N-Acyl-α-triphenylphosphonio-α-amino acids: Synthesis and decarboxylation toα-(N-Acylamino)alkyltriphenylphosphonium salts

Article abstract of DOI:10.1080/10426500902720204

4-Phosphoranylidene-5(4H)-oxazolones 1 undergo hydrolysis in THF in the presence of HBF4 at room temperature to give N-acyl-α- triphenyphosphonioglycines 3 (R2 = H) in very good yields. 4-Alkyl-4- triphenylphosphonio-5(4H)-oxazolones 2 react with water in CH₂Cl ₂/THF solution without any acidic catalyst at 0-5°C in a few days yielding N-acyl-α-triphenylphosphonio-α-amino acids 3 (R ² = Me) or α-(N-acylamino)alkyltriphenylphosphonium salts 4 (R2 = alkyl, other then Me).-Triphenylphosphonio-α-amino acids 3 upon heating to 105-115°C under reduced pressure (5 mm Hg) or upon treatment with a Hunig base in CH₂Cl₂ at 20°C undergo decarboxylation to give the corresponding α-(N-acylamino)-alkyltriphenylphosphonium salts 4, usually in very good yields.

Full text of DOI:10.1080/10426500902720204

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N-Acyl-α -
triphenylphosphonio-α -
amino Acids: Synthesis and
Decarboxylation to α -(N-
Acylamino)alkyltriphenylphosphoni
Salts
Roman Mazurkiewicz a , Agnieszka Październiok-
Holewa a & Mirosława Grymel a
a Department of Organic Chemistry, Biochemistry
and Biotechnology , Silesian University of
Technology , Gliwice, Poland
Published online: 26 Mar 2009.
To cite this article: Roman Mazurkiewicz , Agnieszka Październiok-Holewa &
Mirosława Grymel (2009) N-Acyl-α -triphenylphosphonio-α -amino Acids: Synthesis
and Decarboxylation to α -(N-Acylamino)alkyltriphenylphosphonium Salts,
Phosphorus, Sulfur, and Silicon and the Related Elements, 184:4, 1017-1027, DOI:
10.1080/10426500902720204
To link to this article: http://dx.doi.org/10.1080/10426500902720204
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Phosphorus, Sulfur, and Silicon, 184:1017–1027, 2009
Copyright © Taylor & Francis Group, LLC
ISSN: 1042-6507 print / 1563-5325 online
DOI: 10.1080/10426500902720204
N-Acyl-α-triphenylphosphonio-α-amino Acids: Synthesis
and Decarboxylation to
α-(N-Acylamino)alkyltriphenylphosphonium Salts
´
Roman Mazurkiewicz, Agnieszka Pazdzierniok-Holewa,
and Miroslꢀawa Grymel
Department of Organic Chemistry, Biochemistry and Biotechnology,
Silesian University of Technology, Gliwice, Poland
4-Phosphoranylidene-5(4H)-oxazolones 1 undergo hydrolysis in THF in the pres-
ence of HBF at room temperature to give N-acyl-α-triphenyphosphonioglycines
4
2
3 (R = H) in very good yields. 4-Alkyl-4-triphenylphosphonio-5(4H)-oxazolones
2 react with water in CH Cl /THF solution without any acidic catalyst at 0–
2
2
2
5◦C in a few days yielding N-acyl-α-triphenylphosphonio-α-amino acids 3 (R
=
2
Me) or α-(N-acylamino)alkyltriphenylphosphonium salts 4 (R = alkyl, other then
Me). α-Triphenylphosphonio-α-amino acids 3 upon heating to 105–115◦C under
reduced pressure (5 mm Hg) or upon treatment with a Hu¨nig base in CH Cl
2
2
at 20◦C undergo decarboxylation to give the corresponding α-(N-acylamino)-
alkyltriphenylphosphonium salts 4, usually in very good yields.
Keywords 4-Alkyl-4-triphenylphosphonio-5(4H)-oxazolone hydrolysis; 4-triphenylpho-
sphoranylidene-5(4H)-oxazolone hydrolysis; α-(N-acylamino)alkyltriphenylphospho-
nium salts; decarboxylation; N-acyl-α-triphenyphosphonio-α-amino acids
INTRODUCTION
A few known types of α-amino acid derivatives with a Cα-P bond have
attracted significant attention of organic chemists due to several impor-
tant applications in organic synthesis.1 A few years ago, we described
a simple synthesis of 4-triphenylphosphoranylidene-5(4H)-oxazolones
(TPO) 1 from N-acylglycines2 and effective methods for their 4-C alky-
lation to 4-alkyl-4-triphenylphosphonio-5(4H)-oxazolones (ATPO) 23
Received 28 December 2007; accepted 7 February 2008.
Dedicated to Professor Marian Mikolꢀajczyk from the CBMiM PAN in Lꢀ o´dz´, Poland,
on the occasion of his 70th birthday.
The financial help of the Ministry of Science and Higher Education of Poland (Grant
No. N N204 238334) is gratefully acknowledged.
Address correspondence to Professor Roman Mazurkiewicz, Department of Organic
Chemistry, Biochemistry and Biotechnology, Silesian University of Technology, Krzy-
woustego 4, PL 44-100 Gliwice, Poland. E-mail: roman.mazurkiewicz@polsl.pl
1017

1018
R. Mazurkiewicz et al.
SCHEME 1
(Scheme 1). Both 4-phosphoranylidene-5(4H)-oxazolones 1 and their
alkylation products 2 are quite stable, crystalline compounds, the elab-
orated procedures being useful for their synthesis even on a kilogram
scale.
In this article, we describe simple and effective methods for the
hydrolysis of 4-phosphoranylidene-5(4H)-oxazolones 1 and 4-alkyl-4-
triphenylphosphonio-5(4H)-oxazolones 2 to hitherto unknown N-acyl-
α-triphenylphosphonio-α-amino acids (PAA) 3, as well as the reaction
of their decarboxylation to α-(N-acylamino)alkyltriphenylphosphonium
salts (APS) 4 (Scheme 1).
α-(N-Acylamino)alkyltriphenylphosphonium salts 4 are valuable di-
functional organic reagents used for syntheses of heterocyclic sys-
tems, including oxazole,4–6 thiazole,5–7 imidazole,7,8 tetrazole,9,10
and quinazoline derivatives.10 They have also been applied as
α-amidoalkylating agents.11,12 The most frequently used method
for the synthesis of α-(N-acylamino)alkyltriphenylphosphonium
salts consists of the alkylation of triphenylphosphine with N-
(α-chloroalkyl)amides,4,9–11,13,14N-(α-hydroxyalkyl)amides,7,14,15 or N-
(α-alkoxyalkyl)amides.15 Synthetic equivalents of N-(α-haloalkyl)
amides, such as trimethylsilylmethyl isocyanide,16 chloromethy-
lisocyanate,12 and bromomethylisocyanate17 were also used for the
alkylation of triphenylphosphine; the isocyanide or isocyanate groups
in the alkylation products were hydrolyzed or alcoholized to formy-
lamino or alkoxycarbonylamino groups, respectively. Unfortunately,
these methods are applicable mainly for the synthesis of N-
acylaminomethyltriphenylphosphonium salts (4, R2 = H).

N-Acyl-α-triphenylphosphonio-α-amino Acids
1019
RESULTS AND DISCUSSION
Phosphoranylidene-5(4H)-oxazolones 1, dissolved in CH2Cl2, react
smoothly with an equimolar amount of water in the presence
of tetrafluoroboric acid at room temperature to give N-acyl-α-tripheny-
lphosphonioglycine tetrafluoroborates 3 in excellent yields within 10
min (Table I, Procedure A). The obtained α-triphenylphosphonioglycine
derivatives 3a–c are stable, crystalline compounds; they can be stored
at 0◦C for a few months without decomposition.
Phosphonium salts 2 undergo hydrolysis in CH2Cl2/THF solu-
tion without any acidic catalyst at 0–5◦C in a few days; however,
only in the case of phosphonium salts 2a and 2b we were able
to isolate relatively stable α-triphenylphosphonio-α-amino acids
3d and 3e (Table I, Procedure B). When stored at 0◦C, they
undergo a very slow decarboxylation to the corresponding α-(N-
acylamino)alkyltriphenylphosphonium salts. In the case of other
phosphonium salts (2c–d), we obtained directly the corresponding α-(N-
acylamino)alkyltriphenylphosphonium salts 4f–g as the main reaction
products (Table II, Procedure E). It seems that, in this case, the primar-
ily formed α-triphenylphosphonio-α-amino acids undergo consecutive
decarboxylation to α-(N-acylamino)alkyltriphenylphosphonium salts
4f–g, the decarboxylation being probably faster than hydrolysis
(Table II). In the case of phosphonium salt 2c, we have also obtained
α-(N-pivaloylamino)vinyltriphenylphosphonium iodide 5 in a yield of
18%, apart from the expected hydrolysis product 4f (Scheme 2). The
phosphonium salt 5 is evidently formed as a result of the elimination of
methanol from the starting phosphonium salt 2c, or the corresponding
α-triphenylphosphonio-α-amino acid 3 or the primary decarboxylation
product 4f.
SCHEME 2
The α-triphenylphosphonio-α-amino acids 3a–d, when heated to
105–115◦C under reduced pressure (5 mm Hg) underwent decarboxyla-
tion to the corresponding α-(N-acylamino)alkyltriphenylphosphonium
salts 4a–d, usually in very good yields; only in the case of compound 4d
was the yield of decarboxylation poor (Table II, Procedure C). In the lat-
ter case, we also identified N-pivaloyl-β-triphenylphosphonioalanine io-
dide 6 in the reaction mixture (yield 59 % by 1H NMR). The formation of
this compound can be explained as a result of the thermal elimination of

1020

1021

1022
R. Mazurkiewicz et al.
SCHEME 3
triphenylphosphine and hydrogen iodide from the starting N-pivaloyl-
α-triphenylphosphonioalanine iodide 3d followed by an imine–enamine
type tautomerization of the elimination product, the nucleophilic at-
tack of triphenylphosphine at the β-position of the α-aminoacrylic acid
derivative, and the consecutive addition of hydrogen iodide (Scheme 3).
A similar synthesis of β-triphenylphosphoniocarboxylic acids by the ad-
dition of triphenylphosphine and hydrogen bromide or hydrogen iodide
to α,β-usaturated carboxylic acids was described by Hoffmann.18
Another elaborated, milder, and, in some cases, more efficient pro-
cedure for decarboxylation of α-triphenylphosphonio-α-amino acids 3
involves their decarboxylation in CH2Cl2 at 20◦C, in the presence of
¨
a catalytic amount of diisopropylethylamine (Hunig base) (Table II,
Procedure D).
The structures of N-acyl-α-triphenylphosphonio-α-amino acids 3a–e
and α-(N-acylaminomethyl)triphenylphosphonium salts 4a–g were
confirmed by their spectroscopic properties (IR, 1H, and 13C NMR);
in the case of all new compounds satisfactory elemental analyses were
obtained (Tables I–IV).
CONCLUSION
The hydrolysis of 4-triphenylphosphoranylidene-5(4H)-oxazolones 1
and 4-alkyl-4-triphenylphosphonio-5(4H)-oxazolones 2 provides the
hitherto unknown N-acyl-α-triphenylphosphonio-α-amino acids 3.
Their decarboxylation offers an effective and convenient way for the
synthesis of α-(N-acylamino)alkyltriphenylphosphonium salts 4, in-
cluding α-substituted derivatives (R2 = H), which are difficult to obtain
by other synthetic methods.
EXPERIMENTAL
Melting points were determined in capillary tubes in a Stuart
Scientific SMP3 melting point apparatus and are uncorrected. IR
spectra were recorded on a Zeiss Specord M 80 spectrophotometer.

1023

1024

N-Acyl-α-triphenylphosphonio-α-amino Acids
1025
1H and 13C NMR spectra were recorded in CDCl3 or CD3CN with
a Varian UNITY INOVA-300 spectrometer operating at 300 and
75.5 MHz, respectively, in the FT mode using TMS as an internal
standard. Kieselgel 60 (Merck, 0.063–0.200 mm) was used for column
chromatography.
Starting Materials
Commercial grade acetonitrile, acetone, ethyl acetate, chloroform,
CH2Cl2, and THF were distilled and dried over molecular sieves
˚
(4 A). The following reagents were of commercial quality (Aldrich
or Across): HBF4 (ethereal solution, 54%), iodomethane, iodoacetoni-
trile, iodomethyl methyl ether. 4-Triphenylphosphoranylidene-5(4H)-
oxazolones 1a–c and 4-alkyl-4-triphenyl-phosphonio-5(4H)-oxazolones
2a–d were synthesized as described in the literature.2,3
Synthesis of N-Acyl-α-triphenylphosphonio-α-amino Acids
3a–c from 4-Triphenylphosphoranylidene-5(4H)-oxazolones 1
(Procedure A)
To a stirred solution of 4-triphenylphosphoranylidene-5(4H)-oxazolone
1 (5 mmol) in CH2Cl2 (7.5 mL), water (0.09 mL, 5 mmol) and an
ethereal solution of tetrafluoroboric acid (54%, 0.70 mL, 5.1 mmol)
were added. After 10 min, the solvent was evaporated under reduced
pressure, and the residue was crystallized from THF (3a and 3c) or
chloroform (3b).
Synthesis of N-Acyl-α-triphenylphosphonio-α-amino Acids
3d–e from 4-Methyl-4-triphenylphosphonio-5(4H)-oxazolones
2a–b (Procedure B)
To a suspension of 4-alkyl-4triphenylphosphonio-5(4H)-oxazolone 2
(5 mmol) in CH2Cl2 (6.75 mL for 2a or 13.5 mL for 2b), a solution
of water (0.22 mL, 12.5 mmol) in THF (6.75 mL) was added, and the
mixture was stirred at 0–5◦C for the time given in Table I. The reaction
mixture was diluted with CH2Cl2 (25 mL) dried over MgSO4, and the
solvent was evaporated under reduced pressure. Crude acids 3d–e were
purified by dissolving in CH2Cl2 and precipitating by addition of diethyl
ether.

1026
R. Mazurkiewicz et al.
Synthesis of α-(N-Acylamino)alkyltriphenylphosphonium
Salts 4a–e from N-Acyl-α-triphenylphosphonio-α-amino Acids
3a–e
Procedure C
N-Acyl-α-triphenylphosphonio-α-amino acid 3 was heated at 105–
115◦C under reduced pressure (5 mm Hg) for the time given in Table II.
The residue was purified by dissolving in CH2Cl2 and precipitating by
addition of diethyl ether (4a,b) or by crystallization from ethyl acetate
(4c).
Procedure D
To a stirred suspension of N-acyl-α-triphenylphosphonio-α-amino
acid 3 (4 mmol) in CH2Cl2 (32 mL), diisopropylethylamine (0.14 mL,
0.8 mmol) was added. The reaction mixture was left for the time given
in Table II at room temperature, and then the solvent was evaporated
under reduced pressure. The residue was purified by crystallization
from a mixture of toluene and methanol (6:1, v/v; 4a–c) or ethyl acetate
(4d) or by dissolving in CH2Cl2 and precipitating by addition of diethyl
ether (4e).
Synthesis of α-(N-Acylamino)alkyltriphenylphosphonium
Salts 4f–g from 4-Alkyl-4-triphenylphosphonio-5(4H)-
oxazolones 2c–d (Procedure E)
To
a stirred suspension of 4-alkyl-4-triphenylphosphonio-5(4H)-
oxazolone 2 (5 mmol) in CH2Cl2 (6.75 mL), a solution of water
(0.22 mL, 12.5 mmol for 2c or 0.13 mL, 7.5 mmol for 2d) in THF
(6.75 mL) was added, and the mixture was stirred at 0–5◦C for the
time given in Table II. The reaction mixture was diluted with CH2Cl2
(30 mL), dried over MgSO4, and the solvent was evaporated under
reduced pressure. The crude phosphonium salt 4f was dissolved in
CH2Cl2, and the pure product was precipitated by addition of di-
ethyl ether. In the case of compound 4g, the crude product was iso-
lated by column chromatography, eluted with a mixture of acetone and
CH2Cl2 (1:3, v/v), and finally purified by crystallization as described
above.
Isolation of α-(N-Pivaloylamino)vinyltriphenylphosphonium
Iodide 5
Phosphonium salt 5 was isolated from the residue after crystalliza-
tion of compound 4f (see Procedure E) by column chromatography, and

N-Acyl-α-triphenylphosphonio-α-amino Acids
1027
eluting with a mixture of ethyl acetate and CH2Cl2 (1:1, v/v). The crys-
tallization of the crude chromatography product from ethyl acetate gave
the pure phosphonium salt 5 in a yield of 18%, mp 168.0–169.0◦C.
Spectral and analytical data for compound 5: IR (CH2Cl2, cm−1):
3144br, 1660vs, 1512s. 1H NMR (CDCl3): δ = 10.17 (d, br, J =
12.0 Hz, 1H, NH), 7.84–7.61 (m, 15H, Ph), 7.21 (dd, JPH = 41.7 Hz,
JHH = 2.4 Hz, 1H, C=CH2), 5.64 (dd, JPH = 15.6 Hz, JHH = 1.8 Hz, 1H,
C=CH2), 1.01 (s, 9H, t-Bu). 13C NMR (CDCl3, δ / JPC (Hz)): 179.0 (C=O),
134.2/3.0 (Ph3P+, C4), 134.1/10.0 (Ph3P+, C2), 133.8/17.1 (C=CH2),
129.6/13.1 (Ph3P+, C3), 126.7/100.6 (Ph3P+C), 120.4/92.4 (Ph3P+, C1),
38.5 (CMe3), 27.2 (CMe3). Elemental analysis: Calcd. for C25H27INOP:
C, 58.26; H, 5.28; N, 2.72; P, 6.01; Found: C, 58.21; H, 5.19; N, 2.68; P,
6.04%.
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