One-pot synthesis of cyclic amidinium tetrafluoroborates and hexafluorophosphates; the simplest models of N5, N100methenyltetrahydrofolate coenzyme

Article abstract of DOI:10.1016/S0040-4039(00)93420-8

Reaction of triethyl orthoesters with various N,N′-dialkyl-α,ω-alkanediamines in the presence of ammonium tetrafluoroborate or hexafluorophosphate, all in the same molar ratio, affords cyclic amidinium salts in excellent yields.

Full text of DOI:10.1016/S0040-4039(00)93420-8

l~etrahedron Letters, Vo1.32, No.380 pp 5031-5034, 1991
Printed in Great Britain
0040-4039/91 $3.00 + .00
Pergamon Press pie
ONE-POT SYNTHESIS OF CYCLIC AMIDINIUM TETRAFLUOROBORATES AND
~ U O R O P H O S P H A T E S ; THE SIMPI. F~r MODELS OF
NS,NI°.METHENYLTETRAHYDROFOLATE COENZYME
Shahrokh Saba,* AnneMarie Brescia, and Moses K. Kaloustian*
Department of Chemistry, Fordham University
Bronx, New York 10458
Abstract:
Reaction of triethyl orthoesters with various N,N'-dialkyl-a,co-alkanediamines in the
presence of ammonium tetrafluoroborate or hexafluorophosphate, all in the same molar ratio, affords cyclic
amidinium salts in excellent yields.
The role of tetrahydrofolate coenzymes in the transfer of a one-carbon unit at different
oxidation levels has been well recognized.1 NS,Nl°-Methenyltetrahydrofolate 1, utilizes an
imidazolinium moiety in the transfer of carbon at the formate oxidation level.2 Pandit and
c o - w o r k e r s , 3 have used simple imidazolinium systems, as models of N5,N l°-
methenyltetrahydrofolate, to mimic such carbon-transfer reactions. The utility of simple
imidazolines and imidazolinium salts, as folate models, has also been demonstrated in
recent years in the synthesis of ketones,4 and indoloquinolizidine derivatives.5
For a project directed toward studies of stereoelectronic effects6 in the generation and
breakdown of model, tetrahydrofolate-type tetrahedral intermediates,Ta,b in non-aqueous
media and utilizing neutral oxygen nucleophiles, we required peralkylated cyclic
amidinium systems (2-4) with gegenions of low nucleophilicity. We describe herein a simple
and efficient one-pot process for the synthesis of amidinium tetrafluoroborates and
hexafluorophosphates 2, 3 and 4 from commercially available orthoesters.
H
x_
H
R~
2:n=2
3:n=3
4:n=4
5031

5032
Existing methodologies for the synthesis of such cyclic amidinium salts are sparse
and, with relatively few exceptions, the majority of recorded salts possess a halide as the
counterion. Cook and co-workers,8 prepared 1,3-dimethyl-2-phenyl-4,5-dihydroimidazolium
iodide from 1-methyl-2-phenylimidazoline and excess methyl iodide. Following a similar
approach, Anderson and co-workers4 also reported the synthesis of a series of 2-alkyl-1-
benzyl-3-methyl-4,5-dihydroimidazolium iodides. Pandit and co-workers3 also rerpoted the
reactions between a,co-alkanediamines with 1-acetyl or 1-tosyl-3,4,4-trimethyl-a 2-
imidazolinium iodides as a route to some cyclic amidinium iodides.
Several 1,3-dialkyl-5,5-dimethyl-l,4,5,6-tetrahydropyrimidinium iodides have been
reported as by-products when the corresponding hexahydropyrimidines were treated with
alkyl halides. 9 The perchlorate salts of a n u m b e r of similar compounds have also been
obtained from the reaction of the corresponding hexahydropyrimidines with mercuric
acetate. 10
Desmarchelier et al.11 reported the synthesis of 2-methyl-4,5,6,7-tetrahydro-l,3-
diazepinium chloride by the reaction of acetamidine hydrochloride with 1,4-butanediamine.
Benkovic and co-workers7a prepared a few formadinium fluoroborates by the reaction
of substituted tetrahydroquinoxalines with triethyl orthoformate followed by treatment with
aqueous fluoroboric acid. N-carbomethoxy-N'-methyl-2-ethyloxyimidazolinium fluoroborate
has also been made by O-ethylation (Et30+BF4-) of N-carbomethoxy-N'-methyl-2-
imidazolidone, while N-carbomethoxy-N'-methyl-2-(2',6'-dimethylphenoxy)imidazolinium
fluoroborate was obtained by N-methylation (Me30+BF4-) of N-carbomethoxy-2-(2',6'-
dimethylphenoxy)imidazoline. 12
We have found that reaction of an orthoester 5, with an N,N'-dialkyl-o~o-
alkanediamine 6, in the presence of ammonium tetrafluoroborate or ammonium
hexafluorophosphate (Scheme 1), all in equimolar amounts in the absence of a solvent,
affords directly the corresponding dihydroimidazolium, tetrahydropyrimidinium and
tetrahydro-l,3-diazepinium salts in excellent yields (Table). 13 The requisite diamines were
either commercially available or were prepared by literature procedures or adaptation of
literature procedures.
Scheme 1
OEt
=
/(CRy.\
I
÷NH, X-
R1--C
-OEt
+
R2NH(CH2)nNHR2
I
OEt
5
6
I:tl
2 a - m
3a-h
4a-e
N,N'-Di-tert-butylethylenediamine 14, N,N'-diisopropylethylenediamine, 15 and N,N'-
dimethyl-l,4-butanediamine 16 were prepared as described in the literature, while N,N'-
diethyl-l,4-butanediamine, N,N'-diisopropyl-l,4-butanediamine and N,N'-diisopropyl-l,3-
propanediamine were prepared by adaptation of the method of Klemm et al. 15 from the
corresponding diamines and alkyl halides.

5033
Table. Amidinium Salts 2, 3, 4.17,18
Product
R1
R2
X
Yield(%)
mp(°C)
2a
2b
2c
2d
2e
2f
H
H
H
H
H
H
H
Me
Et
BF4 92
BF4 94
BF4 92
252-255
oil
oil
152-153
200-203
277
i-Pr BF4 96
i-Pr PF6 94
t-Bu BF4 36
2g
2h
2i
Me
Me
Et
Et
Et
Ph
Ph
H
Me
Me
Me
Me
Et
Me
Me
H
BF4 97
PF6 97
BF4 99
PF6 98
PF6 76
BF4 97
PF6 94
BF4 98
215
195-198
210
204-207
199-200
87-88
119-120
263-264
163
204-205
2Z3-224
239-241
240-245
84.5-85
145
2j
2k
21
2m
3a
3b
3c
3d
3e
3f
3g
ah
4a
4b
4c
4d
4e
H
i-Pr PF6 97
Me
Me
Et
Et
Ph
Ph
H
H
H
H
H
Me
Me
Me
Me
Me
Me
H
BF4 94
PF6 98
BF4 88
PF6 97
BF4 89
PF6 95
BF4 90
PF6 92
gel
Me
semi-solid
semi-solid
gel
i-Pr PF6 88
Et
Et
BF4 87
PF6 90
gel
2-Ethyl-l$-d|methyl-l,4~5,~terahydropyrimldinlum tetrafiuoroborate (3e); typical
procedure. A 10 mL round-bottemed flask charged with triethyl orthopropionate (1.76 g,
0.010 mole), ammonium tetrafluoroborate (1.05 g, 0.010 mole) and N,N'-dimethyl-l,3-
propanediamine (1.02 g, 0.010 mole) was heated at 120°C in an oil bath for 3 hrs. The ethanol
formed during the reaction was removed on the rotary evaporator followed by further drying
on the vacuum pump for 2 hrs. The crude product was crystallized from absolute ethanol to
give white needles (see Table). Anal. calcd for CsH17BF4N2: C, 42.13; H, 7.52; N, 12.29.
Found: C, 42.21; H, 7.53; N, 12.38. 1H-NMR (CDC13/CD3CN) 5 1.28 (t, 3H); 2.17 (m, 2H); 2.74
(q, 2H); 3.34 (s, 6H); 3.56 (t, 4H).
This work was supported in part by a grant from the Fordham University Research
Council.
References and Notes
(1)
Bruice, T. C. and Benkovic, S. J. Bioorganic Mechanisms, vol. 2, p. 350, Benjamin,
New York, 1966. Benkovic, S. J. Acc. Chem. Res. 1978, 11,314 and refs cited therein

5034
Benkovic S. J. Ann. Rev. Biochem. 1980, 49, 227 and refs cited therein. Pandit, U. K.
Recl. Trav. Chim. Pays-Bas 1988, 107, 111.
(2)
(3)
(4)
Bieraugel, H.; Plemp, R.; Hiemstra, H. C.; Pandit, U. K. Tetrahedron, 1983, 39, 3971
and refs cited therein.
Anderson, M. W.; Jones, R. C. F.; Saunders, J. J. Chem. Soc. Chem. Commun. 1982,
282.
Steit, A. R.; Pandit, U. K. Tetrahedron, 1989, 45, 849 and refs cited therein.
Perrin, C. L.; Nunez, 0. J. Am. Chem. Soc. 1987, 109, 522 and refs cited therein.
(5)
(6)
(7)
(a) Benkovic, S. J.; Bullard, W. P.; Benkovic, P. A. J. Am. Chem. Soc. 1972, 94, 7542.
(b) Robinson, D. R.; Jencks, W. P. J. Am. Chem. Soc. 1967, 89, 7088.
Cook, M. J.; Katritzky, A. R.; Page, A. D.; Tack, R. D.; Witeck, H. Tetrahedron, 1976,
32, 1773.
(8)
(9)
Piotrowska, H.; Prejzner, H. Bull. Acad. Pol. Sci., Ser. Sci. Chim. 1981, 29,329. C. A.
1983, 98, 215556.
(10) Piotrowska, H.; Prejzner, H.; Sas, W. Rocz. Chem. 1977, 51, 1775. C. A. 1978, 88, 74368.
(11) Desmarchelier, J. M.; Evans, N. A.; Evans, R. F., Johns, R. B. Aus. J. Chem. 1968,
21,257.
(12)
Cravey, M.; Kohn, H. J. Am. Chem. Soc. 1980, 102, 3928.
(13) While compounds 2a-4e are the fully characterized products, NMR evidence
indicates that the method described can be applied to the preparation of macrocyclic
amidinium salts derived from diamines with longer chain lengths as well as other
ammonium salts such as bromides.
(14)
(15)
Shepard, R. G.; Wilkinson, R. G. J. Med. Pharm. Chem. 1962, 5, 823.
Klemm, D.; Bellstedt, K.; Hoerhold, H. J. Prakt. Chem. 1979, 321,680.
(16) Devinsky, F.; Lacko, I.; Krasnec, L. Synthesis, 1980, 303.
(17) The products were characterized by their melting points, elemental analyses and 1H-
NMR. NMR spectra of the amidinium salts showed the expected downfield shifts of
the N-alkyl signals associated with the partial positive charge on the nitrogens as
compared to the absorptions of the corresponding groups in the starting diamines.
Noncrystalline products were purified by shaking the crude products with Et20/EtOH
(1:1; v/v) followed by decantation and vacuum drying for several hours.
(18)
Two-step approaches to the same overall transformation have been worked out
(Garza, V. and Kaloustian, M. K., unpublished results). In the first approach, an
acyclic amidinium acetate is converted to the corresponding fluoroborate salt by
treatment with Et30+BF4- and the product is then made to react with an N,N'-dialkyl-
a,o~-alkanediamine. Alternatively, an acyclic amidinium acetate is made to react
with the a,o~-alkanediarrfine, and the product is subsequently treated with Et30+BF4-.
(Received in USA 22 May 1991)