FeCl3 catalysed two consecutive aminomethylation at the α-position of the β-dicarbonyl compounds: An easy access to hexahydropyrimidines and its spiro analogues

Article abstract of DOI:10.1016/j.tetlet.2011.05.144

Multicomponent synthesis of 1,3-diaryl-hexahydropyrimidines by a one-pot reaction of 1,3-dicarbonyl compounds, amines and formaldehyde catalysed by FeCl₃ in dichloromethane at room temperature (25-30 °C) has been reported. Double amino methylation occurs at the α-position of the 1,3-dicabonyl compounds/β-keto esters. The same methodology leads to spiro compounds with indane-1,3-dione. In this reaction, six molecules condense in one pot to form six new covalent bonds, thus, creating high atom economy. This is the first report of the synthesis of the substituted hexahydropyrimidines involving β-keto esters and its spiro analogues with indane-1,3-dione.

Full text of DOI:10.1016/j.tetlet.2011.05.144

Tetrahedron Letters 52 (2011) 4153–4157
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
FeCl3 catalysed two consecutive aminomethylation at the a-position
of the b-dicarbonyl compounds: an easy access to hexahydropyrimidines
and its spiro analogues
Chhanda Mukhopadhyay a, , Sunil Rana a, Ray J. Butcher b
⇑
a Department of Chemistry, University of Calcutta, 92 APC Road, Kolkata 700 009, India
b Department of Chemistry, Howard University, Washington, DC 20059, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Multicomponent synthesis of 1,3-diaryl-hexahydropyrimidines by a one-pot reaction of 1,3-dicarbonyl
compounds, amines and formaldehyde catalysed by FeCl3 in dichloromethane at room temperature
Received 7 May 2011
Revised 27 May 2011
Accepted 29 May 2011
Available online 12 June 2011
(25–30 °C) has been reported. Double amino methylation occurs at the
a-position of the 1,3-dicabonyl
compounds/b-keto esters. The same methodology leads to spiro compounds with indane-1,3-dione. In
this reaction, six molecules condense in one pot to form six new covalent bonds, thus, creating high atom
economy. This is the first report of the synthesis of the substituted hexahydropyrimidines involving
b-keto esters and its spiro analogues with indane-1,3-dione.
Keywords:
Hexahydropyrimidines
Multicomponent reaction
Double aminomethylation
Lewis acid
Ó 2011 Elsevier Ltd. All rights reserved.
FeCl3
Spiro compounds
Room temperature
Hexahydropyrimidines containing various natural products and
pharmaceutical agents show immense biological activities.1a,b Dif-
ferent N-substituted hexahydropyrimidines are synthetic interme-
diates for spermidine-nitroimidazole drugs for the treatment of
A549 lung carcinoma.2 They form structural units in trypanothione
reductase inhibiting ligands for the regulation of oxidative stress in
parasite cells.3 N-(4-aminobutyl) hexahydropyrimidine and N-(3-
aminopropyl) hexahydropyrimidine are shown to compete with
spermidine for uptake by L1210 cells.4
Some suitably substituted derivatives have metal-complexing
properties.5a–e Such immense application of the hexahydropyrimi-
dines prompted us to synthesise a wide variety of such compounds.
Classically, hexahydropyrimidines are prepared by condensation
between substituted propane-1,3-diamines and aldehydes or keto-
nes.6a–c There are also a few reports in literature describing the
In recent years, multicomponent reactions (MCRs) have
received substantial consideration from the organic community
for their innumerable advantages over conventional multistep
synthesis.9a–i These reactions provide instantaneous access to large
compound libraries with diverse functionalities. Moreover, MCRs
are both atom and step economic as they avoid time consuming
costly purification processes in addition to the protection and
deprotection steps.10
In this methodology, 1,3-dicarbonyl compounds, amines and
formaldehyde react in one step in the presence of Lewis acid FeCl3
in dichloromethane at room temperature (Scheme 1).
To find out the suitable catalyst for the reaction, a series of
experiments were performed with the standard reaction of ethy-
lacetoacetate, aniline and formaldehyde. The results are depicted
in Table 1. Among various Lewis acids including different metal
salts, FeCl3 was found to be the best catalyst (yield 88%, Table 1, en-
try 3) for the reaction. In presence of strong acid like HCl only trace
amount of the product was detected in TLC. This could be due to
decomposition of the product in the presence of strong acid.
A variety of solvents were tested to find out the best solvent for
this transformation. Among various solvents, dichloromethane was
found to give the best result. When the reaction was carried out
under solvent-free conditions, the yield was further low (30%),
probably due to the absence of strong interactions between the
various reactants. The stoichiometric ratio of 1:2:3 (1,3-dicarbonyl
synthesis of hexahydropyrimidine derivatives either by using
a,
b-unsaturated nitriles or by the reaction of substituted alanine and
carbamide.7a,b Liang and coworkers synthesized this type of
compounds using cyclic ketone, amine and formaldehyde.8 In our
approach, hexahydropyrimidines are prepared by the one pot reac-
tion of 1,3-dicarbonyl compounds, amines and formaldehyde in a
multicomponent fashion.
⇑
Corresponding author. Tel.: +91 33 2337110/91 33 23371104.
E-mail address: cmukhop@yahoo.co.in (C. Mukhopadhyay).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.144

4154
C. Mukhopadhyay et al. / Tetrahedron Letters 52 (2011) 4153–4157
O
O
N
NH2
O
O
R1
R1
FeCl3 (5 mol %)
R2
+
1
DCM, r.t.(25-30° C) stirring
N
2
(1 mmol)
(2 mmol)
HCHO
(3 mmol)
3
(4a-4l)
R2
R2
Scheme 1. Synthesis of hexahydropyrimidines using 1,3-dicarbonyl compounds/b-keto esters, amines and formaldehyde.
Table 1
Choice of catalyst for hexahydropyrimidine formation
O
N
O
N
O
O
NH2
OEt
OEt
Catalyst (5 mol %)
DCM, r.t.(25-30° C), stirring
(1 mmol)
+
(1 mmol)
HCHO
(1 mmol)
4a
Entry
Catalyst (5 mol %)
Time (h)
Yield (%) (isolated)
1
2
3
4
5
6
7
AlCl3
ZnCl2
FeCl3
SnCl2
AcOH
H3BO3
HCl
6
6
6
6
6
6
6
40
25
88
30
51
33
—
compound: amine: formaldehyde) in the presence of 5 mol % of
FeCl3 in dichloromethane (5 mL) at room temperature (25–30 °C)
was found to be the optimum condition for the maximum yield
of hexahydropyrimidines. Under these reaction conditions, the
product 4a was obtained in a very good yield of 88% in 6 h. After
the standardization of the reaction condition, a variety of b-keto
esters and 1,3-dicarbonyl compounds like methylacetoacetate,
ethylacetoacetate, allylacetoacetate and 1-benzoyl acetone were
used. Electron donation on the aldehydes moiety increases the
yield of the reaction, while strong electron withdrawing group like
NO2 does not yield any product.
All the compounds were characterized by NMR, IR, CHN analy-
sis and melting points (for the solid compounds). The final struc-
ture was confirmed by an X-ray crystallography study of a single
crystal of the hexahydropyrimidine 4i (Table 2, entry 9) and is gi-
ven below in Figure 1.
After the initial success of the reaction, we extended our meth-
odology for the preparation of spiro hexahydropyrimidines with
Table 2
Synthesis of hexahydropyrimidines using 1,3-dicarbonyl compounds/b-keto ester, amines and formaldehyde
O
N
O
N
NH2
O
O
R1
R1
FeCl3 (5 mol %)
DCM, r.t.(25-30° C) stirring
R2
+
1
2
(1 mmol)
(2 mmol)
HCHO
(3 mmol)
3
(4a-4l)
R2
R2
Entry
R1
Amine
Products
Time (h)
Yield (%) (isolated)
1
2
3
4
5
6
7
8
OEt
OEt
OEt
Aniline
4a
4b
4c
4d
4e
4f
4g
4h
4i
6
6
6
6
6
6
6
6
6
6
6
6
88
92
63
85
91
90
87
79
76
76
73
75
4-Methylaniline
Benzylamine
Aniline
4-Methoxyaniline
4-Methylaniline
3-Methylaniline
2-methylaniline
Aniline
OMe
OMe
OMe
OMe
OMe
Ph
Ph
O-Allyl
O-Allyl
9
10
11
12
4-Methylaniline
Aniline
4-Methylaniline
4j
4k
4l

C. Mukhopadhyay et al. / Tetrahedron Letters 52 (2011) 4153–4157
4155
or b-keto ester. Mechanism for the preparation of the spiro-hexa-
hydropyrimidines is similar to that of normal hexahydro-
pyrimidines.
The methodology for the synthesis of the hexahydropyrimi-
dines and its spiro-analogues with indane-1,3-dione is reported
in the reference section.12
When dimedone was used as 1,3-dicarbonyl compound instead
of hexahydropyrimidines, spiro substituted piperidines were ob-
tained (Scheme 4) with the same methodology.13 One of the
advantages of this methodology is that 3-methylaniline also gives
the desired product (Table 4, entry 2) which was not possible using
the methodology of Kozlov and Kadutskii.9j
This may happen due to the high reactivity of dimedone. Here
maximum yield of the piperidine compound was obtained when
dimedone, aromatic amine and formaldehyde were taken in the ra-
tio of 2:1:3.
Probable mechanism for the formation of the bis spiro-
piperidine is same to that reported by Kadutskii.9j
In conclusion, we have proved the utility of the suitably cho-
sen Lewis acid FeCl3 in synthesizing the hexahydropyrimidines
in good yields in dichloromethane medium. This is the first re-
port of the synthesis of the substituted hexahydropyrimidines
involving b-keto esters and its spiro analogues with indane-
1,3-dione catalysed by FeCl3 in DCM. Room temperature synthe-
sis, very easy reaction protocol and overall high yields are the
main advantages of this methodology. Six molecules condense
to form six new covalent bonds which make the reaction highly
Figure 1. ORTEP plot of a single crystal of the hexahydropyrimidine 4i (Table 2,
entry 9) (CCDC 763614) showing the crystallographic numbering.
the use of indane-1,3-dione as the 1,3-dicarbonyl compound
(Scheme 2, Table 3).
The probable mechanism of the hexahydropyrimidine forma-
tion is given below in Scheme 3. The 1,3-dicarbonyl compounds
undergo two successive
a
a-aminomethylation on the same
-carbon. This step is similar to the Mannich type of reaction.11a–d
atom-economic. Functionalisation at the a-position of the b-keto
The 1,3-diamine compound (B) thus formed reacts with formalde-
hyde to form hexahydropyrimidine. Here the acidic nature of FeCl3
may facilitate both the enolization steps of the 1,3-diketone
esters or b-diketones occurs twice which makes this reaction
significant and increases the interest for further modification
to molecular diversity.
R2
NH2
O
N
O
FeCl3 (5 mol%)
DCM, r.t.(25-30° C) stirring
R2
(2 mmol)
N
+
O
HCHO
(3 mmol)
O
(1 mmol)
5a-5c
R2
Scheme 2. Synthesis of spiro-hexahydropyrimidines using indane-1,3-dione, aromatic amines and formaldehyde.
Table 3
Synthesis of spiro-hexahydropyrimidines using indane-1,3-dione, aromatic amines and formaldehyde
R2
NH2
O
N
N
O
FeCl3 (5 mol%)
R2
(2 mmol)
DCM, r.t.(25-30° C) stirring
+
O
HCHO
O
(1 mmol)
(5a-5f)
(3 mmol)
R2
Entry
Products (compound no.)
Time (h)
Yield (%) (isolated)
1
2
3
4
5
6
R2 = H (5a)
6
6
6
6
6
6
70
72
73
77
65
61
R2 = 4-CH3 (5b)
R2 = 3,4-(CH3)2 (5c)
R2 = 4-OCH3 (5d)
R2 = 3-CH3 (5e)
R2 = 2-CH3 (5f)

4156
C. Mukhopadhyay et al. / Tetrahedron Letters 52 (2011) 4153–4157
H
O
O
-H+
O
O
FeCl3
+H+
R
R
O
H2C
N
R1
H
O
O
O
CH2
N
N
H
N
H
R1
(A)
R1
R1
O
N
O
O
O
R
HCHO
-H2O
R
N
NH HN
R1
R1
(B)
R1
R1
Scheme 3. Probable mechanism of hexahydropyrimidine formation.
R3
R3
O
FeCl3(5 mol%)
O
N
O
NH2
DCM, r.t.(25-30° C) stirring
(1 mmol)
+
HCHO
O
(3 mmol)
O O
(2 mmol)
6a-6c
Scheme 4. Synthesis of bis-spiro piperidines using dimedone, aromatic amines and formaldehyde.
Table 4
Synthesis of bis-spiro piperidines using dimedone, aromatic amines and formaldehyde
R3
R3
O
FeCl3(5 mol%)
O
N
O
NH2
DCM, r.t.(25-30° C) stirring
(1 mmol)
+
HCHO
O
(3 mmol)
O O
(2 mmol)
(6a-6c)
Entry
R3
product
Time (h)
Yield (%) (isolated)
References
9j
1
2
3
4-Methyl
3-Methyl
4-Methoxy
6a
6b
6c
6
6
6
88
86
89
—
9j

C. Mukhopadhyay et al. / Tetrahedron Letters 52 (2011) 4153–4157
4157
11. (a) Blatt, A. H.; Gross, N. J. Org. Chem. 1964, 29, 3306; (b) Kobayashi, S.; Ishitani,
H. Chem. Rev. 1999, 99, 1069; (c) Mannich, C.; Krosche, W. Arch. Pharm. 1912,
250, 674; (d) Mukhopadhyay, C.; Datta, A.; Butcher, R. J. Tetrahedron Lett. 2009,
50, 4246.
Acknowledgements
One of the authors (SR) thanks the Council of Scientific and
Industrial Research, New Delhi, for his fellowship (SRF). We thank
the CAS Instrumentation Facility, Department of Chemistry,
University of Calcutta for spectral data. We also acknowledge the
grant received from the UGC funded Major project, F. No.
37–398/2009 (SR) dated 11-01-2010.
12. General procedure for the synthesis of hexahydropyrimidines and its spiro
analogues.
A
mixture of b-keto ester (1 mmol), aniline (2 mmol),
formaldehyde (3 mmol, 37–41% aqueous solution) and a catalytic amount of
FeCl3 (5 mol %) in dichloromethane (5 mL) was stirred at room temperature for
the stipulated times mentioned in Tables 2 and 3. The progress of the reaction
was monitored by TLC. After the completion of the reaction, FeCl3 was removed
from the reaction mixture by filtration. The solvent was removed under
reduced pressure. The crude product mixture was then purified by silica gel
(60–120 mesh) column chromatography with 5% ethyl acetate in petroleum
ether (60–80 °C) as eluant. Spectral and analytical data of all the compounds in
Table 2–4 are given in the supplementary section. The spectral and analytical
data of one of each representative compounds is given here: 5-acetyl-1,3-
diphenyl-hexahydro-pyrimidine-5-carboxylic acid ethyl ester (4a): (Table 2, entry
1) brown viscous liquid, mmax (KBr)/cmÀ1 3029, 2983, 2923, 2842, 1719, 1596,
1499, 1451, 1382, 1295, 1229, 1136, 1021 and 933; 1H NMR (300 MHz, CDCl3)
dH: 7.35–7.25 (4H, m, ArH), 7.06 (4H, dd, J = 8.7 Hz and 0.9 Hz, ArH), 6.97–6.90
(2H, m, ArH), 4.51 (1H, d, J = 10.8 Hz, equatorial N–CH–N), 4.46 (1H, d, axial
N–CH–N), 4.01 (2H, q, J = 7.2 Hz, O–CH2), 3.90–3.81 (4H, m, 2Â N–CH2), 2.23
(3H, s, CH3-CO), 1.14 (3H, t, J = 7.2 Hz, COOCH2CH3); 13C NMR (75 MHz, CDCl3)
dC: 202.7 (C, CH3-CO–), 169.0 (C, COOEt), 149.3 (C, Caromat), 129.2 (CH, Caromat),
121.1 (CH, Caromat), 117.8 (CH, Caromat), 68.2 (N-CH2-N), 61.8 (CH2, COO-CH2),
60.0 (C, C5), 53.7 (CH2-N), 26.7 (CH3-CO), 13.8 (CH3, COOCH2CH3); Anal. calcd
for C21H24N2O: C: 71.57; H: 6.86; N: 7.95. Found: C: 71.33; H: 6.91; N: 7.84.
2-(2,4-Di-phenyl-2,4-diazaspiro-6-yl)-indane-1,3-dione (5a) (Table 3, entry 1)
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.05.144.
References and notes
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mp: 122–124 °C (EtOAc), m
max (KBr)/cmÀ1 3022, 2930, 2872, 1704, 1594, 1497,
1450, 1373, 1296, 1223, 1024, 926 and 749; 1H NMR (300 MHz, CDCl3) dH:
7.95–7.91 (2H, m, ArH), 7.85–7.80 (2H, m, ArH), 7.29–7.23 (4H, m, ArH), 6.95
(4H, dd, J = 7.8 Hz and 0.9 Hz, ArH), 6.91–6.84 (2H, m, ArH), 4.89 (2H, s, N-CH2-
N), 3.71 (4H, s, N-CH2); 13C NMR (75 MHz, CDCl3) dC: 199.4 (C, CO), 149.1 (C,
C
C
aromat), 140.7 (C, Caromat), 135.9 (CH, Caromat), 129.2 (CH, Caromat), 123.7 (CH,
aromat), 120.0 (CH, Caromat), 116.4 (CH, Caromat), 66.2 (CH2, N-CH2-N), 54.8 (C,
spiro carbon), 50.9 (CH2, N-CH2); Anal. calcd for C24H20N2O2: C: 78.24; H: 5.47;
N: 7.60. Found: C: 78.54; H: 4.39; N: 7.52.
13. General Procedure for the synthesis of spiro piperidines. A mixture of dimedone
(1 mmol), aniline (1 mmol), formaldehyde (3 mmol, 37–41% aqueous solution)
and a catalytic amount of FeCl3 (5 mol %) in dichloromethane (5 mL) was
stirred at room temperature for the stipulated time mentioned in Table 4. The
progress of the reaction was monitored by TLC. After the completion of the
reaction FeCl3 was removed from the reaction mixture by filtration. The
solvent was removed under reduced pressure. The crude product mixture was
then purified directly by crystallization from ethylacetate.
8. Wei, H.-L.; Yan, Z.-Y.; Niu, Y.-N.; Li, G.-Q.; Liang, Y.-M. J. Org. Chem. 2007, 72,
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The spectral and analytical data of one of the representative compounds is
given here: Tetramethyl-15-(4-methylphenyl)-15-azadispiro[5.1.5.3]hexadecane-
1,5,9,13-tetrone (6a) (Table 4, entry 1) mp: 196–198 °C (EtOAc), 1H NMR
(300 MHz, CDCl3) dH: 7.06 (2H, d, J = 8.1 Hz, ArH), 7.00 (2H, d, J = 8.1 Hz, ArH),
3.39 (4H, s, NCH2), 2.83 (4H, d, J = 13.5 Hz, COCH2), 2.64 (4H, d, COCH2), 2.48
(2H, s, CH2), 2.26 (3H, s, CH3), 1.00 (12H, s, CH3); 13C NMR (75 MHz, CDCl3) dC:
205.9, 149.5, 131.3, 129.6, 119.2, 65.8, 55.6, 51.2, 32.2, 30.7, 28.6, 28.3, 20.5;
Anal. calcd for C26H33NO4: C: 73.73; H: 7.85; N: 3.31. Found: C: 73.94; H: 7.79;
N: 3.22.