Synthesis of 2-(N-disubstituted amino)ethyltriphenylphosphonium bromides

Article abstract of DOI:10.1016/j.tetlet.2007.11.182

2-(N-Disubstituted amino)ethyltriphenylphosphonium bromides are prepared in quantitative yields with high purity by reacting secondary amines with 2-methoxyethyltriphenylphosphonium bromide under aqueous conditions. The differential reactivity of this reagent offers advantages for the preparation of aminoethyltriphenylphosphonium bromides possessing nucleophiles such as hydroxy groups.

Full text of DOI:10.1016/j.tetlet.2007.11.182

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Tetrahedron Letters 49 (2008) 824–826
Synthesis of 2-(N-disubstituted amino)ethyltriphenylphosphonium
bromides
G. Venkateswara Rao, G. Chandrasekara Reddy *
Vittal Mallya Scientific Research Foundation, PB No. 406, K. R. Road, Bangalore 560 004, India
Received 4 October 2007; revised 21 November 2007; accepted 29 November 2007
Available online 4 December 2007
Abstract
2-(N-Disubstituted amino)ethyltriphenylphosphonium bromides are prepared in quantitative yields with high purity by reacting sec-
ondary amines with 2-methoxyethyltriphenylphosphonium bromide under aqueous conditions. The differential reactivity of this reagent
offers advantages for the preparation of aminoethyltriphenylphosphonium bromides possessing nucleophiles such as hydroxy groups.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: Phosphonium salts; Ylides; Phosphonioethylation; Displacement reaction; Nucleophile
Phosphonium salts are reagents used in the preparation
of ylides for olefin synthesis. The advantage of the Wittig
reaction is its versatility in preparing olefins without affect-
ing other functional groups such as hydroxy, halo and
carboxylic acid esters, present either in carbonyl com-
pounds or in ylides. 2-(N-Disubstituted amino)ethyltri-
phenylphosphonium bromides are important intermediates
in the synthesis of various active pharmaceuticals such as
acrivastine,1 pyrrobutamine,2 triprolidine3 and zimeldine.4
During the process development of acrivastine and triprol-
idine we required an efficient and practical method for mak-
ing 2-(N-pyrrolidino)ethyltriphenylphosphonium bromide
(3e). Though there are several methods5–8 available for
the preparation of 3e, most suffer from one or more draw-
backs. The task of improving the method for the prepara-
tion of compound 3e resulted in the discovery of the
differential reactivity of 2-methoxyethyltriphenylphospho-
nium bromide (1) towards nucleophiles having displaceable
hydrogen (Scheme 1).
Conventional methods9 for the preparation of phospho-
nium salts involve reacting alkyl halides with trialkyl/
triaryl phosphines at elevated temperature in aprotic
solvents. Since 2-substituted amino ethyl halides are unsta-
ble, many alternative routes have been used to prepare 2-
(N-disubstituted amino)ethylphosphonium salts. Keough
and Grayson5 first reported the phosphonioethylation
reaction, which involves Michael addition of secondary
amines to vinylphosphonium salts. Subsequently, Schweit-
zer6 and other groups7 have reported displacement of the
phenoxy group of 2-phenoxyethyltriphenylphosphonium
+
-
+
-
P Ph3Br
Z
+
P Ph3Br
ZH
MeO
1
2
3
Scheme 1.
*
Corresponding author. Tel.: +91 80 26611664/26620536; fax: +91 80 26612806.
E-mail address: gcreddy@vmsrf.org (G. C. Reddy).
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.182

G. V. Rao, G. C. Reddy / Tetrahedron Letters 49 (2008) 824–826
825
Table 1
insoluble amines were attempted either in aqueous methanol
or in methanol itself but without success. The work-up pro-
cedure involved evaporation of the solvent and precipita-
tion of the product using acetone or ethyl acetate. The
obtained products were highly pure and could be used in
synthesis without further purification. In contrast, when
phenoxyethyltriphenylphosphonium bromide was used for
the preparation of 3e, we obtained an impure product in less
than 60% yield compared to 97% using compound 1.
When compound 1 was reacted with N-substituted ani-
lines or a-amino acid esters such as proline methyl ester or
sarcosine methyl ester, no product was observed. The
methoxy group could not be displaced with thiols such as
thiophenol or butanethiol. From the above we can con-
clude that weaker nucleophiles such as thiols and second-
ary amines, whose lone pair is in conjugation with
electron withdrawing groups like phenyl and carbonyl,
cannot displace the methoxy group of 1. Hence compound
1 can be used for the preparation of a variety of 2-(N-
disubstituted amino)ethyltriphenylphosphonium bromides
possessing other weaker nucleophiles. Displacement of
the methoxy group with a secondary amine perhaps occurs
via an SN2 type mechanism rather than through a vinylic
intermediate, which is believed to be formed in the case
of phenoxyethyl triphenylphosphonium bromide. The
above hypothesis is supported by the fact that no impuri-
ties or by-products were formed when amino displacement
reactions were carried out under aqueous conditions.
In conclusion, a general and expedient synthesis of
substituted aminoethyltriphenylphosphonium bromides
containing nucleophiles such as hydroxy groups (3d and
3i) from compound 1 has been achieved with high purity
and excellent yields. The ready availability of starting
materials distinguishes this route from other literature
methods. Further, these reactions can be performed under
aqueous conditions and we believe that this protocol will
be useful for synthesising phosphonium salt scaffolds for
preparing a variety of Wittig products.
Synthesis of 2-(N-disubstituted amino)ethyltriphenylphosphonium bro-
mides from compound 1
ZH
Product Solvent
%
Mp
Yielda
Dimethylamine
Diethylamine
3a
3b
Water
Water
95
200–202
(204–205)b
176–178
(180)b
194–195
154–155
188–190
(190)b
185–187
(189–190)b
184–187
(181–185)b
—
94
Diisopropylamine
Diethanolamine
Pyrrolidine
3c
3d
3e
Water
Water
Water
94
88
97
Piperidine
3f
Water
Water
Water
Water
93
95
89
95
Morpholine
3g
3h
3i
N-Methyl
piperazine
N-Hydroxyethyl
piperazine
Proline methyl
ester
Sarcosine methyl
ester
N-Methylaniline
195–198
—
—
—
—
—
Aqueous
methanol
Aqueous
methanol
Aqueous
methanol
Aqueous
methanol
Aqueous
methanol
No
product
No
product
No
product
No
product
No
product
—
—
—
—
—
Diphenylamine
Thiophenol
a
Isolated yields.
Reported mp values.
b
bromide with nucleophiles such as secondary amines to
give the title compounds. The above reagents are highly
reactive, require anhydrous conditions and aprotic solvents
and have no selectivity towards nucleophiles. Moreover,
these reagents are highly unstable and their preparation
involves multi-step sequences and the use of phenol.
The method reported by Adrian and Thomas8 involves
reaction of 2-substituted aminoethanol with triphenylphos-
phine hydrobromide at elevated temperature. Though the
above reaction is fairly simple, preparation of the amino
alcohol and the high temperature conditions are disadvan-
tages and this reaction is not suitable for the preparation
of phosphonium salts containing hydroxy groups. Herein,
we report the first efficient synthesis of 2-(N-disubstituted
amino)ethyltriphenylphosphonium bromide by reaction of
secondary amines with 2-methoxyethyltriphenylphosphoni-
um bromide either in water or in alcohols such as methanol
and isopropanol. Further, compound 1 can be prepared
easily in a single step from commercially available methoxy-
ethanol, which is highly stable and gives pure products in
high yields when reacted with secondary amines.
Acknowledgements
The authors thank Dr. Anil Kush, CEO, VMSRF, for
his encouragement and Mr. Narayana Swamy for technical
assistance.
References and notes
1. (a) Brogden, R. N.; Mctavish, D. Drugs 1991, 41, 927–940; (b)
Findlay, J. W. A.; Coker, G. G.; European Patent 85959, 1983; Chem.
Abstr. 1984, 100, 6345.
2. Mills, J. U.S. Patent 2655509, 1953; Chem. Abstr., 1954, 48, 77749.
3. (a) Benezra, S. A.; Yang, Chen-Hwa Anal. Prof. Drug Subst. 1979, 8,
509–528; (b) Adamson, D. W. U.S. Patent 2,712,020, 1955; Chem.
Abstr., 1955, 49, 4026; (c) Adamson, D. W. U.S. Patent 2,712,023,
1955; Chem. Abstr., 1955 49, 10377; (d) Adamson, D. W. J. Chem.
Soc. 1958, 312; (e) Adamson, D. W. DE 1227464, 1966; Chem. Abstr.,
1967, 66, 37780.
Compound 1 was prepared10,11 in high yield by refluxing
2-methoxyethyl bromide with triphenylphosphine in tolu-
ene. This compound is highly stable even on heating in
water at reflux for several hours. Phosphonium salts 3a–i
were prepared12–20 by reacting 1 with secondary amines in
water at around 60 °C (Table 1). Reactions of 1 with water
4. (a) Rydh, T. O. V.; Uttf, C. B. J. BE 842368, 1976; Chem. Abstr.,
1977, 87, 102173; (b) Backvall, J. E.; Nordberg, R. E.; Nystroem, J.

826
G. V. Rao, G. C. Reddy / Tetrahedron Letters 49 (2008) 824–826
E.; Hoegberg, T.; Ulff, B. J. Org. Chem. 1981, 46, 3479–3483; (c)
1434, 1315, 1110, 1022, 991, 952 cmꢀ1; 1H NMR (CDCl3, 200 MHz) d
2.76 (4H, t, J = 5.8 Hz), 3.06 (2H, m), 3.45 (2H, m), 3.60 (4H, t,
J = 5.8 Hz), 7.65 (15H, m); 13C NMR (CDCl3, 50 MHz) d 20.83,
21.76, 47.85, 56.12, 59.30, 116.99, 118.70, 130.03, 130.28, 133.14,
133.34, 134.69. Anal. Calcd for C24H29BrNPO2: C, 60.76; H, 6.16; N,
2.95. Found: C, 60.71; H, 6.06; N, 3.12.
Hoegberg, T.; Ulff, B.; Renyi, A. L.; Ross, S. B. J. Med. Chem. 1981,
24, 1499–1507; (d) Hoegberg, T.; Ulff, C. B. J. EP 52588, 1982; Chem.
Abstr., 1982, 97, 127511.
5. Keough, P. T.; Grayson, M. J. Org. Chem. 1964, 29, 631–635.
6. Schweitzer, E. E.; Bach, R. D. J. Org. Chem. 1964, 29, 1746–
1751.
7. Copp, F. C. U.S. Patent 3,560,494, 1971; Chem. Abstr., 1971, 75,
49330.
8. Adrian, M.; Thomas, L. Helv. Chim. Acta 1978, 61, 1708–1720.
9. Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863–927.
10. Badische, A.; Soda, F. GB 812522, 1959; Chem. Abstr., 1959, 53,
111616.
16. [2-(N-Pyrrolidino)ethyl]triphenylphosphonium bromide (3e): Com-
pound 1 (450 g, 1.12 mol) was reacted with pyrrolidine (87.0 g,
1.22 mol) in water (200 mL) at 60 °C for 2 h. The water was
evaporated under reduced pressure and the solid obtained was
suspended in acetone (1 L), then cooled to 10 °C and filtered to obtain
the product (480 g, 97%): IR (KBr) mmax 2860, 2842, 1585, 1485, 1434,
1
1110, 995 cmꢀ1; H NMR (D2O, 200 MHz) d 1.67 (4H, s), 2.46 (4H,
11. (2-Methoxyethyl)triphenylphosphonium bromide (1): Compound 1
was obtained by refluxing triphenylphosphine (300 g, 1.14 mol) and
2-methoxyethyl bromide (200 g, 1.43 mol) in toluene (1 L) for 24 h.
The reaction was then cooled to 30 °C and filtered to afford a white
solid (450 g, 98%); mp 210–214 °C (lit.10 mp 216 °C); IR (KBr) mmax
3051, 2958, 2877, 2785, 1585, 1481, 1434, 1411, 1377, 1303, 1288,
s), 2.79 (2H, m), 3.41 (2H, m), 7.68 (15H, m); 13C NMR (CDCl3,
50 MHz) d 22.96, 23.73, 24.75, 48.32, 53.22, 117.60, 119.31, 129.62,
129.87, 133.39, 133.59, 134.25.
17. [2-(N-Piperidino)ethyl]triphenylphosphonium bromide (3f): Com-
pound 1 (5 g, 12.5 mmol), piperidine (1.2 g, 14.1 mmol). Product
(5.3 g, 93% yield): IR (KBr) mmax 3047, 3004, 2858, 2758, 1585, 1477,
1153, 1110, 995 cmꢀ1
;
1H NMR (CDCl3, 200 MHz) d 3.04 (3H, s),
1434, 1380, 1311, 1238, 1157, 1107, 1068, 1029, 991 cmꢀ1 1H NMR
;
3.78 (1H, t, J = 5.6 Hz), 3.90 (1H, t, J = 5.6 Hz), 4.11 (1H, t,
J = 5.6 Hz), 4.16 (1H, t, J = 5.6 Hz), 7.74 (15H, m); 13C NMR
(CDCl3, 50 MHz) d 24.38, 25.43, 58.17, 64.89, 65.03, 117.52, 119.25,
129.54, 129.79, 133.32, 133.52, 134.29.
(CDCl3, 200 MHz) d 1.19 (2H, s), 1.21 (4H, s), 2.27 (4H, s), 2.68 (1H,
t, J = 6.2 Hz), 2.79 (1H, t, J = 6.2 Hz), 3.98 (1H, t, J = 6.2 Hz), 4.04
(1H, t, J = 6.2 Hz), 7.74 (15H, m);13C NMR (CDCl3, 50 MHz) d
21.71, 22.14, 23.16, 24.92, 51.44, 53.87, 117.77, 119.49, 129.56, 129.81,
133,37, 133.57, 134.15.
12. [2-(Dimethylamino)ethyl]triphenylphosphonium bromide (3a): Com-
pound 1 (5 g, 12.5 mmol), 40% solution of dimethylamine (3.0 mL,
26.6 mmol). Product (4.9 g, 95% yield): IR (KBr) mmax 2777, 1581,
1434, 1230, 1157, 1107, 1049, 995 cmꢀ1; 1H NMR (D2O, 200 MHz) d
2.31 (6H, s), 2.77 (2H, m), 3.57 (2H, m), 7.85 (15H, m); 13C NMR
(CDCl3, 200 MHz) d 23.52, 24.54, 45.42, 52.65, 52.73, 118.32, 120.04,
130.49, 130.74, 134.16, 134.36, 135.13.
18. [2-(N-Morpholino)ethyl]triphenylphosphonium bromide (3g): Com-
pound 1 (5 g, 12.5 mmol), morpholine (1.2 g, 13.8 mmol). Product
(5.4 g, 95% yield): IR (KBr) mmax 3502, 3433, 3055, 2859, 2808, 2758,
1585, 1434, 1303, 1272, 1230, 1107, 1064, 1026, 995 cmꢀ1 1H NMR
;
(D2O, 200 MHz) d 2.40 (4H, br s), 2.72 (2H, m), 3.44 (2H, m), 3.89
(4H, m), 7.70 (15H, m); 13C NMR (CDCl3, 50 MHz) d 21.75, 22.77,
45.85, 51.20, 53.06, 65.95, 67.38, 117.59, 119.30, 129.67, 129.92,
133.31, 133.51, 134.32.
13. [2-(Diethylamino)ethyl]triphenylphosphonium bromide (3b): Com-
pound 1 (5 g, 12.5 mmol), diethylamine (2.0 g, 27.3 mmol). Product
(5.2 g, 94% yield): IR (KBr) mmax 3047, 3004, 2858, 2758, 1585, 1477,
19. {2-[N-(N0-Methyl)piperizino]ethyl}triphenylphosphonium bromide (3h):
1434, 1380, 1311, 1238, 1158, 1107, 1068, 1029, 991 cmꢀ1
;
1H NMR
Compound
14.0 mmol). Product (5.2 g, 89% yield): IR (KBr) mmax 3409, 2796,
2680, 1585, 1438, 1404, 1284, 1110, 991 cmꢀ1 1H NMR (CDCl3,
1
(5 g, 12.5 mmol), N-methylpiperazine (1.4 g,
(D2O, 200 MHz) d 0.95 (6H, t, J = 6.8 Hz), 2.60 (4H, m), 2.98 (2H, m),
3.48 (2H, m), 7.32 (15H, m); 13C NMR (CDCl3, 50 MHz) d 10.96, 22.87,
23.86, 45.98, 46.88, 118.25, 119.96, 130.53, 130.78, 134.21, 134.41,
135.24.
;
200 MHz) d 2.15 (3H, s), 2.41 (8H, s), 2.72 (1H, t, J = 6.2 Hz), 2.83
(1H, t, J = 6.2 Hz), 4.09 (1H, t, J = 6.2 Hz), 4.15 (1H, t, J = 6.2 Hz),
7.74 (15H, m); 13C NMR (CDCl3, 50 MHz) d 21.96, 22.98, 45.42,
50.63, 52.41, 54.05, 117.57, 119.29, 129.69, 129.95, 133.35, 133.55,
134.34.
14. [2-(Diisopropylamino)ethyl]triphenylphosphonium bromide (3c): Com-
pound
Product (5.5 g, 94% yield): IR (KBr) mmax 2962, 2858, 1585, 1434,
1330, 1299, 1107, 1087, 991 cmꢀ1 1H NMR (D2O 200 MHz) d 0.93
1 (5 g, 12.5 mmol), diisopropylamine (2.7 g, 26.7 mmol).
;
20. {2-[N-(N0-Hydroxyethyl)piperazino]ethyl}triphenylphosphonium bromide
(3i): Compound 1 (5 g, 12.5 mmol), N-(2-hydroxyethyl)piperazine
(1.8 g, 13.8 mmol). Product (5.9 g, 95% yield): IR (KBr) mmax 3282,
2761, 1434, 1157, 1107, 1033, 995 cmꢀ1; 1H NMR (D2O, 200 MHz) d
2.57 (10H, m), 2.84 (2H, m), 3.60 (2H, m), 3.73 (2H, t, J = 6.0 Hz),
7.83 (15H, m); 13C NMR (CDCl3, 50 MHz) d 22.80, 23.82, 51.59,
52.77, 53.39, 58.21, 59.68, 118.44, 120.15, 130.52, 130.77, 134.19,
134.39, 135.16. Anal. Calcd for C26H32BrN2PO: C, 62.52; H, 6.45; N,
5.61. Found: C, 62.06; H, 6.36; N, 5.64.
(12H, d, J = 6.0 Hz), 3.39 (2H, h, J = 6.0 Hz), 3.59 (1H, t, J = 6.0 Hz),
3.66 (1H, t, J = 6.0 Hz), 3.83 (1H, t, J = 6.0 Hz), 3.93 (1H, t,
J = 6.0 Hz), 7.79 (15H, m); 13C NMR (CDCl3, 50 MHz) d 20.97,
24.84, 25.89, 60.47, 60.62, 71.88, 117.84, 119.57, 129.45, 129.70, 133.48,
133.68, 134.23.
15. [2-(Bishydroxyethyl)aminoethyl]triphenylphosphonium bromide (3d):
Compound 1 (5 g, 12.5 mmol), diethanolamine (1.5 g, 14.2 mmol).
Product (5.3 g, 88% yield): IR (KBr) mmax 3363, 3120, 2862, 1581,