Control of regio- and enantioselectivity in the asymmetric organocatalytic addition of acetone to 4-(trifluoromethyl)pyrimidin-2(1H)-ones

Article abstract of DOI:10.1002/ejoc.201301542

The reactions of variously substituted 4-(trifluoromethyl)pyrimidin-2(1H)- ones with acetone in the presence of L-proline or chiral secondary amine organocatalysts were studied. As demonstrated, 4-(trifluoromethyl)pyrimidin- 2(1H)-ones unsubstituted at the 6-position of the heterocyclic ring react with acetone at the endocyclic C=N or C=C bond depending on whether thermodynamic or kinetic control is operative in the addition reaction and also depending on the catalyst used. Racemic kinetically preferred regioisomers, 6-(2-oxopropyl)-4- (trifluoromethyl)-3,4-dihydropyrimidin-2(1H)-ones, were found to undergo intermolecular organocatalytic rearrangement into enantioenriched thermodynamically stable products, 4-(2-oxopropyl)-4-(trifluoromethyl)-3,4- dihydropyrimidin-2(1H)-ones, with enantiomeric ratios up to 83:17. Chiral-amine-catalyzed reactions of simple 4-(trifluoromethyl)ated pyrimidones with acetone represent a general equilibrium system in which Michael-like adducts are formed reversibly under kinetic control and Mannich-like adducts are thermodynamically stable. Only the latter products are obtainable in the enantioenriched form, with up to 83:17 er. Copyright

Full text of DOI:10.1002/ejoc.201301542

FULL PAPER
DOI: 10.1002/ejoc.201301542
Control of Regio- and Enantioselectivity in the Asymmetric Organocatalytic
Addition of Acetone to 4-(Trifluoromethyl)pyrimidin-2(1H)-ones
Volodymyr A. Sukach,*[a] Viktor M. Tkachuk,[a] Veronika M. Shoba,[a]
Volodymyr V. Pirozhenko,[a] Eduard B. Rusanov,[a] Alexey A. Chekotilo,[b]
Gerd-Volker Röschenthaler,[c] and Mykhailo V. Vovk[a]
Keywords: Asymmetric catalysis / Organocatalysis / Nitrogen heterocycles / Fluorine / Regioselectivity / Rearrangement
The reactions of variously substituted 4-(trifluoromethyl)pyr-
imidin-2(1H)-ones with acetone in the presence of -proline
used. Racemic kinetically preferred regioisomers, 6-(2-oxo-
propyl)-4-(trifluoromethyl)-3,4-dihydropyrimidin-2(1H)-
ones, were found to undergo intermolecular organocatalytic
rearrangement into enantioenriched thermodynamically
stable products, 4-(2-oxopropyl)-4-(trifluoromethyl)-3,4-dihy-
dropyrimidin-2(1H)-ones, with enantiomeric ratios up to
83:17.
L
or chiral secondary amine organocatalysts were studied. As
demonstrated, 4-(trifluoromethyl)pyrimidin-2(1H)-ones un-
substituted at the 6-position of the heterocyclic ring react
with acetone at the endocyclic C=N or C=C bond depending
on whether thermodynamic or kinetic control is operative in
the addition reaction and also depending on the catalyst
pounds more easily deliverable to the target site. Further-
more, trifluoromethylation can increase metabolic stability
and diminish toxicity of the compound. Therefore, new ap-
proaches to novel trifluoromethylated heterocyclic deriva-
tives could give valuable building blocks, scaffolds, screen-
ing compounds, and virtual templates for medicinal chemis-
try aims. Among trifluoromethyl-substituted pyrimidones-
(thiones), effective herbicidal,[5a] acaricidal,[5b] promising
anticancer,[5c] antimycobacterial,[5d] and antiviral agents[5e]
were found.
Introduction
Simple heterocyclic compounds, such as pyrimidin-
2(1H)-ones, are well known because of their most impor-
tant natural representatives, namely, the uracil, thymine,
and cytosine nucleobases, which are the essential compo-
nents of DNA and RNA molecules.[1] The chemistry of
these compounds has been studied intensively for decades
since the structures of nucleic acids were discovered, but
there is still much to explore.[2] One of the most promising
research areas in this field is the synthesis and biological
activity of fluorinated analogues.[3] Some of these deriva-
tives have already been used in clinical practice and are now
vital components of modern anticancer and antiviral treat-
ments, for example, fluorouracil, trifluridine, and efavirenz.
It is common knowledge in medicinal chemistry that the
introduction of a trifluoromethyl group, probably the most
popular fluorinated functional group, can substantially af-
fect the physicochemical parameters of the molecule, such
as its reactivity, acidity, and lipophilicity.[4] It is one of the
most lipophilic groups, and it thus provides a convenient
way to improve cell penetration and to make bioactive com-
4-(Trifluoromethyl)pyrimidin-2(1H)-ones
I
represent
fluorinated nucleobase analogues derived from the substitu-
tion of the amino group of cytidine or the hydroxy group
of uracil and thymine (in one of their tautomeric forms) by
the trifluoromethyl group. Their synthesis has been de-
scribed in a series of papers,[6] including our own meth-
od,[6a] but chemical and biological properties still remain
insufficiently explored[7] and are of great promise for syn-
thetic applications and bioactivity studies. It is quite evident
that the introduction of the electron-withdrawing trifluoro-
methyl group at the 4-position of the pyrimidone nucleus
induces electron deficiency at this site, and thus an attract-
ive electrophilic center is created. Another electrophilic re-
action center of the heterocycle is formed at the 6-position
as a result of the p conjugation between the endocyclic
C=N and C=C bonds. Nucleophilic attack at these bonds
could lead to isomeric adducts, dihydropyrimidone deriva-
tives II and III, with asymmetric carbon atoms (Scheme 1).
It is interesting that evidence of reactions of this kind
and their regioselectivity, not to mention possible enantio-
selectivity and catalysis, is still lacking in the literature (the
[a] Institute of Organic Chemistry,
National Academy of Sciences of Ukraine,
Murmans’ka 5, Kyiv 02094, Ukraine
E-mail: vsukach@gmail.com
www.ioch.kiev.ua
[b] Enamine Ltd.,
Oleksandra Matrosova Street, 23, Kyiv 01103, Ukraine
[c] School of Engineering and Science, Jacobs University Bremen,
Campus Ring 1, 28759 Bremen, Germany
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201301542.
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Control of Selectivity in Asymmetric Organocatalytic Additions
rate as well as on the regio- and enantioselectivity of
organocatalyzed addition reactions by using acetone as a
nucleophile. The optimization of the reaction conditions in-
cluded a search for the most efficient chiral organocatalysts
to obtain enantioenriched products. It is also for the first
time that the regio- and enantioselectivity of organocata-
lytic reactions of ambident heterocyclic electrophiles have
been studied in terms of thermodynamic and kinetic con-
trol. In particular, we analyzed how the substituents in the
pyrimidone systems and the chiral organocatalysts used af-
fect the ratio of thermodynamically and kinetically pre-
Scheme 1. 3,6- and 3,4-Addition of the nucleophile (NuH) to 4-
(trifluoromethyl)pyrimidin-2(1H)-ones I with the formation of
Mannich-like regioisomers II (addition to the C=N bond) or
Michael-like regioisomers III (addition to the C=C bond).
only exception is the hydration reaction[7]). Notably, some ferred acetone adducts, their enantiomeric composition,
physiological processes are governed by enzyme-catalyzed and the equilibrium nature of the reactions under study.
reactions of the pyrimidine ring of cytidine in which a cru-
cial role is played by the electrophilic centers at the 4,6-
positions of the heterocycle. Such biochemical conversions
Results and Discussion
are most vividly illustrated by the cytidine deaminase bioca-
talyzed deamination of cytosine starting with hydration of active
Previously, we suggested two synthetic routes to optically
4-aryl-4-(trifluoromethyl)-3,4-dihydropyrimidin-
the endocyclic C=N bond.[8] Another important example is 2(1H)-ones on the basis of the asymmetric l-proline-
the methyltransferase-induced methylation of the cytidine organocatalyzed Mannich reaction of trifluoromethyl-sub-
DNA base, which involves the reversible nucleophilic ad- stituted ketimines with acetone followed by heterocycli-
dition of the cysteine thiol group to the endocyclic C=C zation of the resulting enantioenriched β-aminoketones.[12]
bond.[9] That is why studies on catalytic nucleophilic ad- 4-(Trifluoromethyl)pyrimidin-2(1H)-ones I contain the tri-
ditions to simple pyrimidin-2(1H)-one derivatives promise fluoromethyl ketimine moiety, which is structurally very
deeper insight into both the theory of pyrimidone reactivity close to N-carbamoyl ketimines formerly described by
and relevant biochemical processes.
us.[12b] It might therefore be expected that the organocata-
According to the results of earlier studies,[10] trifluoro- lytic Mannich reaction of I with CH-acidic carbonyl com-
methyl-free pyrimidin-2(1H)-ones react with enolates and pounds would give adducts at the C=N bond. Besides, sim-
various organometallic reagents to provide regioselective ilar asymmetric reactions were performed with benzo ho-
products of types II and III or, alternatively, a mixture of mologous
compounds,
4-(trifluoromethyl)quinazolin-
the two, depending on the structure of the substrate and 2(1H)-ones.[15] However, as already mentioned, such con-
the nature of the nucleophile. In the literature, the applica- versions of the simplest benzo-unfused pyrimidones con-
tion of this synthetic scheme to the enantioselective prepa- taining an activated C=C bond (an additional electrophilic
ration of 3,4-dihydropyrimidin-2(1H)-ones is restricted to center) in the heterocyclic ring have been scarcely investi-
the addition of enantiomerically pure α-lithiated (R)-(+)- gated to date and their course is difficult to predict.
methyl p-tolyl sulfoxide to the C=N bond of 4-unsubsti-
First, we studied the organocatalytic reaction of ketones
tuted 5-alkoxycarbonyl-pyrimidin-2(1H)-ones; the reaction with 6-substituted pyrimidones 1, which, owing to the very
yielded a 5:1 mixture of diastereomeric products.[10a] At the different electrophilicity of the two reaction centers, were
same time, organocatalytic reactions of the simplest pyrim- assumed to react only at the more-active 4-position of the
idin-2(1H)-ones as unique electrophilic substrates offer as pyrimidine ring. Initial experiments were conducted by
yet unexplored opportunities and unexploited advantages using four types of starting pyrimidones, with substituents
for the asymmetric synthesis of chiral dihydropyrimidones. of various nature in the 1,5,6-positions (Table 1);[6a] acetone
From a practical point of view, compounds of types II was chosen as a nucleophilic reagent, l-proline was used as
and III are interesting as prototypes for a plethora of di- a catalyst, and DMSO was the solvent.
hydropyrimidin-2(1H)-ones exhibiting diverse bioactivi-
As found, substrates 1a and 1b entered into the reaction
ties.[11] Their trifluoromethylated analogues belong to diffi- neither at room temperature nor at 60 °C. Compound 1c,
cult-to-obtain type II compounds previously reported by upon reaction at room temperature for 240 h, was 93% con-
us[12] or to hitherto undescribed type III 3-substituted de- verted into product 2c, which was obtained pure in 78%
rivatives. Given that enantiomeric 3,4-dihydropyrimidin- yield (Table 1, entry 4). More reactive pyrimidone 1d pro-
2(1H)-ones were shown to substantially differ in bioactivi- vided the corresponding adduct in 85% yield after a reac-
ty,[11e,13] the presence of an endocyclic stereogenic center in tion time of 40 h (Table 1, entry 5). The conversion of pyr-
such structures is a significant factor that allows enantiose- imidones was much slower in DMF (Table 1, entry 6) and
lective synthetic strategies.[14]
especially in acetone, and did not proceed at all in aceto-
This paper reports the first detailed study on the asym- nitrile. Thus, for the reaction to take place, the pyrimidine
metric organocatalytic reactions of trifluoromethylated pyr- ring must bear electron-withdrawing substituents, an alk-
imidones I to afford derivatives of 3,4-dihydropyrimidin- oxycarbonyl group at the 5-position, and preferably an aryl
2(1H)-ones II and III. We systematically investigated the residue at the 6-position. It is also important that there be
effect of 1-, 5-, and 6-substituents in pyrimidones I on the an alkyl substituent at the N1 atom.
Eur. J. Org. Chem. 2014, 1452–1460
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V. A. Sukach et al.
FULL PAPER
Table 1. l-Proline catalyzed addition of acetone to 6-substituted 4-
(trifluoromethyl)pyrimidin-2(1H)-ones 1.
Table 2. Effect of acid additives on the enantioselectivity of the (S)-
PMP-catalyzed addition of acetone to 4-(trifluoromethyl)pyrim-
idin-2(1H)-one 1d.
Entry Acid additive
Time Yield[a] er[b]
Entry
1
R1
H
R2
R3
Time
[h]
T
[°C]
Yield[a]
[%]
[h]
[%]
1
2
–
48
144
48
96
24
24
24
24
48
48
48
75
71:29
1
2
3
4
5
6
1a
Me Me
240
240
240
240
48
20
20
60
20
20
20
0
0
0
CF3CO2H
n.i.[c] 67:33
1b CO2Et Ph
1b CO2Et Ph
H
H
3
4
p-toluenesulfonic acid
CH3CO2H
74
80
79
72
79
78
77
75
71
78:22
75:25
78:22
77:23
75:25
75:25
78:22
81:19
75:25
1c CO2Et Me Me
1d CO2Et Ph
1d CO2Et Ph
78
85
n.i.[b]
5
6
7
PhCO2H
Me
Me
4-NO2C6H4CO2H
240
l-tartaric acid[d]
d-tartaric acid[d]
dibenzoyl-l-tartaric acid[d]
di(1-naphthoyl)-l-tartaric acid[d]
acetone ketal of l-tartaric acid[d]
[a] Yield of the pure isolated product. [b] DMF was used as the
solvent; the product was not isolated (conversion Ͻ15%).
8
9
10
11
Attempted reaction of 1d with methyl ethyl ketone and
cyclopentanone demonstrated that ketones other than acet-
one, if treated under the same conditions, yielded, at best,
only trace amounts of the corresponding products. This is
generally indicative of the low reactivity of this type of het-
erocyclic trifluoromethylketimine in the organocatalytic
Mannich reaction as compared to quinazolone derivatives,
which react with a variety of aliphatic ketones.[15a] We sup-
pose that acetone is the most active ketone nucleophile, as
its reactive enamine intermediate causes less steric hin-
drance in the transition state with heterocyclic ketimine
possessing the bulky CF3 group. As found, a feature in
common for pyrimidones and quinazolones in this reaction,
with l-proline used as the organocatalyst, is a very low
enantioselectivity (enantiomeric ratio, er, not greater than
57:43).
[a] Yield of the pure isolated product. [b] The er values were deter-
mined by using a chiral shift reagent (see the Supporting Infor-
mation). [c] n.i.: not isolated; catalyst deactivation was observed.
[d] 0.55 equiv. was used.
The optimum conditions found for the asymmetric Man-
nich reaction were used in the reaction of substituted 5-
ethoxycarbonyl-6-arylpyrimidones 1e–j with acetone
(Table 3). Introduction of the p-methoxybenzyl group in-
stead of the methyl group at the 1-position was shown to
reduce the reaction time (Table 3, entry 1) and to give rise
to a considerable enantiomeric excess. Likewise, the pres-
ence of an electron-withdrawing nitro group on the 6-aryl
ring markedly accelerated the addition of acetone (Table 3,
entry 5). In all cases, the enantioselectivity remained nearly
We established that, as with quinazolones,[15a] a much
higher optical purity of resulting product 2d could be
achieved if (S)-(+)-1-(2-pyrrolidinomethyl)pyrrolidine [(S)-
PMP] was used instead of l-proline, especially in the pres-
ence of a Brønsted acid (1.1 equiv.; Table 2, entries 1 and
3): the use of (S)-PMP (30 mol-%) provided 2d with
71:29er, and this selectivity was increased to 78:22er upon
the addition of p-toluenesulfonic acid. Salts of (S)-PMP
with acetic, tartaric, and benzoic acids also proved to be
efficient organocatalysts (Table 2, entries 4–8). It was shown
that the pKa values of the Brønsted acids as well as the
configurations of their chiral centers (e.g., in tartaric acids)
have no significant effect on the enantioselectivity of the
organocatalytic reactions (Table 2, entries 7 and 8). More-
over, the (S)-PMP salts of l-tartaric acid derivatives con-
taining two bulky O-naphthoyl moieties or the configura-
tionally rigid acetone ketal moiety afforded similar yields
and er values as the corresponding derivative of unmodified
benzoic acid; the latter was finally chosen for further experi-
ments as the optimum acid additive to (S)-PMP (Table 2,
entries 9–11).
Table 3. Asymmetric organocatalytic synthesis of 4-(trifluoro-
methyl)-3,4-dihydropyrimidin-2(1H)-ones 2e–j.
Entry
1
R1
R2
Time Yield[a] er[b]
[h]
[%]
1
2
3
4
5
6
1e[c] Me
1f 4-ClC6H4
1g 4-BrC6H4
1h 3-MeOC6H4 Me
1i 4-NO2C6H4 Me
1j 4-NO2C6H4 Me
4-MeOC6H4CH2
Me
Me
40
16
16
79
80
81
77
83
74
71:29
78:22
78:22
80:20
81:19
77:23
16
8
240[d]
[a] Yield of the pure isolated product. [b] The er values were deter-
mined by using a chiral shift reagent (see the Supporting Infor-
mation). [c] Methyl ester 1e was used. [d] (S)-PMP (5 mol-%) and
benzoic acid (5.5 mol-%) were used.
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Control of Selectivity in Asymmetric Organocatalytic Additions
constant, with up to 81:19er. A decrease in the catalyst carbonyl group). Acetone can add to 3 at two electrophilic
loading to 5 mol-% resulted only in a much reduced reac- centers: at the 6-position (1,4-addition, a variation of the
tion rate (Table 3, entry 6).
Michael reaction) and at the 4-position, as for pyrimidones
As was first noticed by Jiang et al.,[15a] benzo homo- 1 (1,2-addition, a heterocyclic variation of the Mannich re-
logues of 2, substituted dihydroquinazolones, are strongly action). In the former case, the product exists in the more
prone to enantiomeric self-discrimination in the course of stable tautomeric form containing an enamine moiety. For
crystallization. This effect is due to the predominant forma- nearly all substrates 3, the resulting isomeric dihydropyrim-
tion of more stable heterochiral dimers in the solid state. As idones 4 and 5 (3,6- and 3,4-acetone adducts, respectively)
a result, recrystallization leads to an almost racemic crystal were isolated in a pure state. However, the regioisomeric
precipitate and a mother liquor that is enriched in the major and enantiomeric ratios of the products were dictated by
enantiomer. In this connection, the enantiocomposition of the nature of the organocatalyst used and the substituent at
2 was always analyzed by using noncrystallized samples.
the 5-position; the selectivity also depended on the reaction
Compound 2g, with 78:22er, was recrystallized from 2- time. The time dependence suggests that the addition of
propanol. The mother liquor was evaporated, and the col- acetone to pyrimidones is an equilibrium process that can
lected residue was recrystallized again; this procedure was be controlled thermodynamically or kinetically.
repeated. An enantiopure sample of 2g was thus obtained
This part of the work started with a thorough investiga-
in 15% yield, and we succeeded to grow its homochiral tion of less-substituted 3a–e. Following the optimum condi-
monocrystal. According to X-ray analysis, the major tions established for the addition of acetone to pyrimidones
enantiomer has the (S) configuration of the chiral center 1, we performed the analogous reaction of substrates 3 with
(Figure 1, see the Supporting Information for details). Im- three chiral organocatalysts, namely, l-proline, (S)-PMP,
portantly, other heterocyclic and acyclic trifluoromethyl and its salt with benzoic acid; DMSO was used as the sol-
ketimines, if treated with acetone in the asymmetric Man- vent.
nich reaction catalyzed by l-proline and its derivatives, also
Upon using l-proline at 20 °C, the reaction was only
produced predominantly the (S)-enantiomeric adducts, 74% complete after 48 h, and it delivered a 93:7 mixture of
which thus indicates a general enantiocontrol scheme gov- regioisomers 4a/5a (Table 4, entry 1). The reaction progress
erning reactions of this kind.[12b,16]
was easily monitored by a shift in the signal for the tri-
fluoromethyl group in the 19F NMR spectrum. With the
reaction time extended to 240 h, a 85% conversion was ob-
served accompanied with a negligible increase in the
amount of regioisomer 5a (Table 4, entry 2). The enantio-
composition of the isolated mixture (i.e., 3a, 4a, and 5a)
was analyzed by 19F NMR spectroscopy by using the chiral
lanthanide shift reagent Eu(hfbc)3 (hfbc = 3-heptafluoro-
butyryl-d-camphor) to reveal that product 4a was formed
as a racemate. It was readily isolated from the mixture as a
pure compound in 47% yield and characterized after
recrystallization from 2-propanol/hexane (3:1). The reac-
tion organocatalyzed with (S)-PMP and benzoic acid pro-
ceeded likewise, with the difference that the conversion was
over 95% after 48 h and product 4a was isolated in a higher
(71%) yield (Table 4, entry 5).
The reaction of pyrimidone 3a with acetone in the pres-
ence of (S)-PMP but without the acid additive was 91%
complete after 24 h; however, the regioselectivity was signif-
icantly decreased, with a 4a/5a ratio of 52:48 in the reaction
mixture (Table 4, entry 3). Notably, 240 h later, this ratio
changed to 19:81 (Table 4, entry 4). One can, therefore, in-
Figure 1. A perspective view of the (S)-enantiomer molecule of 2g
obtained in the X-ray study.
The next stage of our study was concerned with the ad- fer that the addition of acetone at the double bond of 3a is
dition of acetone to 6-unsubstituted 4-(trifluoromethyl)pyr- a reversible process and regioisomer 4a is a kinetically pre-
imidones 3a–m. Simplest 1-alkylpyrimidones 3a–e unsubsti- ferred product that is formed faster but then rearranges into
tuted at the 5,6-positions as well as 1,5-dimethyl derivative more thermodynamically stable regioisomer 5a. Pure 4a iso-
3f were obtained by a known procedure.[6d] 1-Alkyl(aryl)-5- lated in the (S)-PMP benzoate catalyzed reaction was con-
methoxycarbonylpyrimidones 3g–m were synthesized by the verted into isomer 5a by treating with (S)-PMP (30 mol-%)
method previously described by us.[6a] The compounds ob- in DMSO; the conversion degree was, however, only 70%
tained represented a convenient model series to study the after 240 h (Scheme 2) as a result of the absence of an excess
reactivity of 6-unsubstituted 4-(trifluoromethyl)pyrim- amount of acetone.
idones as electrophiles, in relation to the nature of the 5-
Regrettably, 5a, as for 4a, was formed in nearly racemic
substituent (a hydrogen atom, a methyl group, or an alkoxy- form, regardless of the synthetic procedure used. As an ex-
Eur. J. Org. Chem. 2014, 1452–1460
© 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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1455

V. A. Sukach et al.
Table 4. Regioselectivity of the organocatalytic addition of acetone to 5,6-unsubstituted 4-(trifluoromethyl)pyrimidin-2(1H)-ones 3a–e.
FULL PAPER
Entry
3
R
Catalyst[a]
Time
[h]
4/5
Yield[c] [%]
(compd.)
(conv. [%])[b]
1
2
3
4
5
6
7
8
3a
3a
3a
3a
3a
3a
3b
3b
3c
3c
3d
3d
3e
3e
Me
Me
Me
Me
Me
Me
Bn
Bn
l-Pro
l-Pro
PMP
PMP
PMP+acid
PMP+acid
PMP
PMP+acid
PMP
PMP+acid
PMP
PMP+acid
PMP
48
240
24
240
48
240
120
48
120
48
240
48
240
48
93:7 (74)
89:11 (85)
52:48 (91)
19:81
90:10
78:22
11:89
92:8
17:83
85:15
47 (4a)
45 (4a)
n.i.[d]
55 (5a)
71 (4a)
60 (4a)[e]
71 (5b)
73 (4b)
65 (5c)
64 (4c)
67 (5d)
45 (4d)
61 (5a)
50 (4e)
9
4-MeC6H4CH2
4-MeC6H4CH2
iBu
iBu
2-MeOEt
2-MeOEt
10
11
12
13
14
12:88
90:10 (80)
7:93
PMP+acid
89:11 (83)
[a] PMP+acid is a 1:1.1 mixture of (S)-PMP/benzoic acid. [b] If not specified, conversion was almost quantitative. [c] Yield of the pure
isolated product. [d] Not isolated. [e] The er of minor product 5a was about 70:30 (see the Supporting Information).
into 5b in the presence of (S)-PMP (30 mol-%) and of an
equimolar amount of 3c yielded, after 120 h, a mixture of
six compounds: 3b, 3c, 4b 4c, 5b, and 5c. Products 3b, 4c,
and 5c can only result provided the intermolecular re-
arrangement mechanism is operative, which implies the
equilibrium elimination of the acetone molecule from 4b
and its addition at both possible positions of 3c. This is
unambiguous evidence for strong thermodynamic control
in the asymmetric formation of the 6-adduct and hence for
the racemic nature of products 4.[17c] The reaction leading
to regioisomer 5c also showed certain signs of reversibility,
which was illustrated by another cross-experiment: pure 5c
was treated with (S)-PMP (30 mol-%) and an equimolar
amount of 3b. After 120 h, a small amount of 5b was de-
tected in the reaction mixture by GC–MS, which thus
clearly points to the occurrence of a retro-Mannich reaction
of 5c as the only possible source of 5b.
As found, the same features are characteristic of the ad-
dition of acetone to pyrimidones 3d and 3e, which produced
the corresponding isobutyl- and 2-methoxyethyl-substituted
derivatives 4d/4e and 5d/5e (Table 4, entries 11–14). To elu-
cidate the effect caused by the nature of the 5-substituent
on the regio- and enantioselectivity of the reaction, we
studied the analogous conversions of 5-methyl- and 5-meth-
oxycarbonyl-substituted pyrimidones 3f–m (Tables 5 and 6).
1,5-Dimethylpyrimidone 3f reacted with acetone much
more slowly if l-proline or (S)-PMP monobenzoate was
used as the catalyst. In the latter case, the conversion was
47% after 24 h, which increased to 82% after 240 h
(Table 5, entries 1, 3, 4). Notably, 6-adduct 4f largely pre-
vailed in the reaction, though the amounts of isomers 4f
Scheme 2. Organocatalytic rearrangement of kinetic Michael-like
regioisomer 4a into thermodynamic Mannich-like product 5a.
ception, minor product 5a (10–22%), which was detected in
the reaction with the (S)-PMP benzoate catalyst, had an er
of about 70:30 (Table 4, entry 6). The lack of enantio-
selectivity may be attributed to the high reversibility of the
3a to 4a conversion and, possibly, of the 3a to 5a conver-
sion. Indeed, reversible asymmetric processes are controlled
thermodynamically, which thus leads to racemates.[17] Inhi-
bition of the competing asymmetric Mannich reaction by
adding a Brønsted acid (1 equiv.) to (S)-PMP proved to be
an unexpected effect that has yet to be rationalized.[18]
Cross-experiments were performed to verify that there
was an equilibrium between the addition of acetone and
elimination at the 4,6-positions of the pyrimidone ring un-
der organocatalytic conditions (see the Supporting Infor-
mation). First, we synthesized 1-benzyl- and 1-(4-meth-
ylbenzyl)-substituted pyrimidones 3b and 3c and obtained,
by procedures similar to that used for 3a, their pure acetone
adducts 4b/4c and 5b/5c (Table 4). Compounds 3b and 3c
were assumed to have much the same reactivities in view of
their very similar structures. Analytical GC–MS was per-
formed to firmly establish that the conversion of pure 4b
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Control of Selectivity in Asymmetric Organocatalytic Additions
Table 5. Regio- and enantioselectivity of the organocatalytic ad- shift reagent demonstrated the racemic nature of 4f and a
dition of acetone to 1,5-dimethylpyrimidinone 3f.
75:25er for 5f (Table 5, entry 4).
The catalytic action of (S)-PMP in the basic form pro-
vided practical completion of the reaction within 240 h,
with a predominance of thermodynamically preferred iso-
mer 5f possessing a 65:35er (Table 5, entry 2).
We assume that the introduction of a methyl group at
the 5-position of the pyrimidine ring results in a lower free
energy of the Mannich reaction product, which thus favors
the formation of dihydropyrimidone 5f. This may be due to
the fact that initial pyrimidone 3f has a planar structure
that is sterically constrained by the neighboring 4-(tri-
fluoromethyl) and 5-methyl groups, whereas the non-plan-
arity of final dihydropyrimidone 5f reduces the strain in the
molecule. Some degree of enantioselectivity observed in the
(S)-PMP-catalyzed Mannich reaction of 3f is likely to arise
from its decreased reversibility (a higher activation barrier
of the corresponding retro reaction).
Entry Catalyst[a] Time 4f/5f
Yield[c] [%] er
[h]
(conv. [%])[b] (compd.) (compd.)[d]
1
2
3
4
l-Pro
PMP
PMP+acid 24
PMP+acid 240
72
240
78:22 (26)
12:88
81:19 (47)
22:78 (95)
n.i.
n.d.
44 (5f)
n.i.
65:35 (5f)
rac (4f)
37 (5f)
75:25 (5f), rac (4f)
[a] PMP+acid is a 1:1.1 mixture of (S)-PMP/benzoic acid. [b] If not
specified, conversion was almost quantitative. [c] Yield of the pure
isolated product; n.i.: not isolated. [d] The er values were deter-
mined by using a chiral shift reagent (see the Supporting Infor-
mation); rac = nearly racemic; n.d.: not determined.
It is reasonable to expect that adducts 4 and 5 should be
formed most easily if starting pyrimidones 3 bear an elec-
tron-withdrawing alkoxycarbonyl group instead of an elec-
tron-donating methyl group at the 5-position. This assump-
and 5f tended to reverse with time, which is in contrast to tion was verified by using 3g–m with alkyl or aryl substitu-
the nearly constant ratio of likewise prepared 5-unsubsti- ents at the N1 atom and a 5-methoxycarbonyl group. In
tuted products 4a and 5a (cf. Table 4, entries 5 and 6; comparison with other substrates, they exhibited dramati-
Table 5, entries 3 and 4). Analysis of the isolated mixture of cally enhanced reactivity in the l-proline-catalyzed addition
4f and 5f by 19F NMR spectroscopy with the use of a chiral of acetone. For instance, the reaction with pyrimidone 3g
Table 6. Regio- and enantioselectivity of the organocatalytic addition of acetone to 6-unsubstituted 5-methoxycarbonyl-4-(trifluorometh-
yl)pyrimidin-2(1H)-ones 3g–m.
Entry
3
R
Cat.[a]
Time
[h]
T
[°C]
4/5
Yield[c] [%]
(compd.)
er[d]
(conv.[b] [%])
1
2
3
4
5
6
7
8
3g
3g
3g
3g
3g
3h
3h
3i
4-MeOC6H4CH2
4-MeOC6H4CH2
4-MeOC6H4CH2
4-MeOC6H4CH2
4-MeOC6H4CH2
4-EtOC6H4CH2
4-EtOC6H4CH2
4-MeOC6H4(CH2)2
4-MeOC6H4(CH2)2
2,4,6-(MeO)3C6H2CH2 l-Pro
2,4,6-(MeO)3C6H2CH2 PMP+acid
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-ClC6H4
l-Pro
l-Pro
PMP
PMP+acid
PMP+acid
l-Pro
PMP+acid
l-Pro
60
12
12
12
48
12
48
12
60
12
48
8
8
72
8
72
8
72
20
11
11
11
20
11
20
11
20
11
20
11
11
20
11
20
11
20
2:98
89:11 (90)
5:95
10:90
2:98
94:6
3:97
93:7 (93)
2:98
85:15 (40)
2:98
90:10
3:97 (43)
2:98
82 (5g)
61 (4g)
72 (5g)
68 (5g)
69 (5g)
65 (4h)
80 (5h)
66 (4i)
75 (5i)
n.i.[e]
72 (5j)
80 (4k)
ni
77 (5k)
68 (4l)
73 (5l)
69 (4m)
75 (5m)
rac
rac
65:35
76:24
73:27
rac
70:30
rac
75:25
rac
83:17
rac
70:30
77:23
rac
76:24
rac
9
3i
PMP+acid
10
11
12
13
14
15
16
17
18
3j
3j
3k
3k
3k
3l
3l
3m
3m
l-Pro
PMP
PMP+acid
l-Pro
PMP+acid
l-Pro
88:12
2:98
87:13
2:98
4-ClC6H4
4-BrC6H4
4-BrC6H4
PMP+acid
72:28
[a] PMP+acid is a 1:1.1 mixture of (S)-PMP/benzoic acid. [b] If not specified, conversion was almost quantitative. [c] Yield of the pure
isolated product; n.i.: not isolated. [d] The er values were determined by using a chiral shift reagent (see the Supporting Information);
rac = nearly racemic. [e] Product 4j was hardly separable.
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1457

V. A. Sukach et al.
FULL PAPER
was complete within 60 h to give 5g as the major product,
The developed regioselective synthetic route to 5-meth-
which was accompanied by a negligible amount of isomer oxycarbonyl-substituted isomers 4 and 5 was used to pre-
4g (Table 6, entry 1). As for all chiral dihydropyrimidones pare a number of other compounds of this family, such as,
obtained with l-proline, adduct 5g proved to be nearly race- for instance, dihydropyrimidones 4, 5i, and 5j (Table 6, en-
mic.
tries 8–11) and their analogues 4 and 5k–m (Table 6, en-
As found, for isomer 4g (in the racemic form) to be iso- tries 12–18). Compound 5j was isolated with the maximum
lated as the major product, it is necessary that the reaction er among the compounds studied, that is, 83:17. As in the
be kinetically controlled, that is, cooled and stopped after case of 6-aryl-substituted 2, the enantiomeric excess of
a short time, up to 12 h (Table 6, entry 2). If the reaction products 5g–m could be amplified by crystallization from
mixture is allowed to stand at room temperature for a more 2-propanol/hexane. We assume that, as with 2g, all enantio-
prolonged time (2–3 d), initially prevailing product 4g re- selective conversions leading to 5 afford their major
arranges into thermodynamically more stable isomer 5g. In enantiomer with the (S) configuration. This conjecture is
the (S)-PMP-catalyzed reaction (with or without the ben- consistent with the data obtained by 19F NMR spec-
zoic acid additive), the kinetically preferred regioisomer troscopy with the use of a chiral shift reagent, as the down-
cannot be isolated at all (Table 6, entries 3–5). At the same field component of the split resonance for the trifluoro-
time, absolutely major product 5g is characterized by the methyl group is always more intense (except for 5j bearing
predominance of one enantiomer: its er, irrespective of the a bulky trimethoxybenzyl substituent).
temperature regime, is up to 76:24 (Table 6, entry 5).
As with 3b, 4b, and 5b, we performed analogous cross-
Conclusions
syntheses with structurally related substrates 3g and 3h and
corresponding acetone adducts 4g/4h and 5g/5h. First, to
study the reversibility of the addition of acetone at the 6-
position, we used corresponding adduct 4g as a source of
acetone, which would enter into further addition reactions.
The presence of cross-adduct 5h in the reaction mixture was
corroborated by the fact that the rearrangement of kinetic
product 4g into thermodynamically stable 5g under cataly-
sis with (S)-PMP benzoate was governed by the intermo-
lecular mechanism and involved rapid equilibration be-
tween 4g and the starting reagents (3g and acetone). In a
separate experiment, enantioenriched isomer 5g was ob-
tained from racemate 4g (Scheme 3).
This study provides detailed insight into the regio- and
enantioselectivity of the organocatalytic addition of acetone
to 4-(trifluoromethyl)pyrimidin-2(1H)-ones 1 and 3. It was
established that (S)-PMP monobenzoate is the optimum
chiral organocatalyst to afford Mannich-like products 2 and
5 in high yields with enantiomeric ratios up to 83:17. We
showed for the first time that simple 6-unsubstituted 4-(tri-
fluoromethyl)pyrimidones 3 undergo, under the conditions
of kinetic control, equilibrium Michael-like acetone ad-
dition to yield racemic 3,6-adducts 4. These compounds are
always formed as racemates irrespective of the catalyst used.
Owing to the reversibility of the formation of adducts 4,
they rearrange with time through an intermolecular mecha-
nism to give thermodynamically preferred enantioenriched
Mannich-like 3,4-adducts 5. As an unexpected result, a
Brønsted acid additive to the (S)-PMP catalyst was found
to noticeably affect the reaction regioselectivity of 5,6-un-
substituted pyrimidones 3 by hindering the Mannich-like
reaction. Further studies are currently ongoing in our labo-
ratory on organocatalytic transformations of 4-(trifluoro-
methyl)ated pyrimidones to determine whether the ob-
served reaction pathways are common to other types of or-
ganocatalysis (noncovalent activation instead of amino-
catalysis) and nucleophiles.
Scheme 3. Asymmetric organocatalytic rearrangement of kinetic
Michael-like regioisomer 4g into thermodynamic Mannich-like
product 5g (PMB = 4-MeOC6H4CH2).
The second cross-synthesis was aimed to establish the de-
gree of reversibility of the addition of acetone at the 4-posi-
tion. Accordingly, 5h was used in an attempt to provide
acetone for further additions to 3g. However, GC-MS
peaks of expected cross-products 4g and 5g could not be
detected; this suggested that the formation of the 4-adduct
was almost irreversible. The irreversibility of the Mannich
reaction evidently caused by the 5-alkoxycarbonyl substitu-
ent on the pyrimidine ring provides a rationalization for the
nonracemic nature of products 5g and 5h. Indeed, though
these regioisomers are formed under thermodynamic con-
trol, their enantiocomposition is nonetheless controlled ki-
netically.
Experimental Section
General Procedure for the Synthesis of 2, 4, and 5 Starting from
Pyrimidone 1 or 3: Pyrimidone 1 or 3 (1 mmol) and acetone
(0.73 mL, 10 mmol) were dissolved in DMSO (3 mL), and then the
catalyst was added [l-proline or (S)-PMP and optionally 1.1 or
0.55 equiv. of Brønsted acid according to the indications in
Tables 1–6]. The mixture was stirred under the specified conditions,
and then poured into 3% HCl (30 mL) and extracted with dichloro-
methane (30 mL). The organic layer was washed with water (2ϫ
20 mL), 3% sodium hydrocarbonate solution (20 mL), and brine
(20 mL). The combined organic phase was then dried with sodium
sulfate, and the solvent was evaporated. The obtained residue was
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Control of Selectivity in Asymmetric Organocatalytic Additions
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hexane (10 mL). The solid formed was filtered and crystallized
from hexane/iPrOH mixture (1:1–1:3) to yield the target com-
pound.
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V. A. Sukach et al.
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Received: October 10, 2013
Published Online: January 8, 2014
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