Simple and efficient synthesis of N-quaternary salts of quinuclidinium derivatives

Article abstract of DOI:10.1055/s-2007-990908

The rapid and efficient synthesis of 1-alkylquinuclidinium (1-alkyl-1-azabicyclo[2.2.2]octane) and 1-alkyl-4-aza-1-azoniabicyclo[2.2.2] octane iodides are described. The products were characterized by ¹H NMR spectra and elemental analysis. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-990908

3
776
SHORT PAPER
Simple and Efficient Synthesis of N-Quaternary Salts of Quinuclidinium
Derivatives
a
a
a
b
a
S
J
ynthesis
e
of
N
-
Q
uate
a
r
nary Salts
n
of Quinuclid
-
inium
D
Y
e
rivatives ves Kazock,* Mohamed Taggougui, Bernard Carré, Patrick Willmann, Daniel Lemordant
a
Laboratoire Chimie Physique des Interfaces et des Milieux Electrolytiques, Faculté des Sciences, Université de Tours,
Parc de Grandmont, Bat. J, 37200 Tours, France
Fax +33(2)47367073; E-mail: jykazock@yahoo.fr
CNES, 18 Avenue E. Belin, 31055 Toulouse cedex, France
b
Received 28 June 2007
R1
N
R1
N
Abstract: The rapid and efficient synthesis of 1-alkylquinuclidini-
um (1-alkyl-1-azabicyclo[2.2.2]octane) and 1-alkyl-4-aza-1-azo-
niabicyclo[2.2.2]octane iodides are described. The products were
I–
I–
N
X
1
2
R I
R I
EtOAc, r.t.
0 min – 2 h
MeCN, reflux
36 h
1
I–
characterized by H NMR spectra and elemental analysis.
X
N
R2
1
Key words: amines, alkyl halides, alkylation, ammonium, ionic
liquids
1
2
X = C
X = N
3 X = C
4 X = N
5
Scheme 1 Synthesis of 1-alkylquinuclidinium and 1-alkyl-4-aza-1-
azoniabicyclo[2.2.2]octane iodide salts
Despite the growing number of papers describing the syn-
thesis of N-quaternary ammonium salts, there are very
1
few reports in the literature concerning bicyclic amines 1-
alkyl-1-azoniabicyclo[2.2.2]octane (quinuclidinium) and
Alkyl iodides have been chosen for the synthesis of qui-
nuclidinium or 4-aza-1-azoniabicyclo[2.2.2]octane halide
derivatives, because they are more reactive than their bro-
mide and chloride analogues for which long reaction
1
-alkyl-4-aza-1-azoniabicyclo[2.2.2]octane halides. A
2
number of different methodologies have been reported;
most researchers use a simple round-bottomed flask/
reflux condenser experimental setup for the quaterniza-
tion reaction under argon or some other inert gas in order
to exclude water and oxygen during the reaction.
3,10
times have been reported.
As summarized in Table 1 and Table 2, the 1-alkylquinu-
clidinium 3, 1-alkyl-4-aza-1-azoniabicyclo[2.2.2]octane
4
, and 1,4-dialkyl-1,4-diazoniabicyclo[2.2.2]octane io-
3
In their pioneering work, Mosby et al. reported the syn-
dides 5 were prepared with short reaction times in excel-
lent yields. The reactivity of alkyl iodides with
quinuclidine (1) and 1,4-diazabicyclo[2.2.2]octane (2) de-
creases when increasing the alkyl chain length. For exam-
ple, the reaction between quinuclidine (1) and
iodomethane is achieved within 10 minutes, while 30
minutes is necessary with iodoethane, and 2 hours with 1-
iodohexane. Under the same conditions, the reaction time
for 1,4-diazabicyclo[2.2.2]octane (2) with iodomethane is
twice as long as that for quinuclidine (1).
thesis of quinuclidinium halide salts under drastic condi-
4
tions using citrate for 18 hours. In 1983 Brent et al. also
described the synthesis of 1-methylquinuclidinium
5
6
iodide. Yoshiza and MacNeil have recently published
details of the monoquaternized salts of 1,4-diazabicy-
clo[2.2.2]octane. Some quinuclidine derivatives present
7
various pharmacological properties.
Ammonium halide salts are, in fact, necessary for the syn-
thesis of ionic liquids, which display interesting properties
2
,8
for electrochemical and biological applications. Quinu-
clidine (1) and 1,4-diazabicyclo[2.2.2]octane (2) are start-
ing materials for the synthesis of a large number of
Table 1 1-Alkylquinuclidinium Iodides 3
Product
Time
Yield (%) mp (±2 °C)
7
,9
bioactive compounds. For these reasons, the develop-
ment of new and efficient methods for the synthesis of
ammonium salts remains an area of strong interest.
3
a
10 min
91
96
86
91
346
274
147
210
N
I–
Me
Et
Our efforts are focused on the synthesis of bicyclic hetero-
cycle derivatives and in this paper, we report an efficient,
simple, and inexpensive procedure for the synthesis of 1-
alkylquinuclidinium and 1-alkyl-4-aza-1-azoniabicy-
clo[2.2.2]octane iodide salts 3 and 4, respectively
3b
30 min
1 h
N
N
N
N
I–
3
3
c
Pr
I–
(
Scheme 1).
d
1.5 h
Bu
Hex
I–
SYNTHESIS 2007, No. 24, pp 3776–3778
x
x.
x
x
.
2
0
0
7
Advanced online publication: 15.11.2007
DOI: 10.1055/s-2007-990908; Art ID: Z15807SS
Georg Thieme Verlag Stuttgart · New York
3e
2 h
94
130
I–
©

SHORT PAPER
Synthesis of N-Quaternary Salts of Quinuclidinium Derivatives
3777
1
-Methylquinuclidinium Iodide (3a); Typical Procedure
Table 2 1-Alkyl-4-aza-1-azoniabicyclo[2.2.2]octane Iodides and
1
,4-Dialkyl-1,4-diazoniabicyclo[2.2.2]octane Diiodide
1-Azabicyclo[2.2.2]octane (1, 3 g, 27 mmol) was mixed with
EtOAc (50 mL) and cooled before use. An equimolar amount of
MeI was added dropwise into the soln and the mixture was stirred
at r.t. for 10 min. The thus formed precipitate was filtered, washed
several times with petroleum ether (3 × 10 mL), and dried under re-
duce pressure at 80 °C to give 3a (6.22 g, 91%) as white crystals;
Product
Time
Yield (%) Mp (±2 °C)
N
N
I–
Me
Et
4a
4b
5
20 min
98
97
89
95
92
213
187
152
168
144
12
mp 346 °C (Lit. 352 °C).
1
H NMR (200 MHz, DMSO-d ): d = 3.41 (t, J = 7.4 Hz, 6 H, 3
6
N
N
I–
30 min
36 h
CH ), 2.91 (s, 3 H, CH ), 2.08 (q, J = 3.2 Hz, 1 H, CH), 1.86 (m, 6
2
3
H, 3 CH2).
1
3
C NMR (50 MHz, DMSO-d ): d = 56.67 (3 C, 3 CH ), 52.14 (C,
Me
N
N
N
Et
I–
6
2
CH ), 24.28 (3 C, 3 CH ), 19.55 (C, CH).
3 2
2
Anal. Calcd for C H IN: C, 37.96; H, 6.37; N, 5.53. Found: C,
37.82; H, 6.40; N, 5.49.
8
16
4c
4d
1 h
N
N
N
Pr
I–
1
-Ethylquinuclidinium Iodide (3b)
White crystals (6.9 g, 96%); mp 165 °C (Lit.12 273 °C).
N
Bu
Hex
1.5 h
1
I–
H NMR (200 MHz, DMSO-d ): d = 3.36 (t, J = 7.5 Hz, 6 H, 3
6
CH ), 3.19 (q, J = 7.2 Hz, 2 H, CH ), 2.08 (q, J = 3.2 Hz, 1 H, CH),
2
2
1
13
.87 (m, 6 H, 3 CH ), 1.22 (t, J = 7.3 Hz, 3 H, CH ).
N
2
3
4
e
2 h
96
90
I–
C NMR (50 MHz, DMSO-d ): d = 59.40 (C, CH ), 53.99 (3 C, 3
6
2
CH ), 24.14 (3 C, 3 CH ), 19.96 (C, CH), 8.44 (C, CH ).
2
2
3
The synthesized compounds 3–5 have relatively high Anal. Calcd for C
H
18IN: C, 40.46; H, 6.79; N, 5.24. Found: C,
9
4
0.44; H, 6.81; N, 5.23.
melting points, especially 1-methylquinuclidinium iodide
3a, 346 °C). However, increasing length in the alkyl
chain results in a decrease in the melting point and a sig-
nificant decrease is observed with derivatives of quinucli-
dine, with the exception of 3d.
(
1
-Propylquinuclidinium Iodide (3c)
1
2
White crystals (6.53 g, 86%); mp 147 °C (Lit. 144 °C).
1
H NMR (200 MHz, DMSO-d ): d = 3.37 (t, J = 7.5 Hz, 6 H, 3
2
6
CH ), 3.06 (q, J = 7.1 Hz, 2 H, CH ), 2.08 (q, J = 3.2 Hz, 1 H, CH),
2
In contrast with what is generally observed, we found that 1.86 (m, 6 H, 3 CH ), 1.67 (m, 2 H, CH ), 0.90 (t, J = 7.3 Hz, 3 H,
2
2
4
3
).
13
6
2
2
2
10 20
1
The fair reactivity of quinuclidine (1) and 1,4-diazabicy- 1-Butylquinuclidinium Iodide (3d)
clo[2.2.2]octane (2) correlates with their high pKa11 allow- White crystals (7.27 g, 91%); mp 210 °C.
1
ing them to be excellent nucleophiles.
H NMR (200 MHz, DMSO-d ): d = 3.37 (t, J = 8.4 Hz, 6 H, 3
6
CH ), 3.10 (t, J = 7.3 Hz, 2 H, CH ), 2.08 (q, J = 3.2 Hz, 1 H, CH),
1
(
1
2
2
All these N-quaternary quinuclidine derivative salts en-
abled us to carry out the synthesis and physicochemical
study of a series of ionic liquids, and the data of these
studies will be communicated in due time.
.86 (m, 6 H, 3 CH ), 1.62 (m, 2 H, CH ), 1.30 (m, 2 H, CH ), 0.94
2 2 2
t, J = 7.2 Hz, 3 H, CH3).
3
C NMR (50 MHz, DMSO-d ): d = 63.79 (C, CH ), 54.50 (3 C, 3
6
2
CH ), 24.20 (3 C, 3 CH ), 20.24 (2 C, CH ), 19.89 (C, CH), 14.43
2
2
2
In conclusion, new quaternary ammonium iodide salts of (C, CH3).
quinuclidine (1-azabicyclo[2.2.2]octane, 1) and 1,4-di-
azabicyclo[2.2.2]octane (DABCO, 2) bearing different 44.69; H, 42.97; N, 4.72.
Anal. Calcd for C H IN: C, 44.75; H, 42.99; N, 4.74. Found: C,
1
1
22
alkyl substituents have been synthesized in very good
yields and with fast reaction times.
1
-Hexylquinuclidinium Iodide (3e)
White crystals (8.19 g, 94%); mp 130 °C.
1
H NMR (200 MHz, DMSO-d ): d = 3.39 (t, J = 7.6 Hz, 6 H, 3
6
Unless otherwise noted, all reagents were purchased from Sigma-
Aldrich, Alfa Aesar and used without further purification. Melting
points were determined in aluminum pans with a Perkin-Elmer
CH ), 3.11 (t, J = 7.3 Hz, 2 H, CH ), 2.07 (q, J = 3.2 Hz, 1 H, CH),
2
2
1
.87 (m, 6 H, 3 CH ), 1.65 (m, 2 H, CH ), 1.31 (s, 6 H, 3 CH ), 0.89
2
2
2
(
t, J = 7.2 Hz, 3 H, CH3).
1
DSC-6 apparatus. NMR spectra were run at 200 MHz ( H) and 50
13C NMR (50 MHz, DMSO-d
CH ), 26.45 (C, CH ), 24.20 (3 C, 3 CH ), 22. 73 (2 C, 2 CH ), 22.21
): d = 63.96 (C, CH
), 54.48 (3 C, 3
13
6
2
MHz ( C) in DMSO-d or CDCl on Bruker-DPX-200 instruments;
6
3
2
2
2
2
chemical shifts (d) are reported in parts per million (ppm) downfield
from an internal tetramethylsilane reference. The coupling con-
stants (J values) are reported in hertz (Hz).
(
C, CH ), 19.90 (C, CH), 14.73 (C, CH ).
2
3
Anal. Calcd for C13
H26IN: C, 48.30; H, 8.11; N, 4.33. Found: C,
4
8.26; H, 8.13; N, 4.36.
Synthesis 2007, No. 24, 3776–3778 © Thieme Stuttgart · New York

3
778
J.-Y. Kazock et al.
SHORT PAPER
1
-Methyl-4-aza-1-azoniabicyclo[2.2.2]octane Iodide (4a); Typi-
Anal. Calcd for C H IN : C, 44.45; H, 7.77; N, 8.64. Found C,
44.38; H, 7.81; N, 8.67.
1
2
25
2
cal Procedure
The quaternization reaction was performed according to the typical
procedure for 3a but 2 was reacted with less than 1 equiv of alkyl
halide to avoid bis-alkylation, hence 2 (4 g, 35.6 mmol) and MeI
1-Ethyl-4-methyl-1,4-diazoniabicyclo[2.2.2]octane Iodide (5)
To 3b (4 g, 14.9 mmol) in MeCN (30 mL) was added MeI (1 equiv)
and the mixture stirred at reflux temperature for 36 h. After cooling
to r.t., the precipitate was filtered, washed with petroleum ether
(3 × 10 mL) and dried under reduce pressure at 80 °C to give 5 (5.44
g, 89%) as white crystals; mp 152 °C.
(3.54 g, 24.9 mmol) were reacted to give 4a (6.24 g, 98%) as white
crystals; mp 213 °C.
1
H NMR (200 MHz, CDCl ): d = 3.75 (t, J = 7.6 Hz, 6 H, 3 CH ),
3
2
3
.44 (s, 3 H, CH ), 3.30 (t, J = 7.6 Hz, 6 H, 3 CH ).
3
2
1H NMR (200 MHz, DMSO-d
J = 7.3 Hz, 2 H, CH ), 3.32 (s, 3 H, CH ), 1.30 (t, J = 7.2 Hz, 3 H,
): d = 3.89 (s, 12 H, 6 CH ), 3.60 (q,
2
1
3
6
C NMR (50 MHz, DMSO-d ): d = 54.13 (3 C, C2, C6, C2¢), 51.79
3
6
2
3
(
CH ), 45.54 (3 C, C3, C5, C3¢).
CH3).
Anal. Calcd for: C H IN : C, 33.09; H, 5.95; N, 11.02. Found C,
7
15
2
13
C NMR (50 MHz, DMSO-d ): d = 60.17 (C, CH ), 53.25 (3 C, 3
6
2
3
3.11; H, 5.97; N, 11.04.
CH ), 52.28 (C, CH ), 50.69 (3 C, 3 CH ), 8.53 (C, CH ).
2
3
2
3
1
-Ethyl-4-aza-1-azoniabicyclo[2.2.2]octane Iodide (4b)
Anal. Calcd for C H I N : C, 26.36; H, 4.92; N, 6.83. Found C,
9 20 2 2
26.33; H, 4.95; N, 6.86.
5
White crystals (7.44 g, 97%); mp 187 °C (Lit. 189 °C).
1
H NMR (200 MHz, DMSO-d ): d = 3.28 (t, J = 7.2 Hz, 2 H, CH ),
6
2
3
1
.26 (q, J = 7.2 Hz, 6 H, 3 CH ), 3.04 (t, J = 7.6 Hz, 6 H, 3 CH ),
2
2
Acknowledgment
.24 (t, J = 7.4 Hz, 3 H, CH3).
1
3
We express our grateful acknowledgment to Frederic Montigny
SAVIT) for NMR data.
C NMR (50 MHz, DMSO-d ): d = 59. 51 (C, CH ), 51.80 (3 C, 3
6
2
(
CH ), 45 51 (3 C, 3 CH ), 8.2 (CH ).
2
2
3
Anal. Calcd for C H IN : C, 35.83; H, 6.39; N, 10.45. Found C,
8
17
2
3
5.79; H, 6.87; N, 10.69.
References
(
1) See, for examples: (a) MacFarlane, D. R.; Golding, J.;
1
-Propyl-4-aza-1-azoniabicyclo[2.2.2]octane Iodide (4c)
Forsyth, S.; Forsyth, M.; Deacon, G. B. Chem. Commun.
White crystals (6.69 g, 95%); mp 170 °C.
2
001, 1430. (b) Matsumoto, H.; Kageyama, H.; Miyazaki,
1
H NMR (200 MHz, DMSO-d ): d = 3.28 (t, J = 7.2 Hz, 6 H, 3
6
Y. Chem. Commun. 2002, 1726.
CH ), 3.16 (t, J = 7.2 Hz, 2 H, CH ), 3.03 (t, J = 7.6 Hz, 6 H, 3 CH ),
2
2
2
(2) For examples: (a) Batten, S. R.; Jensen, P.; Moubaraki, B.;
Murray, K. S. Chem. Commun. 2000, 2331.
1
.69 (m, 2 H, CH ), 0.92 (t, J = 7.4 Hz, 3 H, CH ).
2
3
1
3
C NMR (50 MHz, DMSO-d ): d = 65.46 (C, CH ), 52.34 (3 C, 3
(b) MacFarlane, D. R.; Meakin, P.; Sun, J.; Amini, N.;
Forsyth, M. J. Phys. Chem. 1999, 103, 4164.
3) Mosby, W. L. Heterocyclic Systems with Bridgehead
Nitrogen Atoms Part II; Weissberger, A., Ed.; Interscience
Publishers: NewYork, 1961, 1339.
6
2
CH ), 45.53 (3 C, 3 CH ), 15.67 (C, CH ), 11.53 (C, CH ).
2
2
2
3
(
Anal. Calcd for C H IN : C, 38.31; H, 6.79; N, 9.93. Found C,
3
9
19
2
8.29; H, 6.82; N, 9.91.
(
(
4) Brent, M.-T. L.; Cannan, T. R.; Flanigen, E. M. EP 91049,
1
-Butyl-4-aza-1-azoniabicyclo[2.2.2]octane Iodide (4d)
1983.
White crystals (6.80 g, 92%); mp 144 °C.
5) Yoshizawa-Fujita, M.; MacFarlane, D. R.; Howlett, P. C.;
1
H NMR (200 MHz, DMSO-d ): d = 3.28 (t, J = 8.3 Hz, 6 H, 3
Forsyth, M. Electrochem. Commun. 2006, 8, 445.
6
CH ), 3.18 (t, J = 7.6 Hz, 2 H, CH ), 3.03 (t, J = 7.6 Hz, 6 H, 3 CH ),
2
2
2
(6) Wykes, A.; MacNeil, S. L. Synlett 2007, 107.
(7) Odzak, R.; Tomic, S. Bioorg. Chem. 2006, 34, 90.
(8) Ionic Liquids in Synthesis; Wasserscheid, P.; Welton, T.,
Eds.; Wiley-VCH: Weinheim, 2002.
1
.64 (m, 2 H, CH ), 1.32 (m, 2 H, CH ), 0.95 (t, J = 7.3 Hz, 3 H,
2
2
CH3).
1
3
C NMR (50 MHz, DMSO-d ): d = 67.38 (C, CH ), 52.29 (3 C, 3
6
2
(
9) (a) Langlois, M.; Soulier, J. L.; Allainmat, M.; Shen, S.;
CH ), 45.54 (3 C, 3 CH ), 23.97 (C, CH ), 20.16 (C, CH ), 14.44 (C,
CH2).
2
2
2
2
Gallais, C. Bioorg. Med. Chem. Lett. 1993, 3, 1555.
(b) Mashkovsky, M. D.; Yakhontov, L. N.; Kaminka, M. E.;
Anal. Calcd for C H IN : C, 40.55; H, 7.15; N, 9.46. Found C,
4
10
21
2
Mikhlina, E. E. Prog. Drug Res. 1983, 27, 9.
0.48; H, 7.19; N, 9.48.
(
(
10) Kovalev, N.; Burakova, E.; Silnikov, V.; Zenkova, M.;
Vlassov, V. Bioorg. Chem. 2006, 34, 274.
1
-Hexyl-4-aza-1-azoniabicyclo[2.2.2]octane Iodide (4e)
11) (a) Reported pK values for protonated quinuclidine,
a
White crystals (7.73 g, 96%); mp 90 °C.
pK = 11.0: Grob, C. Helv. Chim. Acta 1985, 68, 882.
a
1
H NMR (200 MHz, DMSO-d ): d = 3.29 (t, J = 8.0 Hz, 6 H, 3
(b) Reported pK values for protonated 1,4-diazabicy-
6
a
CH ), 3.18 (t, J = 7.4 Hz, 2 H, CH ), 3.03 (t, J = 7.4 Hz, 6 H, 3 CH ),
clo[2.2.2]octane, pK 1 = 2.92, pK 2 = 8.82: Hine, J.; Chen,
2
2
2
a
a
1
.67 (m, 2 H, CH ), 1.31 (s, 6 H, 3 CH ), 0.91 (t, J = 7.2 Hz, 3 H,
Y. J. Org.Chem. 1987, 52, 2091.
2
2
CH3).
(12) Kellet, J. C. Jr.; Doggett, W. C. J. Pharm. Sci. 1996, 55, 414.
1
3
C NMR (50 MHz, DMSO-d ): d = 64.04 (C, CH ), 52.30 (3 C, 3
6
2
CH ), 45.55 (3 C, 3 CH ), 26.37 (C, CH ), 22.73 (2 C, 2 CH ), 21.93
2
2
2
2
(
C, CH ), 14.73 (C, CH ).
2
3
Synthesis 2007, No. 24, 3776–3778 © Thieme Stuttgart · New York