Facile synthesis of aryl-substituted 1,2,5,6-tetrahydropyrimidines and their stereochemical investigation

Article abstract of DOI:10.1135/cccc20040897

The present work is devoted to the investigation of 2,4,6-triaryl-1,2,5,6- tetrahydropyrimidine derivatives. A new facile approach to their synthesis based on the reaction of α,β-unsaturated ketones, carbonyl compounds and ammonia was developed. Some stereochemical features of the compounds obtained were fixed on the base of NMR data (including COSY and NOESY experiments).

Full text of DOI:10.1135/cccc20040897

Aryl-Substituted 1,2,5,6-Tetrahydropyrimidines
897
FACILE SYNTHESIS OF ARYL-SUBSTITUTED 1,2,5,6-TETRAHYDRO-
PYRIMIDINES AND THEIR STEREOCHEMICAL INVESTIGATION
1,
Valentin A. CHEBANOV *, Elena A. MURAVYOVA, Yulia V. SADCHIKOVA,
2
Sergey M. DESENKO , Vitaly N. CHERNENKO, Kiril M. KOBZAR and
Vladimir I. MUSATOV
Department of Photoactive Heterocyclic Compounds, Scientific and Technological Corporation
“Institute for Single Crystals”, National Academy of Science of Ukraine, Lenin Ave. 60,
1
2
61001 Kharkiv, Ukraine; e-mail: chebanov@isc.kharkov.com, desenko@isc.kharkov.com
Received Septem ber 24, 2003
Accepted Jan uary 20, 2004
Th e presen t work is devoted to th e in vestigation of 2,4,6-triaryl-1,2,5,6-tetrah ydropyrim idin e
derivatives. A n ew facile approach to th eir syn th esis based on th e reaction of α,β-un satura-
ted keton es, carbon yl com poun ds an d am m on ia was developed. Som e stereoch em ical fea-
tures of th e com poun ds obtain ed were fixed on th e base of NMR data (in cludin g COSY an d
NOESY experim en ts).
Keyw ord s: Nitrogen h eterocycles; 1,2,5,6-Tetrah ydropyrim idin es; Multicom pon en t reac-
tion s; Syn th etic m eth ods; Structure elucidation ; NMR spectroscopy; Ch alcon es; Pyrim idin es;
Heterocyclization s.
2,4,6-Triaryl-1,2,5,6-tetrah ydropyrim idin es are little studied due to th e ab-
sen ce of con ven ien t m eth ods of th eir syn th esis. Com poun ds of th is class
sh ow a wide spectrum of ph ysiological activity1,2 an d, m oreover, in clude
several fragm en ts (–NH–, –C=N–, aryl substituen ts) suitable for subsequen t
ch em ical m odification , wh ich allows to syn th esize large libraries of n ew
h eterocycles. On th e oth er h an d, th ese substan ces are appropriate objects
for studyin g fun dam en tal problem s con cern in g stereoch em istry an d elec-
tron structure of organ ic com poun ds.
To th e presen t date, on ly on e two-step m eth od of syn th esis of such type
of tetrah ydropyrim idin es is described in th e literature3. Th e first step is a re-
action of arom atic aldeh ydes an d am m on ia with form ation of N,N′-bis(aryl-
m eth yliden e)arylm eth an ediam in es. Th eir reaction with keton es con tain in g
active h ydrogen in α-position is th e secon d step. Th is m eth od h as several
serious weak poin ts. First of all, it does n ot allow to in troduce two aryls in to
position 2 or two differen t substituen ts in to position s 2 an d 6 of th e pyrim -
Collect. Czech. Chem. Commun. (Vol. 69) (2004)
doi:10.1135/cccc20040897

898
Chebanov et al.:
idin e m oiety. Secon d, accordin g to th e literature data3 th e direction of th e
secon d stage of th e reaction depen ds on th e n ature of keton e.
We h ave developed a m eth od of syn th esis of 2,4,6-triaryl-substituted
1,2,5,6-tetrah ydropyrim idin es 3 con sistin g in th e reaction of ch alcon es 1,
carbon yl com poun ds 2 an d am m on ia. A sim ilar approach h as been de-
scribed for preparation of som e alkyl-substituted 1,2,5,6-tetrah ydro-
pyrim idin es4. Auth ors of th is work described reaction of som e α,β-un satu-
rated keton es (propan -2-on e, 4-m eth ylpen t-3-en -2-on e, 2-acetyl-3-ph en yl-
acrylic acid eth yl ester) with aliph atic an d arom atic aldeh ydes an d keton es
in aqueous am m on ia. Th e aim of our work was to exten d th is m eth od for
arom atic un saturated keton es.
In th e course of th e in vestigation , a series of 1,2,5,6-tetrah ydropyrim idin es
3a–3o was syn th esized (Sch em e 1). Better yields of th e target com poun ds
an d sh orter reaction tim e were observed in th e case of form ation of
2-h ydroxy derivatives (com poun ds 3a–3m ). Th is could be associated with
th e h ydrogen bon d between th e h ydroxy group of ch alcon e an d am m on ia,
R3
R3
HA
HA
HB
H
HB
H
4
N3
N
R1
5
6
O
2
NH3
R4
X R1 + R4
X R1
1
R2
+
R4
R5
N
H
N
H
R3
R5
A
R5
B
O
R2
R2
1
2
3
3
R2
H
H
H
H
H
H
H
3-MeO
3-MeO
3-EtO
3-EtO
5-Cl
H
R3
R4
4-ClC6H4
R1
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
OH
H
R5
H
H
H
H
H
H
H
H
H
H
H
H
CH3
H
H
a
b
c
d
e
f
g
h
i
j
k
l
m
n
o
3-BrC6H4
4-MeC6H4
4-MeOC6H4
4-MeOC6H4
4-EtC6H4
4-EtOC6H4
4-MeC6H4
4-ClC6H4
4-ClC6H4
4-ClC6H4
3-MeOC6H4
4-EtC6H4
4-MeC6H4
Ph
3,5-Cl2C6H3
2-EtOC6H4
4-ClC6H4
2-MeO-5-BrC6H3
4-ClC6H4
4-BrC6H4
3-FC6H4
3-MeOC6H4
2-FC6H4
4-FC6H4
4-BrC6H4
CH3
Ph
4-ClC6H4
H
4-OH
4-MeOC6H4
H
SCHEME 1
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

Aryl-Substituted 1,2,5,6-Tetrahydropyrimidines
899
wh ich facilitates th e addition of am m on ia to th e double bon d of α,β-un sat-
urated keton e. An in direct con firm ation of th is assum ption is th e fact th at
in th e case of 4-h ydroxych alcon e (com poun d 3o) an in crease in th e yield
an d reaction rate was n ot observed.
Startin g 2-h ydroxych alcon es were syn th esized by a literature m eth od5,6
from salicylic aldeh ydes an d correspon din g acetoph en on es. Th e syn th esis
of ch alcon es an d 4-h ydroxych alcon es was carried out by th e kn own way7.
Subsequen t reaction of th e α,β-un saturated keton es 1 with carbon yl com -
poun ds 2 an d am m on ia gave 1,2,5,6-tetrah ydropyrim idin es 3a–3o.
Structures of com poun ds 3a–3o were proved by 1H an d 13C NMR spec-
trom etry usin g h ydrogen -deuterium exch an ge between th e obtain ed tetra-
h ydropyrim idin es an d CH3OD to establish position s of th e sign als NH an d
OH groups.
1H NMR spectra of tetrah ydropyrim idin es 3a–3o con tain all n ecessary sig-
n als – m ultiplet of m eth yl proton s at 2.60–3.10 ppm , broad sin glets of pro-
ton s in position s 2 an d 6 of th e h eterocycle (4–6 ppm ) an d m ultiplets of ar-
om atic proton s at 6.5–9 ppm . Sign als of proton s of am in o, h ydroxy an d all
oth er fun ction al groups are also presen t in th e spectra. Data of 13C NMR
spectroscopy are n ot in con tradiction with structures of 3a–3o.
Mass spectra recorded for com poun ds 3c an d 3e also con firm ed th e as-
sign ed structures: 3c: m/z 402 (100%) [M]+, 3e: m/z 466 (100%) [M]+.
Th us, in th e reaction of ch alcon es 1 with arom atic aldeh ydes 2 an d am -
m on ia, 2,4,6-triaryl-1,2,5,6-tetrah ydropyrim idin es 3a–3o were obtain ed.
1
Accordin g to th e H an d 13C NMR spectral data (ch em ical sh ifts an d m ulti-
plicity), altern ative structures, for exam ple 3,4,5,6- or 1,2,3,6-terah ydro-
pyrim idin es, were excluded.
In m ost cases th e target tetrah ydropyrim idin es 3 were obtain ed as m ix-
tures of diastereom ers. Th is con clusion was m ade on th e basis of detailed
an alysis of doublets of th e sign als in 1H NMR spectra. Th e existen ce of
diastereom ers is explain ed by th e presen ce of two ch iral cen ters in all com -
poun ds 3 with th e exception of 3m . Th e am oun t of m in or diastereom er
could vary in quite a wide ran ge. Expectedly, wh en R3 is equal to R4 (com -
poun d 3m ) th e doublets of sign als in th e spectra were n ot observed.
1
It is also n ecessary to n ote a m ultiplet ch aracter of H NMR sign als of pro-
ton s in position s 4 an d 6 of th e pyrim idin e rin g. By proton spin -spin de-
couplin g, th e in teraction of proton in position 2 with CH2 group was
proved in com poun ds 3a–3l, 3n , 3m (5J is about 1 Hz). Suppression of th e
sign al of proton in position 2 of th e h eterocycle led to sim plification of th e
CH2 sign als. Th is allowed to establish couplin g con stan ts in th e ABX sys-
Collect. Czech. Chem. Commun. (Vol. 69) (2004)

900
Chebanov et al.:
3
3
tem : for m ajor diastereom ers A th e JAX are 10–11 Hz, th e JBX are 4–5 Hz
2
an d JAB are about –17 Hz. Th e COSY spectrum of com poun d 3g con tain s
cross-peaks between th e CH2 sign als an d th e proton in position 2 in pyrim i-
din e rin g. It also dem on strates th e lon g-ran ge in teraction in com poun ds
3a–3l, 3n , 3m .
With regard to m agn itudes of spin -spin couplin g con stan ts (Table I),
som e stereoch em ical features of spatial structure of m ajor diastereom ers A
of com poun ds 3 were fixed: th e aryl substituen t in position 6 is equatorial,
th erefore HX is axial. Correspon din gly, HA is axial (tran s to HX) an d HB is
equatorial. To establish a spatial location of R3 an d R4, a NOESY experim en t
for com poun d 3g was m ade. Th e presen ce of cross-peaks between sign als of
C
(2)H an d C(6)H allows to assum e th at in th e m ajor diastereom er A, R4 = H is
axial an d R3 is equatorial. Between sign als of th e m in or diastereom er B,
TABLE I
Spin -spin couplin g con stan ts (in Hz) obtain ed by decouplin g experim en t for com poun ds
3a–3o
2JAB
3JAX
2JBX
Com poun d
A
B
A
B
A
B
3a
3b
3c
3d
3e
3f
–17.2
–17.0
–16.9
–17.5
–17.7
–17.1
–17.0
–16.8
–17.2
–17.0
–16.9
–17.4
–16.5
–16.3
–16.1
–
10.1
10.2
10.4
10.2
10.4
10.5
10.1
10.6
10.5
10.8
11.0
10.4
4.2
4.5
4.0
–
4.5
4.4
4.3
4.9
4.4
4.2
4.6
4.4
4.3
4.1
4.3
4.5
4.4
4.2
4.8
–
–16.7
–
4.8
–
4.4
–
3g
3h
3i
–16.2
–16.1
–16.5
–16.2
–16.1
–
5.1
4.8
4.4
4.2
4.8
–
4.1
4.3
4.3
4.4
4.2
–
3j
3k
3l
3m
3n
3o
–17.2
10.1
4.4
–16.5
–17.2
–16.0
–16.5
10.0
10.2
4.9
4.4
4.7
4.0
4.3
4.0
Collect. Czech. Chem. Commun. (Vol. 69) (2004)