Serial double nucleophilic addition of amines to the imidazole nucleus

Article abstract of DOI:10.1016/S0040-4039(00)01283-1

2-(1-Chloro-2,2-dimethylpropyl)-1-methyl-1H-imidazole hydrochloride (2a·HCl) was treated with an excess of N,N-dimethylamine at room temperature to give an abnormal addition product, 4,5-bis(N,N-dimethylamino)-1-methyl-2-(2,2-dimethylpropyl)-2-imidazoline

Full text of DOI:10.1016/S0040-4039(00)01283-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 7503–7506
Serial double nucleophilic addition of amines to the
imidazole nucleus
Shunsaku Ohta,* Tomohisa Osaki, Satoko Nishio, Akemi Furusawa, Masayuki Yamashita
and Ikuo Kawasaki
Kyoto Pharmaceutical University, Misasagi Nakauchicho 5, Yamashinaku, Kyoto 607-8414, Japan
Received 22 June 2000; revised 21 July 2000; accepted 24 July 2000
Abstract
2-(1-Chloro-2,2-dimethylpropyl)-1-methyl-1H-imidazole hydrochloride (2a·HCl) was treated with an
excess of N,N-dimethylamine at room temperature to give an abnormal addition product, 4,5-bis(N,N-
dimethylamino)-1-methyl-2-(2,2-dimethylpropyl)-2-imidazoline (4a), in 74.2% yield together with a normal
SN2 product, 2-(1-N,N-dimethylamino-2,2-dimethylpropyl)-1-methyl-1H-imidazole (3a), in 15.0% yield.
The former might be evolved from a serial double nucleophilic addition of the secondary amine molecules
to the imidazole nucleus, which has been generally considered as an electron-excessive and stable aromatic
ring. © 2000 Elsevier Science Ltd. All rights reserved.
Keywords: imidazoles; nucleophilic addition; imidazolines; amines; SN2; X-ray crystallography.
Imidazole has been considered as a basic electron-excessive aromatic; therefore, in general, the
nucleus is subjected to ordinary electrophilic reactions, imidazolium salt formation and the nucleo-
philic substitutions of lithioimidazoles.1,2 Nucleophilic reactions on the imidazole ring with no
directly linked electron-withdrawing group such as halogen atom(s) are quite rare† and have been
commonly performed by the activation of imidazole rings by quaternization.1,4 This communi-
cation deals with a stereoselective double nucleophilic addition of the secondary amine molecules
into the 4- and 5-positions of the imidazole ring under mild conditions without quaternization.
In the course of our investigations on the synthesis of imidazole chiral bidentate ligands for
transition metals,‡ we planned the preparation of 2-(1-amino-2,2-dimethylpropyl)-1-methyl-1H-
* Corresponding author. Fax: +81-75-595-4795; e-mail: sohta@mb.kyoto-phu.ac.jp
† For example: an oxidative addition of methanol and benzylalcohol into 2-aminoimidazole derivatives in the
presence of NCS has been known3.
‡ For example, expecting formation of complex III, the sulfides (IIa, IIb) were initially prepared by the reactions as
shown below.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01283-1

7504
imidazoles (3), which would be easily derived by an SN2 reaction of amine with 2-(1-chloro-2,2-
dimethylpropyl)-1-methyl-1H-imidazole (2a). Thus, 2-(1-hydroxy-2,2-dimethyl-propyl)-1-
methyl-1H-imidazole (1a)§ was chlorinated with thionyl chloride in chloroform to give 2a·HCl
as colorless crystals. In order to prepare 2-(1-N,N-dimethylamino-2,2-dimethylpropyl)-1-methyl-
1H-imidazole (3a), 2a·HCl was treated with an excess of N,N-dimethylamine. However, the
expected normal SN2 product (3a) was obtained in only 15.0% yield, and the unexpected
addition product (4a) was obtained in 74.2% yield (Scheme 1).
Scheme 1.
The major compound (4a) has the molecular formula C13H28N4 on the basis of high-resolu-
tion MS (HRMS) and micro-elemental analysis data of its crystalline picrate (4a·dipicrate), and
1
its H NMR spectrum indicated the presence of two dimethylamino groups and the absence of
the olefinic 4- and 5-position protons of the imidazole ring. Finally, the structure of 4a was
determined by X-ray crystallographic analysis of its picrate (4a·dipicrate) as shown in Fig. 1.**
H
H3C
N+ CH3
H
N+
H
H
N
N
H3C
CH3
H3C
Figure 1. ORTEP view of 4a·dipicrate. (The trinitrophenoxide portions are omitted)
§ The alcohols 1a and 1b were prepared by treatment of 2-lithio-1-methyl-1H-imidazole with pivalaldehyde and
isobutyraldehyde in THF at −78°C, respectively.
** Detailed data of the X-ray analysis were sent to Cambridge Crystal Data Centre (UK).

7505
The adduct (4a) might be produced, interestingly, through a double nucleophilic addition of
dimethylamine molecules to the electron-rich imidazole ring of 2a, and the plausible reaction
mechanism is given in Scheme 2. The addition probably proceeded because of the steric
hindrance around the ꢀCHClꢀ moiety of 2 and the instability of the intermediate (5).
Scheme 2. Plausible reaction mechanism
The reaction of 2a and 2b with various amines was examined, and the results are listed in
Table 1. The addition products (4) were obtained in 28.7–78.2% yields except for the case of
benzylamine, a primary amine (entries 1–10). In the cases of benzylamine (entries 4, 9) the
corresponding addition products were not isolated, and in the case of N,N%-dimethylethylenedi-
amine (entries 5, 10), the cyclic products (4e and 4j) were obtained in variable yields.
Table 1
Reaction of 2a·HCl and 2b·HCl with various amines
Entry
R1 of 2
Amine
R2
Yield of 4 (%)
Yield of 3 (%)
R3
1
2
3
4
5
6
7
8
9
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
N,N-Dimethylamine
Pyrrolidine
Piperidine
CH3
ꢀ(CH2)4ꢀ
ꢀ(CH2)5ꢀ
C6H5CH2
CH3
CH3
4a: 74.2a
4b: 67.9a
4c: 60.8a
3a: 15.0a
3b: 4.8a
3c: 13.4a
3d: 67.5a
c
Benzylamine
H
–
e
CH3NH(CH2)2NHCH3
N,N-Dimethylamine
Pyrrolidine
Piperidine
Benzylamine
ꢀ(CH2)2NHCH3 4ed: 78.2a
–
CH3
CH3
4f: 63.9b
4g: 57.5b
4h: 61.1b
3f: 17.1b
3f: 7.0b
ꢀ(CH2)4ꢀ
ꢀ(CH2)5ꢀ
C6H5CH2
CH3
3h: 17.3b
3ib: 36.2
c
H
–
e
10
CH3NH(CH2)2NHCH3
ꢀ(CH2)2NHCH3 4jd: 28.7b
–
a Isolated yield from 2a·HCl.
b Isolated yield from 1b.
c The expected product 4d (entry 4) or 4i (entry 9) was not isolated.
d Product
e Expected product

7506
Preparation of a C2-symmetry chiral ligand from 4a may be an interesting subject for
investigation and we are now examining an application of the present addition to carbanion-
type nucleophiles and other azoles.††
Reaction of 2a with N,N-dimethylamine (typical procedure). Aq 50% Me2NH (3 ml) was added
to a solution of 2a (3 mmol) in THF (3 ml) at 0°C. Stirring was continued for 3 h at 0°C. Water
(1.5 ml) was added, and the mixture was extracted with AcOEt (20 ml×3). The organic layer was
dried over Na2SO4 and evaporated to give an oily residue, which was purified by column
chromatography (activated alumina) to give 3a (AcOEt/n-hexane=1/1, 88 mg, 15.0%) as the
1
first fraction and 4a (AcOEt, 535 mg, 74.2%) as the second fraction. 3a: oily product. H NMR
(400 MHz, in CDCl3) l 1.06 (s, 9H, ꢀC(CH3)3), 2.34 (s, 6H, ꢀN(CH3)2), 3.38 (s, 1H,
ꢀCHN(CH3)2), 3.64 (s, 3H, NCH3), 6.81 (d, 1H, J=1.3 Hz, ImꢀH), 7.05 (d, 1H, J=1.3 Hz,
ImꢀH). IR (CHCl3): 2926, 1476 cm−1. LR-EIMS m/z (relative intensity): 195 [M+, 5.5], 138
1
(100). HR-EIMS m/z: calcd for C11H21N3, 195.1735. Found: 195.1732. 4a: oily product. H
NMR (400 MHz, in CDCl3) l 1.08 (s, 9H, ꢀC(CH3)3), 2.21 (d, 1H, J=13.6 Hz, ꢀCH2C(CH3)3),
2.24 (s, 6H, ꢀN(CH3)2), 2.26 (d, 1H, J=13.7 Hz, ꢀCH2C(CH3)3), 2.30 (s, 6H, ꢀN(CH3)2), 2.90
(s, 3H, ꢀNCH3), 3.96 (d, 1H, J=3.8 Hz, ꢀCHN(CH3)2), 4.25 (d, 1H, J=3.8 Hz, ꢀCHN(CH3)2).
IR (CHCl3): 2920, 1585 cm−1. LR-EIMS m/z (relative intensity): 240 [M+, 1.7], 138 (100).
HR-EIMS m/z: calcd for C13H28N4, 240.2314. Found: 240.2309. 4a·dipicrate, mp 147.0–150.0°C
(recrystallized from MeOH). Anal. calcd for C25H34N10N14: C, 42.98; H, 4.91; N, 20.05. Found:
C, 43.13; H, 4.95; N, 19.34. X-ray crystallographic data, triclinic; P-1(c2); a=12.2412(8),
3
,
,
b=13.3569(8), c=10.9801(4) A, h=92.526(4), i=94.827(4), k=65.166(5)°; V=1623.4(2) A ;
3
−1
,
Z=2; Dcalc=1.429 g/cm ; u(Cu Ka)=1.54178 A; v(Cu Ka)=10.20 cm ; F(000)=732.00;
T=296 K; R=0.061 (Rw=0.102) for 3505 observations.
Acknowledgements
This research was financially supported in part by the Frontier Research Program of the
Ministry of Education, Science, Sports and Culture of Japan.
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†† New compounds reported in this communication were fully characterized by HRMS (oily compounds),
1
micro-elemental analysis (crystalline compounds), H NMR, IR, and LRMS.