An efficient preparation and some reactions of 2-dimethylaminomethylene-1, 3-bis(dimethylimonio)propane diperchlorate

Article abstract of DOI:10.1016/j.tetlet.2006.02.101

An alternative preparation of 2-dimethylaminomethylene-1,3- bis(dimethylimonio)propane diperchlorate from malonic acid is described along with its application to the synthesis of 2,4,6-trisubstituted phenols and 2-(N-(2,2-diformylethenyl)amino)pyridine.

Full text of DOI:10.1016/j.tetlet.2006.02.101

Tetrahedron Letters 47 (2006) 2973–2975
An efficient preparation and some reactions of 2-dimethyl-
aminomethylene-1,3-bis(dimethylimonio)propane diperchlorate
Khiari Jameleddine, Hadj Ayed Med Adnen and Ben Hassine B e´ chir*
Laboratoire de Synth e` se Organique Asym e´ trique et Catalyse Homog e` ne (01UR1201), Facult e´ des Sciences de Monastir 5019, Tunisia
Received 1 November 2005; revised 25 January 2006; accepted 16 February 2006
Available online 9 March 2006
Abstract—An alternative preparation of 2-dimethylaminomethylene-1,3-bis(dimethylimonio)propane diperchlorate from malonic
acid is described along with its application to the synthesis of 2,4,6-trisubstituted phenols and 2-(N-(2,2-diformylethenyl)-
amino)pyridine.
Ó 2006 Elsevier Ltd. All rights reserved.
If one examines the literature of vinamidinium salts,1
their potential utility as three-carbon building blocks
for a wide array of carbocycles and heterocycles
becomes apparent. Vinamidinium salts can regioselec-
tively incorporate an appended substituent onto a new
ring system, making them attractive starting materials
We now report, that 2-dimethylaminomethylene-1,3-
bis(dimethylimonio)propane diperchlorate 2 can be
prepared in excellent yield (92%) from commercially
available and inexpensive malonic acid under Vilsme-
ier–Haack conditions and was precipitated as the
perchlorate. Compound 2 has been previously prepared
2
10
11
for the synthesis of new medicinal agents. The regenera-
from a-bromoacetic acid and phosphonoacetic acid
tive character of vinamidinium salts has been demon-
strated in both electrophilic reactions such as
halogenation, nitration and Vilsmeier type alkylations,
and in nucleophilic reactions with amines and carbon
nucleophiles.
in yields of 60% under the same conditions. We obtained
the vinamidinium salt 2 by the reaction of malonic acid
with phosphorus oxychloride and N,N-dimethylform-
amide at 90 °C until carbon dioxide evolution ceased
(approximately 6 h). When the aqueous sodium perchlo-
rate was added to the corresponding vinamidinium salt
precipitated (Scheme 1).
3
1
2
The nucleophilic reactions have been the most exploited
and have led to the synthesis of some polycyclic aro-
4
–6
matic and heterocyclic compounds.
Vinamidinium
This preparation of 2-iminiovinamidinium salt 2 from
malonic acid has distinct advantages over the bromoace-
tic acid method since the reaction is less exothermic and
so is easier to control. In addition, malonic acid is less
irritant than bromoacetic acid.
salts have been used to alkylate the activated methylenes
6
,7
of various nitriles, however, there are few reports on
the alkylation of other types of activated methylene
8
,9
compounds.
O
NMe
2
O
1
)
)
POCl3/DMF
,
Δ
Me N
2
NMe2 2 ClO4
HO
OH
2
NaClO , H O
4
2
1
2
Scheme 1.
Keywords: 2-Iminiovinamidinium salt; b-Keto-esters; 2-Aminopyridine; Condensation; Cyclisation; Bifunctional phenol; a,b-Unsaturated dialde-
hyde.
*
Corresponding author. E-mail: bechirbenhassine@yahoo.fr
0040-4039/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2006.02.101

2974
K. Jameleddine et al. / Tetrahedron Letters 47 (2006) 2973–2975
NMe2
2
ClO4
NMe2
O
Me N
O
O
2
O
O
CO R'
R
2
R
2
R
NaOR'
OR'
OR'
NMe2
3
Me N
2
ClO
4
Me N
2
NMe2
4
5
OH
R
CO R'
2
HCl / THF
CHO
6
Scheme 2.
Table 1. Condensation of various b-keto-esters with 2-iminiovinamid-
inium salt 2
0
a
b-Keto-ester
R
R
Product
Yield (%)
3
3
3
3
3
3
a
b
c
d
e
f
H
H
CH
3
6a
6b
6c
6d
6e
6f
1
83
80
78
82
74
73
C
2
H
5
C
C
2
H
H
5
CH
3
2
5
C
C
C
2
H
2
H
2
H
5
5
5
n-C
n-C
3
H
H
7
9
4
a
13
All products were characterised from their H NMR, C NMR and
mass spectroscopic data.
15
With the desired salt in hand, we next condensed it with
various b-keto-esters (Scheme 2).
When vinamidinium salt 2 was treated with enolates
generated in situ by reaction of sodium alkoxide with
1
3
14
b-keto-esters 3 at 80 °C for 4 h, the desired phenols
6
were isolated in good yields after hydrolysis with
N HCl in THF at room temperature. The results are
1
shown in Table 1.
When salt 2 was reacted with 2-aminopyridine in etha-
nol, 2-(N-(2,2-diformylethenyl)amino)pyridine 8 was
Figure 1. ORTEP view of compound 8.
1
4
produced unexpectedly in 81% yield. This presumably
happens because the intermediate 4-hydroxy(4H)pyr-
ido[1,2-a]pyrimidine-3-carbaldehyde 7 is water sensitive
and ring-opens to an aldehyde (Scheme 3). The structure
of 8 was confirmed by X-ray analysis and is depicted in
In conclusion, we have found that 2-dimethylamino-
methylene-1,3-bis(dimethylimonio)propane diperchlorate
2 can be prepared in excellent yield from commercially
available malonic acid. This salt undergoes annulation
reactions with b-keto-esters 3 to provide 2,4,6-trisubsti-
1
5
Figure 1.
O
O
2
ClO
4
NMe2
NMe
NMe
2
Me
2
N
2
O
H
H
2
2
Me N
N
HCl / THF
H
N
NH
N
NH
2
Me
2
N
N
HO
N
N
7
8
Scheme 3.

K. Jameleddine et al. / Tetrahedron Letters 47 (2006) 2973–2975
2975
tuted phenols 6 in satisfactory yields and also reacts with
-aminopyridine to give 2-(N-(2,2-diformylethenyl)-
amino)pyridine 8.
cooling to room temperature, the solvent was removed
and THF (10 mL) and 1 N HCl (8 mL) were added with
stirring for 2 h. The mixture was neutralised with satu-
2
3
rated aqueous NaHCO and extracted with three portions
of chloroform. The combined organic extracts were dried
Acknowledgements
over MgSO , filtered and concentrated. The crude reaction
4
mixture was purified by flash column chromatography
(
80% hexane–20% ethyl acetate).
The authors would like to thank Dr. Taha Guerfel, for
the X-ray crystallographic analysis.
Condensation of iminiovinamidinium salt 2 with 2-amino-
pyridine:
A mixture of vinamidinium salt 2 (0.3 g, 0.78 mmol) and
2-aminopyridine (0.12 g, 1.28 mmol) in ethanol (15 mL)
was refluxed for 10 h. After cooling to room temperature,
the ethanol was removed and THF (2 mL) and 1 N HCl
(2 mL) were added. The mixture was allowed to stir at
room temperature for 2 h, then neutralised with saturated
References and notes
1
2
. Lloyd, D.; NcNab, H. Angew. Chem., Int. Ed. Engl. 1976,
5, 459–468.
. Niedrich, H.; Hegne, H.; Schrotter, E.; Heidrich, H.;
1
Faust, G.; Lohman, D. Pharmazie 1986, 41, 173–
aqueous NaHCO
portions of CH Cl
extracts over MgSO
residue was purified by chromatography on silica gel
[SiO ; CHCl ] to give 0.11 g (81% yield) of dialdehyde 8.
15. Selected spectroscopic data:
Compound 6a: white solid: mp 66–68 °C; H NMR
(300 MHz, CDCl ): d 4.01 (s, 3H), 7.01 (d, J = 8.7 Hz,
1H), 8.01 (d, J = 8.7 Hz, 1H), 8.39 (d, J = 2.1 Hz, 1H),
3
solution and extracted with three
. After drying the combined organic
2
4
and concentrating in vacuo, the
1
77.
. Lloyd, D.; Marshall, D. R.; Gorringe, A. D. J. Chem. Soc.
970, 617–620.
. Reichardt, D.; Halbritter, K. Angew. Chem., Int. Ed. Engl.
975, 14, 86–88.
. Arnold, Z.; Holy, A. Collect. Czech. Chem. Commun.
973, 38, 1371–1373.
. Jutz, C.; Wagner, R. M. Angew. Chem., Int. Ed. Engl.
972, 11, 315–318.
. Jutz, C.; Wagner, R. M. Angew. Chem., Int. Ed. Engl.
974, 13, 737–740.
2
3
4
5
6
7
8
9
1
2
3
1
1
1
3
1
3
1
9.88 (s, 1H), 11.37 (s, 1H); C NMR (75 MHz, CDCl
52.8, 112.6, 118.8, 128.6, 133.9, 135.7, 166.4, 169.9, 190.0.
Anal. Calcd for C : C, 60.00; H, 4.48; O, 35.52%.
Found: C, 59.98; H, 4.36; O, 35.48%. Mass m/z (EI, 30 ev):
3
): d
1
9 8 4
H O
. Jutz, C.; Wagner, R. M.; Krartz, A.; Lobering, H.; Justus,
G. Liebigs Ann. Chem. 1975, 874–876.
. Marcoux, J. F.; Davies, I. W.; Taylor, M.; Dormer, P. T.
J. Org. Chem. 2001, 66, 251–255.
+
M
180.
Compound 6c: white solid: mp 83–85 °C; H NMR
(300 MHz, CDCl ): d 1.18 (t, J = 7.3 Hz, 3H), 2.61 (q,
J = 7.3 Hz, 2H), 3.85 (s, 3H), 7.88 (s, 1H), 8.17 (s, 1H),
1
3
1
0. Arnold, Z. Collect. Czech. Chem. Commun. 1965, 30,
125–2127.
1
3
2
9.90 (s, 1H), 10.12 (s, 1H); C NMR (75 MHz, CDCl
14.2, 22.7, 52.6, 116.6, 126.1, 126.7, 128.8, 132.0, 164.2,
169.0, 189.4. Anal. Calcd for C11 : C, 63.45; H, 5.81;
3
): d
1
1. Gall, J. E.; Riesinger, S. W.; Stanton, Q. S.; Berrit, K. T.;
Gupton, J. T.; Sikorski, J. A.; Dahl, M. L.; Arnold, Z. J.
Heterocycl. Chem. 1991, 28, 1281–1285.
H O
12 4
O, 30.74. Found: C, 63.42; H, 5.72; O, 30.74%. Mass m/z
+
1
2. Preparation of 2-dimethylamino-1,3-bis(dimethylimonio)-
(EI, 30 ev): M 208.
Compound 6e: white solid: mp 92–94 °C; H NMR
(300 MHz, CDCl ): d 0.90 (t, J = 7.5 Hz, 3H), 1.32 (t,
3
1
propane bis-perchlorate 2 from malonic acid: POCl
3
(
(
4.3 mL, 50.6 mmol) was added over 15 min to DMF
7 mL, 91 mmol) and the mixture was allowed to react for
J = 6.8 Hz, 3H), 1.59 (m, 2H), 2.73 (t, J = 7.2 Hz, 2H),
3
1
0 min. To the resulting solution, malonic acid (1.56 g,
5 mmol) was added and the mixture was heated at 90 °C
4.26 (q, J = 6.8 Hz, 2H), 7.79 (s, 1H), 8.15 (s, 1H), 9.92 (s,
1
3
1H), 10.10 (s, 1H); C NMR (75 MHz, CDCl
14.2, 23.1, 31.8, 60.7, 116.4, 126.0, 126.7, 128.5, 131.9,
164.2, 168.9, 191.6. Anal. Calcd for C13 : C, 66.09;
3
): d 13.8,
for 6 h until gas evolution ceased. The reaction mixture
was cooled in an ice-water bath and poured into 40 mL of
ice-water containing 3.7 g of sodium perchlorate mono-
hydrate. The resulting tan solid was removed by filtration
and dried at room temperature in vacuo to yield 5.2 g
16 4
H O
H, 6.82; O, 27.09. Found: C, 65.98; H, 6.70; O, 27.09%.
+
Mass m/z (EI, 30 ev): M 236.
Compound 8: yellow solid: mp 140–141 °C; H NMR
3
(300 MHz, CDCl ): d 6.98 (d, J = 8.1 Hz, 1H), 7.10–7.14
1
1
2
(
91%) of a solid, mp 222–223 °C (literature mp 222 °C);
1
H NMR (300 MHz, DMSO-d
6
): d 3.33 (s, 9H), 3.50 (s,
(m, 1H), 7.67–7.73 (m, 1H), 8.35 (dd, J
J = 1.2 Hz, 1H), 8.81 (d, J = 10.8 Hz, 1H), 9.57 (s, 1H),
2
1
= 4.8 Hz,
1
3
9
H), 8.40 (s, 3H); C NMR (75 MHz, DMSO-d ): d 43.3,
6
1
3
4
9.1, 91.2, 164.8.
9.94 (s, 1H), 12.17 (s, 1H); C NMR (75 MHz, CDCl
113.5, 113.8, 122.0, 139.5, 149.4, 149.7, 152.0, 189.3, 191.8.
Anal. Calcd for C : C, 61.36; H, 4.58; N, 15.90; O,
3
): d
1
3. b-Keto-esters 3c–f were prepared by condensation of acid
chlorides with the appropriate lithium enolates of methyl
or ethyl acetate. For details, see: Heathcock, C. H.;
Stafford, J. A. J. Org. Chem. 1992, 57, 2566–2568.
4. Preparation of phenols 6a–e: General procedure:
9 8 2 2
H N O
18.16%. Found: C, 61.34; H, 4.51; N, 15.88; O, 18.14%.
+
Mass m/z (EI, 30 ev): M 176. Crystallographic data for
1
structure 8 has been deposited with the Cambridge
Crystallographic Data Centre as supplementary publica-
tion number CCDC 297480. Copies of the data can be
obtained, free of charge, on application to CCDC, 12,
Union Road, Cambridge, CB2 1EZ, UK [fax: +44(0)-
1223-336033 or email: deposit@ccdc.cam.ac.uk].
0
a 250 mL flame-dried flask containing NaOR
To
11 mmol) and 80 mL of R OH, b-keto-ester 3 (3.5 mmol)
0
(
0
in R OH was added, followed by ‘vinamidinium’ bis-
perchlorate 2 (3.5 mmol). Then, the mixture was heated at
8
0 °C for 4 h. The reaction was monitored by TLC. After