Covert Mannich reaction via carbon transfer

Article abstract of DOI:10.1080/00397910600941299

1,3-Dimethylbenzimidazolidine reacts with ketones, which can provide activating α hydrogens and primary or secondary amines under acidic conditions, to yield aminomethylation derivatives by a covert Mannich reaction. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910600941299

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Covert Mannich Reaction via Carbon Transfer
Huan Gu a , Yuan Guo a & Zhen Shi a
a Department of Chemistry , Northwest University , Xi'an, China
Published online: 23 Nov 2006.
To cite this article: Huan Gu , Yuan Guo & Zhen Shi (2006) Covert Mannich Reaction via Carbon Transfer,
Synthetic Communications: An International Journal for Rapid Communication of Synthetic Organic Chemistry,
36:22, 3335-3338, DOI: 10.1080/00397910600941299
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Synthetic Communicationsw, 36: 3335–3338, 2006
Copyright # Taylor & Francis Group, LLC
ISSN 0039-7911 print/1532-2432 online
DOI: 10.1080/00397910600941299
Covert Mannich Reaction via Carbon
Transfer
Huan Gu, Yuan Guo, and Zhen Shi
Department of Chemistry, Northwest University, Xi’an, China
Abstract: 1,3-Dimethylbenzimidazolidine reacts with ketones, which can provide acti-
vating a hydrogens and primary or secondary amines under acidic conditions, to yield
aminomethylation derivatives by a covert Mannich reaction.
Keywords: Aminomethylation derivative, 1,3-dimethylbenzimidazolidine, Mannich
reaction
In recent years, many researchers have tried to discover the mechanism of
various coenzymes related to tetrahydrofolate coenzymes that lead in the bio-
chemical transfer of a one carbon fragment at different oxidation levels.[1] The
role of six one-carbon derivatives of tetrahydrofolic acid (THF 1) in the
enzyme-catalyzed transfer of a C1-unit at the level of formate, formaldehyde,
and methanol has been determined.[2] So, how to mimic the carbon-transfer
process in model reactions and develop suitable coenzyme models for
potential utilization in the “biomimetic transfer” of C1-units and larger (even-
tually functionalized) carbon fragments is becoming an intriguing challenge.
The synthesis and application of such models has been reported.[3]
We now present results describing the transfer of synthetically useful
carbon fragments from the related N5,N10-methylenetetrahydrofolate models
1,[3] which can be prepared from 1,3-dimethyl-benzimidazolinium iodide by
reduction with sodium borohydride.
Received in Japan January 31, 2006
Address correspondence to Zhen Shi, Department of Chemistry, Northwest Univer-
sity, Xi’an 710069, China. E-mail: guhuan2046@yahoo.com.cn
3335

3336
H. Gu, Y. Guo, and Z. Shi
When a mixture of the coenzyme model 1, primary or secondary amine,
and ketones with activating a hydrogens was heated (CH3CN, reflux) in
the presence of acetic acid, the corresponding aminomethylation derivatives
2–7 were obtained with good yields. This carbon-transfer reaction is
derived from the reported equilibrium between 1,3-dimethyl-imidazolidine
and N-methyl-N-(2-N-methylamino)ethyl-N-methylenium trifluoroacetate[4]
and other analogues.[5] The mechanism of formation of the aminomethylation
derivatives can be rationalized via this sequence:
Actually, this carbon-transfer reaction can be regarded as a covert
Mannich reaction. Furthermore it should be emphasized that the particular
merit of the reported synthetic approach lies in the fact that the use of the rela-
tively unstable aldehydes, required in the Pictet–Spengler procedure for
related synthesis, is avoided.
The application of the folate model synthetic methodology to
isoquinoline and b-carboline derivatives is being vigorously investigated,
and our results on these studies will be presented elsewhere.

Covert Mannich Reaction via Carbon Transfer
EXPERIMENTS
3337
Melting points were taken on a XT-4 micromelting apparatus (Beijing) and are
uncorrected. Thin-layer chromatography (TLC) analysis was carried out on
glass plates coated with silica gel-G, and spots were visualized using an ultra-
violet (UV) lamp. Infrared (IR) spectra in centimeters21 were recorded on a
Brucker Equiox-55 spectrometer (Germany). Mass spectra were obtained
1
with a Varian 1200-L spectrometer. Proton magnetic resonance spectra (1H
NMR) spectra were recorded at 400 MHz on a Varian Inova-400 spectrometer
(USA), and chemical shifts were reported relative to internal Me4Si. With the
exception of aqueous reactions, all reactions were conducted under a nitrogen
atmosphere.
General Procedure for the Synthesis of Compounds 2–7
A mixture of 1,3-dimethyl-benzimidazolidine (296 mg, 2 mmol) 1, appro-
priate amine (2 mmol), ketone (2 mmol), acetic acid (1 ml), and acetonitrile
(10 ml) was refluxed for 6 h, and the solvent was removed. The residue was
taken up in CH2Cl2 and washed with NaHCO3 solution; the organic layer
was dried and evaporated to obtain the crude product.
1-Phenyl-3-phenylamino-propan-1-one 2 and 4-phenylamino-butan-2-
one 3 were crystallized from hexane.
2: A light yellow powder was obtained. Yield: 158 mg (35%). Mp: 107–
1088C (lit.[6] 1138C); mass (ESI): 226 (Mþ); IR (KBr): 3425 (m), 1690 (s);
1H NMR (DMSO-d6): d 7.35–7.90 (m, 5H), d 6.4 –7.1 (m, 5H), d 4.0
(d, 1H), d 3.40 (m, 2H), d 2.65 (t, 2H).
3: A light yellow power was obtained. Yield: 134 mg (41%). Mp: 38–398C
(lit.[7] 35–35.58C); mass (ESI): 164 (Mþ); IR (KBr): 3425 (m), 1715 (s);
1H NMR (DMSO-d6): d 6.4–7.1 (m, 5H), d 4.0 (d, 1H), d 3.40 (m, 2H),
d 2.65 (t, 2H), d 2.1 (s, 3H).
2-Diethylamino-1-phenyl-propan-1-one 4, 3-diethylamino-1-methyl-
propan-1-one 5, 3-diethylamino-1-phenyl-propan-1-one 6, and N,N-dibenzyl-
2-aminoethyl-methylketon 7 were purified by chromatography (SiO2, EtOAc).
4: A white power was obtained. Yield: 267 mg (65%). Mp: 101–1028C
1
(lit.[8] 105–1088C); mass (ESI): 206 (Mþ); IR (KBr): 1690 (s); H NMR
(DMSO-d6): d 7.35–7.90 (m, 5H), d 2.68 (t, 2H), d 2.50 (t, 2H), d 2.29
(s, 6H).
5: A light yellow oil was obtained. Yield: 195 mg (68%). Mp (diethyl methyl
(3-oxo-butyl) ammonium iodide): 82–848C (lit.[9] 868C); mass (ESI): 144
1
(Mþ); IR (CHCl3): 1720 (s); H NMR (DMSO-d6): d 2.70 (m, 6H), d 2.52
(t, 2H), d 2.1 (s, 3H), d 1.1 (t, 6H).

3338
H. Gu, Y. Guo, and Z. Shi
6: A white power was obtained. Yield: 362 mg (55%). Mp: 37–40 (lit.[10]
1
358C); mass (ESI): 330.5 (Mþ); IR (KBr): 1690 (s); H NMR (DMSO-d6):
d 7.35–7.90 (m, 5H), d 6.5–7.2 (m, 10H), d 3.56 (s, 4H), d 2.70 (t, 2H),
d 2.52 (t, 2H).
7: A white power was obtained. Yield: 290 mg (54%). Mp: 63–648C (lit.[11]
1
598C); mass (ESI): 268 (Mþ); IR (KBr): 1715 (s); H NMR (DMSO-d6):
d 6.5–7.2 (m, 10H), d 3.56 (s, 4H), d 2.70 (t, 2H), d 2.52 (t, 2H), d2.1 (s, 3H).
ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation
of China (Nos. 20472046 and 20172041), the Ph.D. Program Foundation of
Chinese University (No. 20050692003), and the National Foundation of
Shaanxi Province.
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