A facile route to the synthesis of novel 2-amino-1,4,5,6- tetrahydropyrimidines from Baylis-Hillman products of acrylonitrile

Article abstract of DOI:10.1055/s-2005-863728

A facile route for the synthesis of novel 5-substituted-2-amino- 1,4,5,6-tetrahydro pyrimidines from the Baylis-Hillman adducts obtained from reaction of aldehydes and acrylonitrile is described.

Full text of DOI:10.1055/s-2005-863728

848
LETTER
A Facile Route to the Synthesis of Novel 2-Amino-1,4,5,6-
tetrahydropyrimidines from Baylis–Hillman Products of Acrylonitrile1
Route to the
S
ynt
i
hesis
o
c
f
Novel 2-A
h
mino-1,4, 5,
a
6-tetrahydropyrim
P
idines athak, Amrendra K. Roy, Sanjay Batra*
Medicinal Chemistry Division, Central Drug Research Institute, Lucknow-226001, India
Fax +91(522)2623405, +91(522)2623938; E-mail: batra_san@yahoo.co.uk
Received 2 December 2004
diamines (7a–e, 8a–e, 9a, 10a) was accomplished in high
yields through the action of LiAlH4. As the purification of
diamines led to significant reduction of yields, these com-
pounds (7a–e, 8a–e, 9a, 10a) were used crude for further
reactions. Treatment of diamines 7a–e, 8a–e, 9a, 10a with
cyanogen bromide then afforded the 2-amino-1,4,5,6-tet-
rahydro-pyrimidines 11a–e, 12a–e, 13, 14 in moderate to
good yields.11 As expected these compounds were ob-
tained as diastereoisomeric mixtures. To assess the gener-
al applicability of this synthetic strategy we utilized a
range of Baylis–Hillman adducts and amines (Table 1).
Abstract: A facile route for the synthesis of novel 5-substituted-2-
amino-1,4,5,6-tetrahydro pyrimidines from the Baylis–Hillman
adducts obtained from reaction of aldehydes and acrylonitrile is
described.
Key words: Baylis–Hillman, 2-amino-1,4,5,6-tetrahydropyrimi-
dines, 5,6,7,8-tetrahydro-2H-imidazo[1,2-a] pyrimidin-3-one
The Baylis–Hillman reaction has been one of the most in-
tensively studied C-C bond forming reactions of present
times. The major reason for the success of this reaction
has been the ease with which it can be performed and the
synthetic utility of multifunctional products obtained.
These products are suitable substrates for further elabora-
tion into useful molecular frameworks including hetero-
cycles and natural products.2,3
The 2-amino-1,4,5,6-terahydro-pyrimidines described
herein are amenable for further elaboration. For example,
they can be readily converted to 5,6,7,8-tetrahydro-2H-
imidazo[1,2-a]pyrimidin-3-ones employing bromoethyl
acetate. Therefore, the reaction of compounds 11e and 12c
with bromoethyl acetate in the presence of potassium
carbonate afforded the products 15 and 16, respectively,
in excellent yields.12
Although a variety of nitrogen heterocycles have already
been generated through Baylis–Hillman chemistry,4 we
were specifically interested in the generation of nitrogen
containing heterocyclic structures having the cyclic
guanidine pharmacophore since such heterocycles are of
immense biological significance.5–8 It was envisaged that
the Baylis–Hillman product of acrylonitrile and aldehydes
may offer entry into appropriately substituted 2-amino-
1,4,5,6-tetrahydropyrimidine derivatives, a facile synthe-
sis of which has only recently been reported.9 In principle,
the Michael addition of a primary amine to the double
bond of the Baylis–Hillman adduct followed by reduction
of the nitrile group would result in a diamino-derivative
which could lead to the desired compounds. Thus, we ex-
amined the possibility and report herein our preliminary
attempts on the development of a facile route for the
synthesis of 2-amino-1,4,5,6-tetrahydropyrimidines.
RCHO
1a–e
+
R
Ref. 10
CN
OH
CH2=CHCN
2a–e
R'NH2, MeOH
r.t., 4–18 h (5d for 2b),
40–87%
NHR'
CN
NHR'
NH2
LiAlH4,
Et2O
R
R
r.t., 30 min
OH
OH
3a–e, 4a–e
5a, 6a
7a–e, 8a–e
9a,10a
Synthesis of the title compounds is outlined in Scheme 1.
The Baylis–Hillman reaction of several aldehydes with
acrylonitrile was carried out according to the literature
procedure10 to obtain the corresponding Baylis–Hillman
adducts (2a–e) in excellent yields. Michael reaction of
different primary amines with adducts (2a–e) led to the
amino derivatives 3a–e, 4a–e, 5a, 6a. Interestingly,
though most reactions were complete within 4–18 hours,
reactions of compound 2b took 5 days. Reduction of ami-
no derivatives (3a–e, 4a–e, 5a, 6a) to the corresponding
CNBr, EtOH,
reflux, 4–6 h,
35–95%
R'
N
R'
N
BrCH2CO2Et,
K2CO3, DMF
N
NH2
R
N
R
N
80 °C, 6 h
82–92%
O
OH
OH
15,16
11a–e, 12a–e
13,14
SYNLETT 2005, No. 5, pp 0848–0850
Advanced online publication: 09.03.2005
2
1.
0
3.
2
0
0
5
Scheme 1 For key to R refer to Table 1.
DOI: 10.1055/s-2005-863728; Art ID: D35804ST
© Georg Thieme Verlag Stuttgart · New York

LETTER
Route to the Synthesis of Novel 2-Amino-1,4,5,6-tetrahydropyrimidines
849
Table 1 Yields and Physical Characteristics of New Compoundsa
Entry
R
R¢
Compound No., yield (%), Compound No., yield (%),
Compound No., yield
appearance, mp (°C)
appearance, mp (°C); MS (ES+ or
(%), appearance, mp
(°C); MS (ES+ or FAB+);
nmax (cm–1) C=O, OH
FAB+); nmax (cm–1) OH and NH2
R'
R'
NHR'
N
N
N
NH2
R
CN
R
N
R
N
OH
O
OH
OH
1
C6H5
C6H5CH2
3a, 75, Colorless
11a, 40, Yellow sticky solid, 296;
sticky solid
3420
2
3
4-Cl-C6H4
C6H5CH2
C6H5CH2
3b, 40, Brown oil
3c, 58, Brown oil
11b, 95, Yellow oil, 330; 3393
3-Phenyl-isoxazol-
5-yl
11c, 84, Brown solid, 85–87;
363.60; 3377
4
5
6
3-(4-Methyl-phenyl)- C6H5CH2
isoxazol-5-yl
3d, 68, Brown solid,
105–107
11d, 49, Brown solid, 162–164;
378; 3405
3-(2-Chloro-phenyl)- C6H5CH2
isoxazol-5-yl
3e, 71, Yellow oil
4a, 72, Yellow oil
4b, 41, Brown oil
11e, 40, Brown solid, 90–92;
397.67; 3352
15, 92, Brown oil,
437.47; 1662, 3408
C6H5
4-F-C6H4CH2
12a, 44, Colorless solid, 210–212;
314; 3343
7
8
4-Cl-C6H4
4-F-C6H4CH2
4-F- C6H4CH2
12b, 91, Yellow oil, 348.73; 3335
12c, 57, Brown oil, 381; 3370
3-Phenyl-isoxazol-
5-yl
4c, 62, Colorless solid,
135–137
16, 82, Brown oil, 421;
1667, 3390
9
10
11
12
3-(4-Methyl-phenyl)- 4-F-C6H4CH2
isoxazol-5-yl
4d, 76, Off white solid,
79–81
12d, 35, Colorless solid, 229–230
(dec.); 396; 3401
3-(2-Chloro-phenyl)- 4-F-C6H4CH2
isoxazol-5-yl
4e, 86, Light brown oil
12e, 44, Brown solid, 98–100;
415.33; 3353
C6H5
Cyclohexyl
5a, 87, Colorless solid,
164–166
13, 89, Yellow oil, 289; 3424
C6H5
CH3(CH2)3
6a, 84, Off white solid,
14, 88, Colorless solid, 178–179;
122–124
262.3; 3379
a All compounds gave satisfactory microanalyses.
Thus, we have presented a very simple synthetic strategy
to obtain 5-substituted-2-amino-1,4,5,6-tetrahydro-pyri-
midines utilizing Baylis–Hillman adducts. Further work is
underway to understand the scope and limitations of this
strategy to generate variety of annulated systems using
these pyrimidines.
(3) Kim, J. N.; Lee, K. Y. Curr. Org. Chem. 2002, 6, 627.
(4) Weinhardt, K.; Wallach, M. B.; Marx, M. J. Med. Chem.
1985, 28, 694.
(5) (a) Cho, H. I.; Lee, S. W.; Lee, K.-J. J. Heterocycl. Chem.
2004, 41, 799. (b) Basavaiah, D.; Rao, J. S.; Reddy, R. J. J.
Org. Chem. 2004, 69, 7379. (c) Lee, C. G.; Lee, K. Y.;
GowriSankar, S.; Kim, J. N. Tetrahedron Lett. 2004, 45,
7409. (d) Singh, V.; Saxena, R.; Batra, S. J. Org. Chem.
2005, 70, 353.
Acknowledgments
(6) Dunbar, P. G.; Durant, G. J.; Fang, Z.; Abuh, Y. F.; El-
Assadi, A. A.; Ngur, D. O.; Periyasamy, S.; Hoss, W. P.;
Messer, W. S. Jr. J. Med. Chem. 1993, 36, 842.
Two of the authors (RP and AKR) gratefully acknowledge the
financial support from the CSIR in the form of fellowships. The
financial support for the work from DST is gratefully acknowl-
edged.
(7) Messer, W. S. Jr.; Rajeswaran, W. G.; Cao, Y.; Zhang, H.-J.;
El-Assadi, A. A.; Dockery, C.; Liske, J.; O’Brien, J.;
Williams, F. E.; Huang, X.-P.; Wroblewski, M. E.; Nagy, P.
I.; Peseckis, S. M. Pharmaceut. Acta Helv. 2000, 74, 135.
(8) Greenhill, J. V.; Lue, P. Prog. Med. Chem. 1993, 30, 203.
(9) (a) Sandin, H.; Swanstein, M.-L.; Wellner, E. J. Org. Chem.
2004, 69, 1571. (b) Wellner, E.; Sandin, H.; Swanstein, M.-
L. Synlett 2004, 1817.
References
(1) CDRI Communication no. 6645, presented as poster at
CBISNF-2004, 21st–26th Nov, N. Delhi.
(2) Basavaiah, D.; Jaganmohan Rao, A.; Satyanarayana, T.
Chem. Rev. 2003, 103, 811.
Synlett 2005, No. 5, 848–850 © Thieme Stuttgart · New York

850
R. Pathak et al.
LETTER
(10) (a) Patra, A.; Batra, S.; Kundu, B.; Joshi, B. S.; Roy, R.;
Bhaduri, A. P. Synthesis 2001, 276. (b) Cai, J.; Zhou, Z.;
Zhao, G.; Tang, C. Org. Lett. 2002, 4, 4723.
(11) General Procedure for the Synthesis of 1,4,5,6-
Tetrahydropyrimidines (11, 12a–e, 13, 14).
4.95, 5.01 (2 d, 2 H, 2 × CH-OH), 6.58, 6.67 (2 s, 2 H, 2 ×
=CH), 7.05–7.33 (m, 12 H, ArH), 7.55 (d, 4 H, J = 8.0 Hz,
ArH). 13C NMR (75.4 MHz, CDCl3 + TFAd): d = 20.8, 21.6,
36.0, 36.4, 39.5, 40.3, 47.2, 47.8, 53.1, 53.2, 65.4, 66.2,
101.4, 109.2, 113.0, 116.7, 116.8, 116.9, 120.6, 124.3,
127.0, 128.8, 128.9, 129.0, 129.1, 129.6, 130.2, 130.7,
141.9, 154.1, 163, 164.8, 171.8, 171.9, 178.4. Anal. Calcd
for C22H23FN4O2: C, 64.06; H, 6.11; N, 13.58. Found: C,
63.91; H, 6.18; N, 13.72.
A solution of appropriate diamines from 7, 8a–e, 9, 10a (2.3
mmol) and cyanogen bromide (2.3 mmol, 0.243 g) in
absolute EtOH (5 mL) was allowed to stir at 80 °C for 4–6 h.
Thereafter the excess solvent was evaporated and the
reaction mixture was washed with 10% aq NaHCO3 and
extracted with EtOAc. The organic layers were combined,
dried over Na2SO4 and evaporated to furnish a residue. The
residue upon triturating with hexane or through column
chromatography (CHCl3–MeOH, 9.5:0.5, v/v) yielded the
pyrimidines.
(12) General Procedure for the Synthesis of 5,6,7,8-
Tetrahydro-2H-imidazo[1,2-a]pyrimidin-3-ones (15, 16).
To the solution of compound 11e or 12c (0.63 mmol) in dry
DMF was added K2CO3 (0.63 mmol, 0.104 g) and
bromoethyl acetate (0.63 mmol, 0.28 mL) and the mixture
was heated at 80 °C under stirring for 6 h. Then the reaction
mixture was extracted with EtOAc and H2O. The usual work
up of the organic layer afforded a residue that upon column
chromatography over silica gel using hexane–EtOAc (70:30,
v: v) yielded the pure compounds as oils.
Representative Data (as Diastereoisomeric Mixture) of
5,6,7,8-Tetrahydro-2H-imidazo[1,2-a]pyrimidin-3-ones.
Compound 15: 1H NMR (300 MHz, CDCl3): d = 2.62–3.44
(m, 10 H, 2 × CH2-NH, 2 × CH2-N and 2 × CH), 3.86–3.93
(m, 8 H, 2 × CH2CO and 2 × CH2-Ph), 4.52, 4.57 (2 d, 2 H,
J = 3.8 Hz, 2 × CH-OH), 6.47, 6.67 (2 s, 2 H, 2 × =CH),
7.22–7.64 (m, 18 H, ArH). 13C NMR (75.4 MHz, CDCl3 +
TFAd): d = 36.7, 36.9, 42.3, 43.5, 45.0, 45.7, 54.1, 54.3, 56.2,
65.1, 65.7, 103.8, 127.4, 128.4, 128.6, 129.1, 130.7, 131.1,
131.3, 133.1, 135.8, 161.2, 167.8, 172.5, 172.8, 185.1,
185.4. Anal. Calcd for C23H21ClN4O3: C, 63.23; H, 4.84; N,
12.82. Found: C, 63.10; H, 5.01; N, 13.07.
Representative Data (as Diastereoisomeric Mixture) of 2-
Amino-1,4,5,6-Tetrahydropyrimidines.
Compound 11e: 1H NMR (300 MHz, CDCl3 + TFAd): d =
2.66–2.71 (m, 2 H, 2 × CH), 3.28–3.63 (m, 8 H, 2 × CH2-NH
and 2 × CH2-N), 4.49, 4.53 (2 s, 4 H, 2 × CH2-Ph), 4.95, 5.01
(2 d, 2 H, 2 × CH-OH), 6.67, 6.73 (2 s, 2 H, 2 × =CH), 7.19–
7.64 (m, 18 H, ArH). 13C NMR (75.4 MHz, CDCl3 + TFAd):
d = 35.9, 36.1, 39.4, 40.4, 47.5, 48.0, 53.9, 54.2, 65.3, 66.1,
105.3, 109.0, 112.8, 116.5, 120.3, 124.7, 126.2, 126.9,
127.1, 127.7, 129.3, 129.4, 129.8, 130.1, 130.3, 130.9,
131.0, 132.4, 132.7, 132.8, 133.2, 134.7, 148.7, 154.0,
171.0, 171.1. Anal. Calcd for C21H21ClN4O2: C, 63.55; H,
5.33; N, 14.12. Found: C, 63.19; H, 5.58; N, 13.88.
Compoumd 12d: 1H NMR (300 MHz, CDCl3 + TFAd): d =
2.42 (s, 6 H, 2 × CH3), 2.69 (br s, 2 H, 2 × CH), 3.31–3.35
(m, 2 H, 2 × 1 H of CH2-NH), 3.48–3.59 (m, 6 H, 2 × CH2-
N and 2 × 1 H of CH2-NH), 4.49, 4.52 (2 s, 4 H, 2 × CH2-Ph),
Synlett 2005, No. 5, 848–850 © Thieme Stuttgart · New York