H, NH), 5.38 (d, J = 3.3 Hz, 1H, H-4), 3.65 (s, 3H, CO2CH3), 3.23 (s,
3H, NCH3-1), 2.52 (s, 3H, CH3-6); 13C NMR (101 MHz, CDCl3) δ= 166.6,
153.9, 149.7, 143.3, 128.8 (2C), 127.9, 126.2 (2C), 104.1, 54.0, 51.4, 30.4,
Me
Me
5aa, 83:17 er
14, 55%, 80:20 er
Scheme 4. Synthetic elaboration of enantioenriched DHPM 5aa.
+
16.7; HRMS(ESI): calcd. for C14H17N2O3 (M + H+): 261.1234; found:
Conclusion
261.1244.
In conclusion, we have developed an asymmetric N-acylation
strategy based on oxidative NHC catalysis to readily access the
class of pharmaceutically relevant N3-acylated DHPMs in
enantioenriched form. Although the enantioselectivity of the
process was moderate, the use of aldehydes as mild acylating
agents appear well suited for the (stereo)chemical decoration of
the DHPM nucleus and, in general, for the direct N-acylation of
molecules containing the ureido functionality.
Methyl
4-(3-bromophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1b)
The product readily precipitated from MeOH cooled at 0 °C. Filtration
followed by washing with cold MeOH and drying under vacuum afforded
the product 1b as a yellowish powder (1.08 g, 80%); m. p. 138-140 °C. 1H
NMR (300 MHz, CDCl3) δ= 7.38 (s, 2H, ArH), 7.18 (d, J = 5.0 Hz, 2H, ArH),
5.47 (s, 1H, NH), 5.36 (s, 1H, H-4), 3.67 (s, 3H, CO2CH3), 3.24 (s, 3H,
NCH3-1), 2.54 (s, 3H, CH3-6); 13C NMR (101 MHz, CDCl3) δ= 166.3, 153.6,
150.2, 145.5, 131.1, 130.5, 129.4, 124.8, 122.9, 103.3, 53.6, 51.5, 30.5,
16.7; HRMS(ESI): calcd. for C14H16BrN2O3 (M + H+): 339.0339; found:
339.0352.
+
Experimental Section
1H and 13C NMR spectra were recorded on 300 and 400 MHz
spectrometers in CDCl3 at room temperature. 13C NMR spectra were
acquired with the 1H broad-band decoupled mode, and chemical shifts (δ)
are reported in ppm relative to residual solvents signals. Reactions were
monitored by TLC on silica gel 60 F254 with detection by UV lamp operating
at 254 nm and by spraying with vanillin-sulphuric acid reagent (6% vanillin
[w/v] and 1% H2SO4 [v/v] in ethanol) followed by a short, gentle heating.
Flash column chromatography was performed on silica gel 60 (230−400
mesh). All reactions were performed in oven-dried (100 °C) glassware
under an atmosphere of argon. Optical rotations were measured at 25 ±
2 °C in the stated solvent; [α]D are given in 10−1 deg cm2 g−1 (concentration
c given as g/100 mL). The enantiomeric ratios were determined by chiral
stationary phase HPLC (Daicel Chiralpak IA), using an UV detector
operating at 254 nm. Melting points were measured on an Electrothermal
9100 apparatus and are uncorrected. All commercially available reagents
and compounds 3a, 8-11 were purchased from TCI and used as received
without further purification. Solvents were distilled from appropriate drying
agents. Liquid aldehydes 2a, 4a and DBU base were freshly distilled
before their utilization. Catalysts C4,[27a] C5,[27b] and C6[21c] were prepared
by following literature procedure. Catalysts A, C1, C2, C3 and C7 were
purchased from Sigma-Aldrich. Compounds 1 were prepared following a
slightly modified literature procedure.[28] DHPMs 1e,[29a] 1g,[29b] 1i[29c] are
known compounds.
Methyl
4-(4-chlorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1c)
The product readily precipitated from MeOH cooled at 0 °C. Filtration
followed by washing with cold MeOH and drying under vacuum afforded
the product 1c as a yellow powder (1.00 g, 85%); m. p. 118-120 °C (Lit.[31]
117-119 °C). 1H NMR (300 MHz, CDCl3) δ= 7.28 (d, J = 8.5 Hz, 2H, ArH),
7.18 (d, J = 8.5 Hz, 2H, ArH), 5.45 (s, 1H, NH), 5.36 (s, 1H, H-4), 3.66 (s,
3H, CO2CH3), 3.24 (s, 3H, NCH3-1), 2.52 (s, 3H, CH3-6); 13C NMR (101
MHz, CDCl3) δ= 166.4, 153.7, 149.9, 141.8, 133.7, 129.0 (2C), 127.6 (2C),
103.7, 53.4, 51.5, 30.5, 16.7; HRMS(ESI): calcd. for C14H16ClN2O3+ (M +
H+): 295.0844; found: 295.0854.
Methyl
4-(2-chlorophenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1d)
The product readily precipitated from MeOH cooled at 0 °C. Filtration
followed by washing with cold MeOH and drying under vacuum afforded
the product 1d as a yellowish powder (0.95 g, 80%); m. p. 115-117 °C. 1H
NMR (300 MHz, CDCl3) δ= 7.38 (dt, J = 5.1, 2.8 Hz, 1H, ArH), 7.25 - 7.08
(m, 3H, ArH), 5.76 (s, 1H, NH), 5.72 (s, 1H, H-4), 3.58 (s, 3H, CO2CH3),
3.22 (s, 3H, NCH3-1), 2.65 (s, 3H, CH3-6); 13C NMR (101 MHz, CDCl3) δ=
166.5, 159.1, 153.9, 149.2, 135.5, 127.3 (2C), 114.0, 104.2, 55.2, 53.3,
51.3, 30.3, 16.6; HRMS(ESI): calcd. for C14H16ClN2O3+ (M + H+): 295.0844;
found: 295.0856.
General procedure for the synthesis of 3,4-dihydropyrimidin-2(1H)-
ones 1 and 12
Methyl
4-(4-methoxyphenyl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1e)[29a]
A mixture of aldehyde (4 mmol), dicarbonyl compound (4 mmol), N-
substituted urea/thiourea (6 mmol) and p-toluenesulfonic acid (100 mg)
was refluxed in 5 mL of methanol for 16 h. Reaction progress was followed
by TLC and after the completion, the reaction mixture was cooled down to
Column chromatography on silica gel with cyclohexane/EtOAc = 1:1
afforded 1e as a yellowish powder (0.81 g, 70%); m. p. 148-150 °C (Lit.[29a]
149-151 °C). 1H NMR (300 MHz, CDCl3) δ= 7.22 - 7.09 (m, 2H, ArH), 6.87
-6.76 (m, 2H, ArH), 5.59 (s, 1H, NH), 5.32 (d, J = 3.2 Hz, 1H, H-4), 3.78 (s,
3H, CO2CH3), 3.65 (s, 3H, ArOCH3), 3.23 (s, 3H, NCH3-1), 2.51 (s, 3H,
CH3-6); 13C NMR (101 MHz, CDCl3) δ= 166.5, 159.1, 153.9, 149.2, 135.5,
0
°C. In some cases, the products precipitated readily, otherwise
nucleation was promoted by scratching the surface of the flask with a
spatula. The solids were collected by filtration, washed with water and ice-
cold methanol. In other cases, the organic mixture was concentrated and
5
This article is protected by copyright. All rights reserved.

10.1002/ejoc.202000151
European Journal of Organic Chemistry
FULL PAPER
127.3 (2C), 114.0 (2C), 104.2, 55.2, 53.3, 51.3, 30.3, 16.6; HRMS(ESI):
calcd. for C15H19N2O4+ (M + H+): 291.1339; found: 291.1328.
Methyl 1,6-dimethyl-4-phenyl-2-thioxo-1,2,3,4-tetrahydropyrimidine-
5-carboxylate (12)
Methyl
4-(furan-2-yl)-1,6-dimethyl-2-oxo-1,2,3,4-
The product readily precipitated from MeOH cooled at 0 °C. Filtration
followed by washing with cold MeOH and drying under vacuum afforded
the product 12 as a white powder (0.98 g, 89%); m. p. 117-118 °C. 1H NMR
(300 MHz, CDCl3) δ= 7.54 - 6.95 (m, 6H, ArH and NH), 5.41 (s, 1H, H-4),
3.72 (s, 3H, CO2CH3), 3.62 (s, 3H, NCH3-1), 2.52 (s, 3H, CH3-6); 13C NMR
(101 MHz, CDCl3) δ= 179.7, 166.0, 146.9, 141.5, 128.9 (2C), 128.2, 126.0
(2C), 107.4, 53.7, 51.7, 37.1, 16.9; HRMS(ESI): calcd. for C14H17N2O2S+
(M + H+): 277.1005; found: 277.1014.
tetrahydropyrimidine-5-carboxylate (1f)
Column chromatography on silica gel with cyclohexane/EtOAc = 1:1.5
afforded 1f as a white powder (0.70 g, 70%); m. p. 155-157 °C. 1H NMR
(300 MHz, CDCl3) δ= 7.34 - 7.26 (m, 1H, ArH), 6.24 (dd, J = 3.1, 1.8 Hz,
1H, ArH), 6.10 - 6.01 (m, 1H, ArH), 5.85 (s, 1H, NH), 5.41 (d, J = 3.4 Hz,
1H, H-4), 3.68 (s, 3H, CO2CH3), 3.19 (s, 3H, NCH3-1), 2.52 (s, 3H, CH3-6);
13C NMR (101 MHz, CDCl3) δ= 166.1, 154.6, 154.3, 151.2, 142.3, 110.1,
+
105.6, 101.2, 51.4, 47.5, 30.4, 16.5; HRMS(ESI): calcd. for C12H15N2O4
(M + H+): 251.1026; found: 251.1034.
General procedure for the synthesis of racemic N3-acylated DHPMs
Ethyl
1,6-dimethyl-2-oxo-4-phenyl-1,2,3,4-tetrahydropyrimidine-5-
((rac)-5,6) (Table 1)
carboxylate (1g)[29b]
A stirred mixture of 1a (stated amount) and anhydrous THF (2.0 mL) was
degassed under vacuum and saturated with argon (by an Ar-filled balloon)
three times. Then the reaction mixture was cooled at 0 °C with an ice bath
and NaH (stated amount) was added slowly. After 15 min at 0 °C, the ice
bath was removed allowing the reaction to warm up till room temperature
and the reaction mixture was stirred for an additional 15 min. Then, oxidant
8 (82 mg, 0.20 mmol), catalyst C1 (6 mg, 0.02 mmol) and 4 Å MS were
added under an argon environment. Aldehyde 2-4 (0.20 mmol) was finally
added and the reaction was stirred at room temperature for the stated time
(Table 1). The resulting solution was quenched with 0.5 M HCl (3.0 mL),
partially concentrated under vacuum to reduce the amount of THF,
The product readily precipitated from MeOH cooled at 0 °C. Filtration
followed by washing with cold MeOH and drying under vacuum afforded
the product 1g as a white powder (0.98 g, 90%); m. p. 181-183 °C (Lit.[29b]
180-182 °C). 1H NMR (300 MHz, CDCl3) δ= 7.42 - 7.21 (m, 5H, ArH), 5.66
(s, 1H, NH), 5.40 (s, 1H, H-4), 4.11 (q, J = 7.1 Hz, 2H, CO2CH2CH3), 3.24
(s, 3H, NCH3-1), 2.52 (s, 3H, CH3-6), 1.18 (t, J = 7.1 Hz, 3H, CO2CH2CH3);
13C NMR (101 MHz, CDCl3) δ= 166.0, 154.0, 149.1, 143.2, 128.8 (2C),
128.0, 126.3 (2C), 104.5, 60.3, 54.1, 30.4, 16.6, 14.2; HRMS(ESI): calcd.
for C15H19N2O3+ (M + H+): 275.1390; found: 275.1379.
extracted with DCM (3
concentrated. Elution of the resulting residue from a column of silica with
´ 15 mL), dried (anhydrous Na2SO4), and
Methyl 6-methyl-2-oxo-1,4-diphenyl-1,2,3,4-tetrahydropyrimidine-5-
carboxylate (1h)
the suitable elution system afforded (rac)-5,6.
Column chromatography on silica gel with cyclohexane/EtOAc = 2:1
afforded 1h as a white powder (0.97 g, 75%); m. p. 140-142 °C. 1H NMR
(300 MHz, CDCl3) δ= 7.57 - 7.27 (m, 8H, NArH-1 and ArH-4), 7.24 (d, J =
11.9 Hz, 2H, ArH-4), 5.54 (s, 1H, NH), 5.49 (d, J = 3.0 Hz, 1H, H-4), 3.68
(s, 3H, CO2CH3), 2.11 (s, 3H, CH3-6); 13C NMR (101 MHz, CDCl3) δ= 166.5,
153.1, 149.1, 143.3, 137.6, 129.4 (2C), 129.0 (2C), 128.6 (2C), 128.1 (2C),
126.3 (2C), 104.8, 54.5, 51.5, 18.7; HRMS(ESI): calcd. for C19H19N2O3+ (M
+ H+): 323.1390; found: 323.1403.
Methyl
(E)-3-cinnamoyl-1,6-dimethyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate ((rac)-5aa)
Column chromatography on silica gel with cyclohexane/EtOAc = 3:1
afforded (rac)-5aa as a pale yellow oil (58 mg, 74%; Table 1, entry 7). See
below for full characterization.
Methyl
1-benzyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1i)[29c]
Methyl (E)-3-(4-chlorobenzoyl)-1,6-dimethyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate ((rac)-6aa)
Column chromatography on silica gel with cyclohexane/EtOAc = 2:1
afforded 1i as a white powder (0.99 g, 74%); m. p. 139-140 °C (Lit.29c 136-
137 °C). 1H NMR (300 MHz, CDCl3) δ= 7.33 - 7.15 (m, 8H, Ar-4 and
NCH2ArH-1), 7.10 (d, J = 7.7 Hz, 2H, NCH2ArH-1), 6.27 (s, 1H, NH), 5.44
(d, J = 3.2 Hz, 1H, H-4), 5.21 (d, J = 16.6 Hz, 1H, NCH2Ar-1), 4.86 (d, J =
16.6 Hz, 1H, NCH2Ar-1), 3.63 (s, 3H, CO2CH3), 2.44 (s, 3H, CH3-6); 13C
NMR (101 MHz, CDCl3) δ= 166.5, 154.1, 149.4, 143.0 (2C), 137.9 (2C),
128.7 (4C), 127.8, 127.2, 126.4, 126.3, 104.6, 53.7, 51.4, 45.9, 16.5;
HRMS(ESI): calcd. for C20H21N2O3+ (M + H+): 337.1547; found: 337.1559.
Column chromatography on silica gel with cyclohexane/EtOAc = 3:1
afforded (rac)-6aa as a pale yellow oil (8 mg, 10%). 1H NMR (300 MHz,
CDCl3) δ= 7.48 (d, J = 8.4 Hz, 2H, COArH), 7.40 - 7.30 (m, 7H, COArH
and ArH-4), 6.46 (s, 1H, H-4), 3.79 (s, 3H, CO2CH3), 3.15 (s, 3H, NCH3-1),
2.63 (s, 3H, CH3-6); 13C NMR (101 MHz, CDCl3) δ= 170.2, 165.7, 152.4,
149,2, 138.5, 137.7, 134.1, 129.2, 128.7, 128.5, 128.1, 126.4, 109.6, 53.4,
51.9, 31.2, 16.3; HRMS(ESI): calcd. for C21H20ClN2O4+ (M + H+): 399.1106;
found: 399.1121.
Methyl
1-benzyl-6-methyl-2-oxo-4-propyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (1j)
General procedure for the synthesis of N3-acylated DHPMs (5) and
thione (13)
Column chromatography on silica gel with cyclohexane/EtOAc = 3:1
afforded 1j as a white powder (0.43 g, 35%); m. p. 131-133 °C. 1H NMR
(300 MHz, CDCl3) δ= 7.42 - 7.12 (m, 5H, ArH), 5.75 (s, 1H, NH), 5.14 (d,
J = 16.7 Hz, 1H, NCH2Ar-1), 4.85 (d, J = 16.6 Hz, 1H, NCH2Ar-1), 4.28 (s,
1H, H-4), 3.72 (s, 3H, CO2CH3), 2.36 (s, 3H, CH3-6), 1.59 - 1.23 (m, 4H,
CH2CH2CH3), 0.91 (t, J = 7.1 Hz, 3H, CH2CH2CH3); 13C NMR (101 MHz,
CDCl3) δ= 166.7, 154.8, 149.2, 138.3, 128.7 (2C), 127.1, 126.3 (2C), 105.2,
51.29, 50.1, 45.9, 39.2, 17.9, 16.4, 13.8; HRMS(ESI): calcd. for
C17H23N2O3+ (M + H+): 303.1703; found: 303.1716.
A stirred mixture of 1 or 12 (0.40 mmol) and anhydrous THF (4.0 mL) was
degassed under vacuum and saturated with argon (by an Ar-filled balloon)
three times. Then the reaction mixture was cooled at 0 °C with an ice bath
and n-BuLi (230 μL of a 2.0 M solution in n-hexane, 0.46 mmol) was added
slowly. After 15 min at 0 °C, the ice bath was removed allowing the reaction
to warm up till room temperature for another 15 min. Then, oxidant 8 (82
mg, 0.20 mmol), catalyst C6 (22 mg, 0.04 mmol) and 4Å MS were added
under an argon environment. Aldehyde 2 (0.2 mmol) was finally added and
the reaction was stirred for 16 h at room temperature. The resulting
6
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10.1002/ejoc.202000151
European Journal of Organic Chemistry
FULL PAPER
solution was quenched with 0.5 M HCl (5 mL) and partially concentrated
under vacuum to reduce the amount of THF. The crude of the reaction was
NCH3-1), 2.52 (s, 3H, CH3-6); 13C NMR (75 MHz, CDCl3) δ= 167.2, 166.0,
152.9, 147.9, 145.0, 137.6, 135.3, 133.8, 131.0, 130.4, 129.6, 129.1 (2C),
128.7 (2C), 128.5, 127.5, 120.6, 109.3, 52.0, 51.5, 31.6, 16.6; HRMS(ESI):
calcd. for C23H22ClN2O4+ (M + H+): 425.1263; found: 425.1246.
extracted with DCM (3
´ 15 mL), dried (anhydrous Na2SO4), and
concentrated. Elution of the resulting residue from a column of silica with
the suitable elution system afforded 5 or 13.
Methyl (R,E)-3-cinnamoyl-4-(4-methoxyphenyl)-1,6-dimethyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (5ea)
Methyl
(R,E)-3-cinnamoyl-1,6-dimethyl-2-oxo-4-phenyl-1,2,3,4-
Column chromatography on silica gel with cyclohexane/EtOAc = 2.5:1
afforded 5ea as a pale yellow oil (42 mg, 50%). Chiral HPLC analysis 84:16
er (Chiralpak IA column, n-Hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min,
λ = 254 nm, tR = 23.5 min for minor isomer, tR = 28.2 min for major isomer);
[α]25D = +67.5 (c = 0.2, CH3OH); 1H NMR (300 MHz, CDCl3) δ= 7.83 (d, J
= 15.6 Hz, 1H, C=CH), 7.64 - 7.52 (m, 3H, ArHCH=C), 7.44 - 7.36 (m, 3H,
ArHCH=C and C=CH), 7.20 (d, J = 8.6 Hz, 2H, ArH-4), 6.82 (d, J = 8.6 Hz,
2H, ArH-4), 6.70 (s, 1H, H-4), 3.77 (s, 3H, CO2CH3), 3.75 (s, 3H, ArOCH3),
3.23 (s, 3H, NCH3-1), 2.59 (s, 3H, CH3-6); 13C NMR (101 MHz, CDCl3) δ=
167.1, 165.8, 159.2, 144.8, 144.5, 134.9, 132.8, 130.8, 130.1, 128.9, 128.7,
128.6, 128.5, 128.4, 128.3, 127.8, 122.1, 120.3, 114.0, 55.2, 51.8, 51.1,
31.3, 16.1; HRMS(ESI): calcd. for C24H25N2O5+ (M + H+): 421.1758; found:
421.1739.
tetrahydropyrimidine-5-carboxylate (5aa)
Column chromatography on silica gel with cyclohexane/EtOAc = 3:1
afforded 5aa as a pale yellow oil (42 mg, 55%). Chiral HPLC analysis 83:17
er (Chiralpak IA column, n-Hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min,
λ = 254 nm, tR = 26.0 min for minor isomer, tR = 29.6 min for major isomer);
[α]25D = +49.7 (c = 0.3, CH3OH); 1H NMR (300 MHz, CDCl3) δ= 7.84 (d, J
= 15.6 Hz, 1H, C=CH), 7.62 - 7.54 (m, 2H, ArHCH=C), 7.48 - 7.35 (m, 4H,
ArHCH=C and C=CH), 7.32 - 7.26 (m, 5H, ArH-4), 6.76 (s, 1H, H-4), 3.77
(s, 3H, CO2CH3), 3.22 (s, 3H, NCH3-1), 2.59 (s, 3H, CH3-6); 13C NMR (101
MHz, CDCl3) δ= 167.1, 165.8, 149.3, 144.6, 142.8, 138.9, 134.9, 130.1,
128.8 (2C), 128.6 (2C), 128.3 (2C), 127.9, 126.3 (2C), 120.2, 109.1, 51.8,
51.4, 31.3, 16.2; HRMS(ESI): calcd. for C23H23N2O4+ (M + H+): 391.1652;
found: 391.1638.
Methyl
(S,E)-3-cinnamoyl-4-(furan-2-yl)-1,6-dimethyl-2-oxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (5fa)
Methyl
(R,E)-4-(3-bromophenyl)-3-cinnamoyl-1,6-dimethyl-2-oxo-
Column chromatography on silica gel with cyclohexane/EtOAc = 4:1
afforded 5fa as a pale yellow oil (39 mg, 52%). Chiral HPLC analysis 62:38
er (Chiralpak IA column, n-Hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min,
λ = 254 nm, tR = 19.1 min for minor isomer, tR = 22.6 min for major isomer);
[α]25D = +12.5 (c = 0.2, CH3OH); 1H NMR (300 MHz, CDCl3) δ= 7.82 (d, J
= 15.6 Hz, 1H, C=CH), 7.60 - 7.53 (m, 2H, ArHCH=C), 7.45 - 7.33 (m, 4H,
ArHCH=C and C=CH), 7.32 - 7.27 (m, 1H, ArH-4), 6.74 (s, 1H, H-4), 6.29
- 6.24 (m, 1H, ArH-4), 6.20 (d, J = 3.3 Hz, 1H, ArH-4), 3.76 (s, 3H, CO2CH3),
3.29 (s, 3H, NCH3-1), 2.58 (s, 3H, CH3-6);13C NMR (101 MHz, CDCl3) δ=
166.9, 165.5, 152.5, 151.7, 150.2, 144.9, 142.9, 135.2, 130.4, 129.0 (2C),
128.6 (2C), 120.5, 110.4, 107.6, 106.7, 52.0, 46.9, 31.6, 16.4; HRMS(ESI):
calcd. for C21H21N2O5+ (M + H+): 381.1445; found: 381.1429.
1,2,3,4-tetrahydropyrimidine-5-carboxylate (5ba)
Column chromatography on silica gel with cyclohexane/EtOAc = 3.5:1
afforded 5ba as a pale yellow oil (63 mg, 68%). Chiral HPLC analysis
72:28 er (Chiralpak IA column, n-Hexane/i-PrOH = 95:5, flow rate = 1.0
mL/min, λ = 254 nm, tR = 22.6 min for minor isomer, tR = 25.8 min for major
isomer); [α]25 = +35.6 (c = 0.5, CH3OH); 1H NMR (300 MHz, CDCl3) δ=
D
7.84 (d, J = 15.6 Hz, 1H, C=CH), 7.63 - 7.53 (m, 2H, ArHCH=C), 7.49 -
7.27 (m, 6H, ArHCH=C, Ar-4 and C=CH), 7.25 - 7.07 (m, 2H, ArH-4), 6.72
(s, 1H, H-4), 3.77 (s, 3H, CO2CH3), 3.22 (s, 3H, NCH3-1), 2.60 (s, 3H, CH3-
6);13C NMR (101 MHz, CDCl3) δ= 167.0, 165.5, 152.3, 149.8, 145.0, 141.2,
134.8, 131.1, 130.2, 130.2, 129.6, 128.8 (2C), 128.4 (2C), 125.1, 122.8,
+
119.9, 108.3, 51.9, 51.0, 31.4, 16.2; HRMS(ESI): calcd. for C23H22BrN2O4
(M + H+): 469.0757; found: 469.0774.
Ethyl
(R,E)-3-cinnamoyl-1,6-dimethyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (5ga)
Methyl
(R,E)-4-(4-chlorophenyl)-3-cinnamoyl-1,6-dimethyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (5ca)
Column chromatography on silica gel with cyclohexane/EtOAc = 3:1
afforded 5ga as a pale yellow oil (46 mg, 57%). Chiral HPLC analysis
77:23 er (Chiralpak IA column, n-Hexane/i-PrOH = 90:10, flow rate = 1.0
mL/min, λ = 254 nm, tR = 13.6 min for minor isomer, tR = 15.9 min for major
isomer); [α]25D = +33.9 (c = 0.13, CH3OH); 1H NMR (300 MHz, CDCl3) δ=
7.83 (d, J = 15.6 Hz, 1H, C=CH), 7.62 - 7.55 (m, 2H, ArHCH=C), 7.48 -
7.32 (m, 4H, ArHCH=C and C=CH ), 7.30 - 7.26 (m, 5H, ArH-4), 6.74 (s,
1H, H-4), 4.35 - 4.14 (m, 2H, CO2CH2CH3), 3.22 (s, 3H, NCH3-1), 2.58 (s,
3H, CH3-6), 1.29 (t, J = 7.1 Hz, 3H, CO2CH2CH3);13C NMR (101 MHz,
CDCl3) δ= 167.3, 165.4, 150.0, 144.7, 139.1, 135.0, 130.2 (2C), 128.9 (2C),
128.7, 128.6, 128.4 (2C), 127.9, 126.4 (2C), 120.4, 109.7, 60.9, 51.8, 31.4,
16.3, 14.3; HRMS(ESI): calcd. for C24H25N2O4+ (M + H+): 405.1809; found:
405.1827.
Column chromatography on silica gel with cyclohexane/EtOAc = 3:1
afforded 5ca as a pale yellow oil (61 mg, 72%). Chiral HPLC analysis
73:27 er (Chiralpak IA column, n-Hexane/i-PrOH = 80:20, flow rate = 1.0
mL/min, λ = 254 nm, tR = 12.3 min for major isomer, tR = 13.8 min for minor
isomer); [α]25 = +10.3 (c = 0.3, CH3OH); 1H NMR (300 MHz, CDCl3) δ=
D
7.84 (d, J = 15.6 Hz, 1H, C=CH), 7.62 - 7.52 (m, 2H, ArHCH=C), 7.45 -
7.34 (m, 4H, ArHCH=C and C=CH), 7.30 - 7.26 (m, 1H, ArH-4), 7.25 - 7.18
(m, 3H, ArH-4), 6.69 (s, 1H, H-4), 3.76 (s, 3H, CO2CH3), 3.22 (s, 3H, NCH3-
1), 2.59 (s, 3H, CH3-6); 13C NMR (101 MHz, CDCl3) δ= 167.2, 165.7, 152.4,
149.7, 145.0, 137.5, 134.9, 133.9, 130.3, 128.9 (4C), 128.5 (2C), 128.0
(2C), 120.1, 108.7, 52.0, 51.1, 31.4, 16.3; HRMS(ESI): calcd. for
C23H22ClN2O4+ (M + H+): 425.1263; found: 425.1244.
Methyl
(R,E)-3-cinnamoyl-6-methyl-2-oxo-1,4-diphenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (5ha)
Methyl
(S,E)-4-(2-chlorophenyl)-3-cinnamoyl-1,6-dimethyl-2-oxo-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (5da)
Column chromatography on silica gel with cyclohexane/EtOAc = 5:1
afforded 5ha as a pale yellow oil (52 mg, 58%). Chiral HPLC analysis
57:43 er (Chiralpak IA column, n-Hexane/i-PrOH = 90:10, flow rate = 1.0
mL/min, λ = 254 nm, tR = 11.4 min for major isomer, tR = 15.9 min for minor
isomer); [α]25D = -8.2 (c = 0.6, CH3OH); 1H NMR (300 MHz, CDCl3) δ= 7.88
(d, J = 15.6 Hz, 1H, C=CH), 7.62 - 7.55 (m, 2H, ArCH=C), 7.51 (d, J = 15.6
Hz, 1H, C=CH), 7.48 - 7.26 (m, 12H, NAr-1 and Ar-4), 7.07 (bs, 1H, NAr-
1), 6.90 (s, 1H, H-4), 3.81 (s, 3H, CO2CH3), 2.19 (s, 3H, CH3-6); 13C NMR
(101 MHz, CDCl3) δ= 167.2, 165.8, 151.9, 149.5, 145.0 (2C), 139.4, 136.9,
Column chromatography on silica gel with cyclohexane/EtOAc = 3:1
afforded 5da as a pale yellow oil (34 mg, 41%). Chiral HPLC analysis
81:19 er (Chiralpak IA column, n-Hexane/i-PrOH = 85:15, flow rate = 1.0
mL/min, λ = 254 nm, tR = 13.2 min for minor isomer, tR = 17.2 min for major
isomer); [α]25 = +12.5 (c = 0.4, CH3OH); 1H NMR (300 MHz, CDCl3) δ=
D
7.78 (d, J = 15.6 Hz, 1H, C=CH), 7.59 - 7.51 (m, 2H, ArHCH=C), 7.45 (d,
J = 15.6 Hz, 1H, C=CH), 7.40 - 7.31 (m, 4H, ArHCH=C and Ar-4), 7.23 -
7.14 (m, 3H, ArH-4), 6.89 (s, 1H, H-4), 3.74 (s, 3H, CO2CH3), 3.33 (s, 3H,
7
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10.1002/ejoc.202000151
European Journal of Organic Chemistry
FULL PAPER
134.9, 130.2, 129.4 (2C), 129.2, 128.9 (3C), 128.7 (2C), 128.4 (2C), 128.0,
126.4 (2C), 120.1, 109.7, 51.9, 51.8, 17.9; HRMS(ESI): calcd. for
C28H25N2O4+ (M + H+): 453.1809; found: 453.1789.
NMR (101 MHz, CDCl3) δ= 166.9, 165.8, 152.7, 149.4, 143.1, 138.86,
136.1, 133.5, 129.6 (2C), 129.1 (2C), 128.7 (2C), 128.0, 126.4 (2C), 120.9,
109.2, 51.9, 51.6, 31.4, 16.3; HRMS(ESI): calcd. for C23H22ClN2O4+ (M +
H+): 425.1263; found: 425.1246.
Methyl (R,E)-1-benzyl-3-cinnamoyl-6-methyl-2-oxo-4-phenyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (5ia)
Methyl
(R)-3-cinnamoyl-1,6-dimethyl-4-phenyl-2-thioxo-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (13)
Column chromatography on silica gel with cyclohexane/EtOAc = 6:1
afforded 5ia as a pale yellow oil (57 mg, 62%). Chiral HPLC analysis 78:22
er (Chiralpak IA column, n-Hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min,
λ = 254 nm, tR = 17.3 min for minor isomer, tR = 19.4 min for major isomer);
[α]25D = +22.5 (c = 0.6, CH3OH);1H NMR (300 MHz, CDCl3) δ= 7.89 (d, J =
15.5 Hz, 1H, C=CH), 7.63 - 7.56 (m, 2H, ArHCH=C), 7.44 (d, J = 15.6 Hz,
1H, C=CH), 7.40 - 7.34 (m, 3H, ArHCH=C), 7.29 - 7.08 (m, 8H, ArH-4 and
NCH2ArH-1), 6.80 (s, 1H, H-4), 6.71 (d, J = 7.3 Hz, 2H, NCH2ArH-1), 5.43
(d, J = 16.5 Hz, 1H, NCH2Ar-1), 4.61 (d, J = 16.4 Hz, 1H, NCH2Ar-1), 3.77
(s, 3H, CO2CH3), 2.50 (s, 3H, CH3-6); 13C NMR (101 MHz, CDCl3) δ= 167.3,
166.0, 149.3, 144.9 (2C), 139.0, 136.4, 135.0, 130.3 (2C), 128.9 (2C),
128.8 (2C), 128.7 (2C), 128.5 (2C), 127.9, 127.5, 126.8 (2C), 126.5 (2C),
120.2, 52.0, 51.4, 46.7, 16.3; HRMS(ESI): calcd. for C29H27N2O4+ (M + H+):
467.1965; found: 467.1946.
Column chromatography on silica gel with cyclohexane/EtOAc = 5:1
afforded 13 as a pale yellow oil (64 mg, 79%). Chiral HPLC analysis 58:42
er (Chiralpak IA column, n-Hexane/i-PrOH = 95:5, flow rate = 1.0 mL/min,
λ = 254 nm, tR = 17.8 min for major isomer, tR = 18.7 min for minor isomer);
[α]25D = +12.2 (c = 0.6, CH3OH); 1H NMR (300 MHz, CDCl3) δ= 7.70 (d, J
= 15.5 Hz, 1H, C=CH), 7.57 - 7.49 (m, 2H, ArHCH=C), 7.44 - 7.35 (m, 4H,
ArHCH=C and C=CH), 7.33 - 7.26 (m, 5H, ArH-4), 6.64 (s, 1H, H-4), 3.79
(s, 3H, CO2CH3), 3.50 (s, 3H, NCH3-1), 2.62 (s, 3H, CH3-6); 13C NMR (101
MHz, CDCl3) δ= 178.8, 169.1, 165.5, 147.8, 141.3, 137.9, 135.2, 130.0,
128.9 (2C), 128.6 (2C), 128.4 (2C), 128.1, 126.4 (2C), 121.8, 113.8, 52.8,
52.2, 37.8, 16.9; HRMS(ESI): calcd. for C23H23N2O3S+ (M + H+): 407.1424;
found: 407.1409.
Methyl (R,E)-1-benzyl-3-cinnamoyl-6-methyl-2-oxo-4-propyl-1,2,3,4-
tetrahydropyrimidine-5-carboxylate (5ja)
Recycle of oxidant 8
Column chromatography on silica gel with cyclohexane/EtOAc = 6:1
afforded 5ja as a pale yellow oil (50 mg, 58%). Chiral HPLC analysis 71:29
er (Chiralpak IA column, n-Hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min,
λ = 254 nm, tR = 14.1 min for minor isomer, tR = 17.8 min for major isomer);
[α]25D = +5.5 (c = 0.2, CH3OH); 1H NMR (300 MHz, CDCl3) δ= 7.78 (d, J =
15.6 Hz, 1H, C=CH), 7.58 - 7.51 (m, 2H, ArHC=CH), 7.40 - 7.27 (m, 9H,
ArHC=CH, NCH2ArH-1 and C=CH), 5.59 (t, J = 7.0 Hz, 1H, H-4), 5.30 (d,
J = 16.3 Hz, 1H, NCH2Ar-1), 4.85 (d, J = 16.0 Hz, 1H, NCH2Ar-1), 3.75 (s,
3H, CO2CH3), 2.47 (s, 3H, CH3-6), 1.45 - 1.36 (m, 4H, CH2CH2CH3), 0.84
(t, J = 7.2 Hz, 3H, CH2CH2CH3);13C NMR (101 MHz, CDCl3) δ= 167.0,
165.9, 152.9, 147.4, 144.1, 136.8, 135.0, 130.0, 128.8 (2C), 128.7 (2C),
128.3 (2C), 127.7, 127.1 (2C), 120.3, 111.1, 51.6, 49.3, 46.9, 36.1, 18.4,
16.2, 13.9; HRMS(ESI): calcd. for C26H29N2O4+ (M + H+): 433.2122; found:
433.2139.
The alcohol resulting from oxidant 8 reduction (3,3',5,5'-tetra-tert-butyl-
[1,1'-biphenyl]-4,4'-diol) was recovered by column chromatography after
each run of Table 3. The subsequent oxidation to 8 was performed stirring
the 3,3',5,5'-tetra-tert-butyl-[1,1'-biphenyl]-4,4'-diol (578 mg, 1.41 mmol)
with 11 (80 mg, 0.14 mmol) in THF (10 mL) under air atmosphere (1 atm,
balloon) for 16 h. Filtration over
a pad of Celite and subsequent
concentration under reduced pressure afforded 8 as a dark red amorphous
solid (572 mg, 88%).[5,6]
Methyl (R)-3-(3,3-diphenylpropanoyl)-1,6-dimethyl-2-oxo-4-phenyl-
1,2,3,4-tetrahydropyrimidine-5-carboxylate (14)
A mixture of DHPM 5aa (39 mg, 0.1 mmol), TfOH (50 µL, 0.56 mmol),
benzene (22 µL, 0.24 mmol) and DCM (0.5 mL) was stirred at room
temperature for 2 h. The mixture was poured into ice water (3 mL) and
extracted with DCM (3 x 10 mL). The combined extracts were washed with
water (5 mL), saturated aqueous solution of NaHCO3 (5 mL), water again
(5 mL), dried (anhydrous Na2SO4), concentrated, and eluted from a
column of silica gel with cyclohexane/EtOAc = 3:1 to afford 14 as a white
amorphous solid (25 mg, 55%). Chiral HPLC analysis 80:20 er (Chiralpak
IA column, n-Hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min, λ = 254 nm,
Methyl (R,E)-3-(3-(4-methoxyphenyl)acryloyl)-1,6-dimethyl-2-oxo-4-
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5ab)
Column chromatography on silica gel with cyclohexane/EtOAc = 3:1
afforded 5ab as a pale yellow oil (50 mg, 60%). Chiral HPLC analysis
53:47 er (Chiralpak IA column, n-Hexane/i-PrOH = 90:10, flow rate = 1.0
mL/min, λ = 254 nm, tR = 31.3 min for major isomer, tR = 33.1 min for minor
isomer); [α]25 = +10.1 (c = 0.2, CH3OH); 1H NMR (300 MHz, CDCl3) δ=
D
7.82 (d, J = 15.6 Hz, 1H, C=CH), 7.53 (d, J = 8.7 Hz, 2H, ArHCH=C), 7.37
- 7.26 (m, 6H, C=CH and ArH-4), 6.89 (d, J = 8.8 Hz, 2H, ArHCH=C), 6.77
(s, 1H, H-4), 3.84 (s, 3H, CO2CH3), 3.77 (s, 3H, ArOCH3), 3.21 (s, 3H,
NCH3-1), 2.58 (s, 3H, CH3-6); 13C NMR (101 MHz, CDCl3) δ= 167.2, 165.8,
161.3, 149.4, 144.6, 139.0, 130.1 (2C), 128.6 (2C), 127.8, 127.7, 126.3
(2C), 117.7, 114.2 (2C), 114.1, 109.0, 55.3, 51.8, 51.3, 31.3, 16.1;
HRMS(ESI): calcd. for C24H25N2O5+ (M + H+): 421.1758; found: 421.1741.
tR = 15.9 min for minor isomer, tR = 17.2 min for major isomer); [α]25
=
D
+45.2 (c = 0.2, CH3OH); 1H NMR (300 MHz, CDCl3) δ= 7.31 - 7.26 (m, 5H,
ArH), 7.23 - 7.21 (m, 5H, ArH), 7.18 - 7.03 (m, 5H, ArH), 6.55 (s, 1H, H-4),
4.64 (t, J = 7.8 Hz, 1H, Ar2CH-), 3.76 (d, J = 8.4 Hz, 2H, Ar2CHCH2-), 3.70
(s, 3H, CO2CH3), 3.12 (s, 3H, NCH3-1), 2.49 (s, 3H, CH3-6); 13C NMR (101
MHz, CDCl3) δ= 173.1, 165.6, 152.4, 149.0, 143.8, 143.6, 138.7, 128.5
(2C), 128.4 (2C), 128.3 (2C), 127.9 (2C), 127.8 (2C), 127.7 (2C), 126.4,
126.3, 126.2, 108.6, 51.7, 50.8, 47.7, 43.0, 31.2, 16.1; HRMS(ESI): calcd.
for C29H29N2O4+ (M + H+): 469.2122; found: 469.2102.
Methyl
(R,E)-3-(3-(4-chlorophenyl)acryloyl)-1,6-dimethyl-2-oxo-4-
phenyl-1,2,3,4-tetrahydropyrimidine-5-carboxylate (5ac)
Column chromatography on silica gel with cyclohexane/EtOAc = 4:1
afforded 5ac as a yellowish oil (46 mg, 55%). Chiral HPLC analysis 63:37
er (Chiralpak IA column, n-Hexane/i-PrOH = 90:10, flow rate = 1.0 mL/min,
λ = 254 nm, tR = 22.9 min for minor isomer, tR = 24.9 min for major isomer);
[α]25D = +24.2 (c = 0.2, CH3OH); 1H NMR (300 MHz, CDCl3) δ= 7.77 (d, J
= 15.6 Hz, 1H, C=CH), 7.50 (d, J = 8.5 Hz, 2H, ArHCH=C), 7.44 - 7.26 (m,
7H, C=CH, ArHCH=C and ArH-4), 7.25 - 7.18 (m, 1H, ArH-4), 6.75 (s, 1H,
Acknowledgements
We gratefully acknowledge the University of Ferrara (fondi FAR)
for financial support. Thanks are also given to Paolo Formaglio for
NMR experiments and to Tatiana Bernardi for MS analysis.
H-4), 3.77 (s, 3H, CO2CH3), 3.21 (s, 3H, NCH3-1), 2.58 (s, 3H, CH3-6); 13
C
8
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10.1002/ejoc.202000151
European Journal of Organic Chemistry
FULL PAPER
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Mohammadkhani, B. Moradi, Mol. Diversity 2018, 22, 751-767.
Keywords: acylation • carbenes • dihydropyrimidines •
organocatalysis • oxidation
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10.1002/ejoc.202000151
European Journal of Organic Chemistry
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Entry for the Table of Contents
R2
R2
O
triazolium* (20 mol%)
n-BuLi
quinone oxidant
O
R3O2C
N
N
R3O2C
R4
Ph
N
F
NH
(R)
N
R
+
R
F
Ph
THF, RT
R4
N
O
N
O
BF4
F
R1
R1
F
F
up to 72% Y
up to 84:16 er
NHC-catalysis under oxidative conditions is an effective synthetic platform for the production of enantioenriched biologically relevant
N3-acylated 3,4-dihydropyrimidin-2-(1H)-ones (DHPMs, Biginelli products)
Key Topic: Oxidative Acylation
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This article is protected by copyright. All rights reserved.