1-Imidoalkylphosphonium salts with modulated Cα–P+ bond strength: synthesis and application as new active α-imidoalkylating agents

Article abstract of DOI:10.3762/bjoc.13.142

An effective synthesis of the hitherto unknown 1-imidoalkylphosphonium salts has been developed in the reported study. The crucial step in the method included the decarboxylative α-methoxylation of N-phthaloyl- or N-succinylamino acids to the corresponding N-(1-methoxyalkyl)imides, followed by the displacement of the methoxy group by the triarylphosphonium group through melting of the imide derivative with triarylphosphonium tetrafluoroborate. The imidoalkylating properties of the obtained 1-imidoalkylphosphonium salts were tested using the Tscherniac–Einhorn-type reaction with aromatic hydrocarbons as a model reaction. It was found that the C_α–P⁺ bond strength can be considerably reduced and the imidoalkylation of arenes can be markedly facilitated using 1-imidoalkylphosphonium salts derived from triarylphosphines with electron-withdrawing substituents such as tris(m-chorophenyl)phosphine, tris(p-chlorophenyl)phosphine and tris[p-(trifluoromethyl)phenyl]phosphine. Microwave irradiation also considerably facilitates the cleavage of the highly polar C_α–P⁺ bond.

Full text of DOI:10.3762/bjoc.13.142

1-Imidoalkylphosphonium salts with modulated Cα–P+ bond
strength: synthesis and application as new active
α-imidoalkylating agents
Jakub Adamek*1,2,§, Roman Mazurkiewicz1,2, Anna Węgrzyk1,2 and Karol Erfurt3
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2017, 13, 1446–1455.
1Department of Organic Chemistry, Bioorganic Chemistry and
Biotechnology, Silesian University of Technology, B. Krzywoustego 4,
44-100 Gliwice, Poland, 2Biotechnology Centre of Silesian University
of Technology, B. Krzywoustego 8, 44-100 Gliwice, Poland and
3Department of Chemical Organic Technology and Petrochemistry,
Silesian University of Technology, B. Krzywoustego 4, 44-100
Gliwice, Poland
doi:10.3762/bjoc.13.142
Received: 04 May 2017
Accepted: 05 July 2017
Published: 24 July 2017
Associate Editor: J. A. Murphy
Email:
© 2017 Adamek et al.; licensee Beilstein-Institut.
License and terms: see end of document.
Jakub Adamek* - jakub.adamek@polsl.pl
* Corresponding author
§ Tel: +48 32 237 10 81; Fax: +48 32 237 20 94
Keywords:
N-(1-arylalkyl)imides; α-imidoalkylating agents; imidoalkylation
reactions; 1-imidoalkylphosphonium salts; Tscherniac–Einhorn-type
reaction
Abstract
An effective synthesis of the hitherto unknown 1-imidoalkylphosphonium salts has been developed in the reported study. The
crucial step in the method included the decarboxylative α-methoxylation of N-phthaloyl- or N-succinylamino acids to the corre-
sponding N-(1-methoxyalkyl)imides, followed by the displacement of the methoxy group by the triarylphosphonium group through
melting of the imide derivative with triarylphosphonium tetrafluoroborate. The imidoalkylating properties of the obtained
1-imidoalkylphosphonium salts were tested using the Tscherniac–Einhorn-type reaction with aromatic hydrocarbons as a model
reaction. It was found that the Cα–P+ bond strength can be considerably reduced and the imidoalkylation of arenes can be markedly
facilitated using 1-imidoalkylphosphonium salts derived from triarylphosphines with electron-withdrawing substituents such as
tris(m-chorophenyl)phosphine, tris(p-chlorophenyl)phosphine and tris[p-(trifluoromethyl)phenyl]phosphine. Microwave irradiation
also considerably facilitates the cleavage of the highly polar Cα–P+ bond.
Introduction
The aminomethylation of C–H acidic compounds by the con- bonyl compounds, known as the Mannich reaction, plays an im-
densation of non-enolizable aldehydes or ketones (mainly form- portant role in organic synthesis, despite some limitations of
aldehyde) with ammonia or aliphatic amines and CH-acidic car- this reaction. α-Amidoalkylation reactions are considered an im-
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portant extension of the Mannich reaction [1-3]. They are Recently, we have described a simple and efficient two-step
crucial methods for the formation of >NC–C and >NC–Het transformation of N-acylated α-amino acids to 1-(N-
bonds used, inter alia, for the generation of the β-aminocar- acylamino)alkyltriphenylphosphonium salts 1 (Z = PPh3+ A−)
bonyl substructure and for the construction of new carbo- or [18]. We have also demonstrated that the obtained stable, crys-
heterocyclic systems, especially in pharmaceutical chemistry talline phosphonium salts are new, powerful, and easy to use
and in the synthesis of natural products [3-12]. Most of the α-amidoalkylating agents, which are active either without the
α-amidoalkylating reagents possess the structure of α-functio- need for a catalyst or in the presence of organic bases (e.g.,
nalized N-alkylamides 1, where Z = OH, OR, OCOR, Cl, Br, I, Hünig’s base) [20-23].
NHCOR, SO2Ar, 1-benzotriazolyl or PPh3+ X− and acts as a
nucleofugal leaving group (Scheme 1) [3,8-10,13-18]. It is a well-known problem, that the reactivity of α-amidoalky-
N-Acylimine 2 or the much more reactive N-acyliminium cation lating agents toward nucleophiles of low reactivity (e.g., aro-
3 are active reagents in α-amidoalkylation reactions, usually matic systems without strong electron-donating substituents) is
generated in situ from a precursor of structure 1 under basic or insufficient. This limits the scope of α-amidoalkylation reac-
acidic conditions, respectively (Scheme 1) [3].
tions of aromatic systems (including important intramolecular
α-amidoalkylations with the formation of new carbo- or hetero-
The limitations and disadvantages of the most commonly used cyclic products) to aromatic systems with strong electron-donat-
amidoalkylating agents have been comprehensively discussed in ing substituents (e.g., alkoxy-, polyalkoxy- and aminoarenes),
the literature [3,8]. Many of these (Z = OR, OCOR, Cl, Br, I) or some activated heterocyclic systems such as indole
are quite unstable compounds that cannot be stored for a [3,8,10,24,25]. The α-imidoalkylation reaction using N-(1-
prolonged time and thus have to be prepared in situ. Further, the hydroxyalkyl)imides (almost entirely N-hydroxymethylphthal-
preparation of some of these reagents (Z = Cl, Br, I) is often imide) in sulfuric acid, oleum or other strong acids is consid-
difficult and elaborate. Most of these, including the most ered an alternative to α-amidoalkylation (Scheme 2) [3-6,24].
frequently used α-alkoxy derivatives (Z = OR), N-[1-(benzotri- Olah et al. successfully applied N-hydroxymethylphthalimide
azol-1-yl)alkyl]amides (Z = 1-benzotriazolyl) and 1-(N-acyl- (4) in the imidomethylation of benzene, halo-, polyhalo- and
amino)alkyl sulfones (Z = SO2Ar) require activation with Lewis halonitrobenzenes using superacidic trifluoromethanesulfonic
acids, which are expensive (e.g., ZrCl4, VCl3, CeCl3, Bi(OTf)3 acid as the solvent [24]. According to the authors, the enhanced
or InCl3) [11,17,19]. Moreover, the application of Lewis acids reactivity of N-hydroxymethylphthalimide (4) under these
can diminish the activity of a reacting nucleophile, and usually conditions is probably caused by the protonation of the interme-
requires a labor-intensive aqueous work-up procedure of the diate imidomethylcarbenium ion on the nitrogen or carbonyl
reaction mixture. The inevitable equilibrium between the oxygen (protosolvation) to the corresponding superelectrophilic
N-acyliminium cation 3 and the less reactive uncharged dication [24]. To the best of our knowledge, Olah’s imido-
N-acylimine 2 also reduces the general reactivity of this reac- methylation in the presence of trifluoromethanesulfonic acid
tion system.
has not been extended to other N-(1-hydroxyalkyl)imides.
Scheme 1: α-Amidoalkylation reactions under basic or acidic conditions.
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Beilstein J. Org. Chem. 2017, 13, 1446–1455.
Scheme 2: Synthetic routes of α-amido- and α-imidoalkylation of aromatic and heteroaromatic compounds.
Moreover, the employment of a large amount of superacidic tri- cant attention from chemists and biochemists due to their bioac-
fluoromethanesulfonic acid as a solvent is expensive and tivity as herbicides, and anticancer, anti-inflammatory, anal-
complicates the work-up procedure. Obviously, Olah’s gesic or anticonvulsant agents [26-31]. Especially interesting is
imidoalkylating procedure and other similar imidoalkylating apremilast (brand name Otezla), a tumor necrosis factor-α
systems using strong acids as catalysts and solvents cannot be (TNF-α) inhibitor used for the treatment of psoriasis, psoriatic
applied to aromatics or heteroaromatics of basic character, such dermatitis and other inflammatory diseases related to the
as tertiary aromatic amines or azines.
immune system [31].
In the present paper we report the synthesis and properties of Results and Discussion
hitherto unknown 1-imidoalkylphosphonium salts 5 1-Imidoalkylphosphonium salts 5 were synthesized in a three-
(Scheme 2). We expected that the 1-imidoalkylcarbenium step procedure starting from α-amino acids and cyclic dicar-
cation generated from these salts (see Scheme 2) would display boxylic acid anhydrides. 2-(N-Imido)alkanecarboxylic acids 6
greater electrophilic reactivity in comparison with N-acyl- were obtained in good to very good yields by melting phthalic
iminium cation 3, due to the strong electron-withdrawing effect or succinic acid anhydride with the corresponding amino acid at
of the two carbonyl groups attached to the nitrogen atom. 140–170 °C, according to the McKenzie and Walker’s proce-
Furthermore, the tertiary nitrogen atom of the 1-imidocarbe- dure (Table 1) [32]. To the best of our knowledge, attempts at
nium cation cannot be deprotonated to the less reactive an electrochemical decarboxylative α-methoxylation of
uncharged form.
2-imidoalkanecarboxylic acids have been reported only twice in
the literature [33,34]. The reactions were carried out in MeOH
Subsequently we demonstrate the strong imidoalkylating prop- in the presence of sodium methoxide. Unfortunately, because of
erties of the obtained 1-imidoalkylphosphonium salts 5 applied the low reaction selectivity related to side reactions (for exam-
in the Tscherniac–Einhorn-type reaction with aromatic ple Kolbe-dimerization), the yields were only poor (10–35%)
hydrocarbons as a model reaction. The obtained N-(1- [33,34]. According to our previously reported procedure for the
arylalkyl)imides can easily be transformed to the corresponding electrochemical decarboxylative α-methoxylation of N-acyl-α-
primary 1-arylalkylamines, following the well-known proce- amino acids [18], amino acid derivatives 6 were converted to
dures developed for the Gabriel synthesis of primary amines. N-(1-methoxyalkyl)imides 7. The reaction was performed in an
Moreover, this class of compounds is itself attracting signifi- undivided cylindrical glass electrolyzer in MeOH at 0 °C in the
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Beilstein J. Org. Chem. 2017, 13, 1446–1455.
Table 1: Synthesis of 2-(N-imido)alkanecarboxylic acids 6 and N-(1-methoxy)alkylimides 7.
A
R1
2-(N-imido)alkanecarboxylic acids 6
N-(1-methoxyalkyl)imides 7
time, h
T, °C
6
yield, %
charge, F/mol
7
yield, %
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
(CH2)2
H
1.0
2.5
2.5
2.5
2.5
6.5
6.5
5.0
170
170
170
170
170
140
140
120
6a
6b
6c
6d
6e
6f
50
94
93
75
90
46
67
84a
2.7
3.0
2.9
2.9
2.9
2.7
3.5
3.75
7a
7b
7c
7d
7e
7f
28
65
42
60
46
33
85
52
Me
Bn
Ph
iBu
H
(CH2)2
Me
Me
6g
6h
7g
7h
1,8-C10H6
a2-(1,8-Naphthalimido)propionic acid (6h) was obtained according to Reger’s procedure [35].
presence of 3-(1-piperidino)propyl-functionalized silica gel cases preliminary purification by column chromatography
(SiO2-Pip) as the base, at a constant current density, and at the proved to be necessary. Their structures were confirmed by 1H,
charge consumption of 2.70–3.75 F/mol. Under these condi- 13C, 31P and 19F NMR spectroscopy, as well as IR spectrosco-
tions the expected N-(1-methoxyalkyl)imides 7 were obtained py and HRMS spectrometry.
in most cases in moderate to good yields (Table 1).
Next the phosphonium salts were used in the Tscherniac–Ein-
The synthesis of 1-imidoalkyltriarylphosphonium tetrafluoro- horn–type imidoalkylation of aromatic hydrocarbons of diverse
borates 5 represents a substitution of the methoxy group of reactivity. The reaction was carried out without a catalyst, using
N-(1-methoxyalkyl)imides 7 by the triarylphosphonium group. a considerable excess of the reacting hydrocarbon as a solvent
For this, a mixture of N-(1-methoxyalkyl)imide 7 with (the molar ratio of reactants was about 1:75 to 1:90 and
triarylphosphonium tetrafluoroborate was melted at 85–140 °C depended on the molecular mass of hydrocarbon). In some
in the presence of NaBr as a catalyst under reduced pressure cases, the additional application of unreactive nitrobenzene or
(0.1–0.2 mmHg) for 0.5–10 h (Table 2).
chlorobenzene as cosolvents was found to be necessary to
improve the solubility of the phosphonium salts (Table 3).
Phthalimide-derived phosphonium salts 5 (A = o-C6H4) were
usually obtained in good to excellent yields, whereas the yields The reaction of 1-phthalimidoethyltriphenylphosphonium tetra-
of succinimide-derived products 5 (A = (CH2)2) were generally fluoroborate (5b) with anisole required a relatively high temper-
lower. In the case of N-(1-methoxyethyl)-1,8-naphthalimide the ature (180 °C; Table 3, entry 1). The reaction temperature could
triphenylphosphine attack on the α-carbon resulted in the split- be reduced considerably to 150 °C together with a reduced reac-
ting of the Cα–N bond instead of the Cα–OMe bond and the cor- tion time using microwave irradiation in a sealed glass vial
responding 1-methoxyethyltriphenylphosphonium tetrafluoro- (Table 3, entry 2). The reaction with the much more reactive
borate was isolated in 73% yield accompanied by only trace 1,3-dimethoxybenzene required only a slightly lower tempera-
amounts of the expected phosphonium salt 5o (Table 2, last ture (170 °C; Table 3, entry 16). The reactivity of 1-phthal-
entry). It is assumed that both the extraordinary effective reso- imido-3-methylbutyltriphenylphosphonium salt 5i was similar
nance stabilization of the imide anion and the excessive steric to that displayed by 1-phthalimidoethyltriphenylphosphonium
congestion in the transition state make the splitting of the Cα–N salt 5b (cf Table 3, entries 1 against 12 and 16 against 21). As
bond instead of the Cα–OMe bond more favorable in this case.
expected, the reaction of anisole with 1-phthalimido-1-phenyl-
methyltriphenylphosphonium salt 5f, which generates a more
The phosphonium salts 5 were purified by crystallization, stable benzyl-type carbenium cation, started at a lower tempera-
usually from a mixture of CH2Cl2/Et2O. However, in a few ture (150 °C; Table 3, entry 8). Under microwave conditions,
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Beilstein J. Org. Chem. 2017, 13, 1446–1455.
Table 2: Synthesis of 1-imidoalkyltriarylphosphonium tetrafluoroborates 5.
A
R1
R
1-imidoalkyltriarylphosphonium salts 5
time, h
T, °C
5
yield, %
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
o-C6H4
(CH2)2
(CH2)2
(CH2)2
(CH2)2
1,8-C10H6
H
Ph
Ph
6
7
140
90
5a
5b
5c
5d
5e
5f
49
92
83
89
95
94
88
80
79
75
65
58
28
51
<10a
Me
Me
Me
Me
Ph
Ph
Ph
iBu
iBu
H
m-C6H4Cl
p-C6H4Cl
p-C6H4CF3
Ph
8
95
6
95
7
95
4
90
m-C6H4Cl
p-C6H4CF3
Ph
8
95
5g
5h
5i
7
95
5.5
7
95
m-C6H4Cl
Ph
95
5j
7
140
85
5k
5l
Me
Me
Me
Me
Ph
10
7
m-C6H4Cl
p-C6H4CF3
Ph
95
5m
5n
5o
0.5
2
120
120
aYield estimated by 1H NMR. 1-Methoxyethyltriphenylphosphonium tetrafluoroborate (8) was isolated from the reaction mixture as the main product in
73% yield.
the reaction had already started at about 130 °C (Table 3, entry dimethoxybenzene at much lower temperatures (Table 3, entries
9). Again, the reaction of the same phosphonium salt with the 3–7, 10, 11, 13, 17–19, 22 and 23). The most clear-cut results
much more reactive 1,3-dimethoxybenzene started at the same were obtained for tris[p-(trifluoromethyl)phenyl]phosphine
temperature (150 °C; Table 3, entry 20). This observation sug- derivatives. 1-Phthalimidoethyltris[p-(trifluoromethyl)phenyl]-
gests that the generation of a 1-imidocarbenium cation via the phosphonium tetrafluoroborate (5e) and 1-phthalimido-1-
thermal splitting of the Cα–P+ bond (Scheme 2) is the rate-de- phenylmethyltris[p-(trifluoromethyl)phenyl]phosphonium
termining step in the Tscherniac–Einhorn–type imidoalkylation tetrafluoroborate (5h) already react with anisole at 90 °C
of the relatively reactive hydrogen carbons such as anisole or (Table 3, entries 5 and 10) and even at 60 °C when using
1,3-dimethoxybenzene. Consequently, the higher reactivity of microwave irradiation (Table 3, entry 7); the reaction
1,3-dimethoxybenzene in relation to anisole does not exert an of 5e with 1,3-dimethoxybenzene started at 80 °C (Table 3,
impact on the reaction rate. As expected, microwave irradiation entry 18).
effectively facilitates the splitting of the highly polar Cα–P+
bond.
All attempts to carry out the imidoalkylation of 1,3,5-
trimethoxybenzene with phosphonium salt 5e failed. In this case
In order to reduce the Cα–P+ bond strength, and to facilitate the 1-(2,4,6-trimethoxyphenyl)ethyltris(4-trifluoromethyl-
generation of the corresponding 1-imidocarbenium cation, phenyl)phosphonium tetrafluoroborate (10) was isolated from
1-imidoalkylphosphonium salts derived from triarylphosphines the reaction mixture in 73% yield as the only reaction product.
with electron-withdrawing substituents such as tris(m- It seems that the steric congestion caused by two methoxy
chorophenyl)phosphine, tris(p-chlorophenyl)phosphine and groups in ortho positions to the attacking carbon caused the dis-
tris[p-(trifluoromethyl)phenyl]phosphine were synthesized and placement of a phthalimide anion by triarylphosphine in the pri-
tested in the reaction. As expected, the phosphonium salts with mary reaction product and thus leading to the phosphonium salt
a reduced Cα–P+ bond strength reacted with anisole and 1,3- 10 as an unexpected side product (Scheme 3).
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Table 3: Synthesis of N-(1-arylalkyl)imides 9.
1-imidoalkyltriaryl-
entry
ArH
solvent T, °C time, h
MW
USa
9
yield, %
o:pb
phosphonium salts
5
A
R1
R
1
2
3
4
5
6
7
5b o-C6H4 Me
5b o-C6H4 Me
Ph
Ph
anisole
–
–
–
–
–
–
–
180
150
100
75
2
1
–
70 Wc
–
–
–
–
–
–
+
–
72
66
77
78
91
78
82
1.0:1.2
1.0:1.1
1.0:1.2
1.0:1.1
1.0:1.1
1.0:1.1
1.0:1.0
5c o-C6H4 Me m-ClC6H4
5c o-C6H4 Me m-ClC6H4
5e o-C6H4 Me p-CF3C6H4
5e o-C6H4 Me p-CF3C6H4
5e o-C6H4 Me p-CF3C6H4
3.5
1
10 Wc
–
9aa+9ab
9ba+9bb
90
2
–
90
1
60
4
6 Wc
–
–
–
–
–
–
–
+
8
9
5f o-C6H4 Ph
5f o-C6H4 Ph
Ph
Ph
150
130
90
2.5
1
–
58
60
81
83
1.0:1.6
1.0:2.8
1.0:2.3
1.0:1.9
25 Wc
–
–
10 5h o-C6H4 Ph p-CF3C6H4
11 5h o-C6H4 Ph p-CF3C6H4
2
90
1
–
–
–
–
–
–
12
13
5i o-C6H4 iBu
Ph
170
100
2
2
58
88
1.0:3.0
1.0:2.1
9ca+9cb
9da+9db
5j o-C6H4 iBu m-ClC6H4
–
–
–
–
–
–
14
5l (CH2)2 Me
Ph
195
140
2
2
41
56
1.4:1.0
1.3:1.0
15 5n (CH2)2 Me p-CF3C6H4
1,3-dimethoxy-
benzene
–
–
–
–
16 5b o-C6H4 Me
Ph
170
2.5
71
–
–
–
–
–
+
–
–
–
17
18
19
5c o-C6H4 Me m-ClC6H4
5e o-C6H4 Me p-CF3C6H4
5e o-C6H4 Me p-CF3C6H4
C6H5NO2 100
4
4
3
73
76
82
9e
C6H5Cl
C6H5Cl
80
80
–
–
–
20
5f o-C6H4 Ph
5i o-C6H4 iBu
Ph
Ph
C6H5NO2 150
0.5
9f
9g
–
60
–
–
–
–
–
–
–
–
–
21
22
23
–
170
100
100
2
2
2
76
56
63
5j o-C6H4 iBu m-ClC6H4
5j o-C6H4 iBu m-ClC6H4
C6H5Cl
1,3,5-trimethoxy-
benzene
–
–
–
–
24
5e o-C6H4 Me p-CF3C6H4
110
2
–d
25
26
27
5e o-C6H4 Me p-CF3C6H4
5e o-C6H4 Me p-CF3C6H4
5e o-C6H4 Me p-CF3C6H4
toluene
–
–
–
130
120
100
2
–
–
–
–
–
23e
50f
46f
1.0:2.6
1.0:3.4
1.0:4.0
0.25
9ha+9hb
9ia+9ib
0.25 100 Wc
–
–
–
28 5h o-C6H4 Ph p-CF3C6H4
29 5h o-C6H4 Ph p-CF3C6H4
C6H5NO2 130
C6H5NO2 120
2
2
51
60
1.0:2.3
1.0:3.8
140 Wc
aThe exposition to ultrasound irradiation. bMolar ratio of ortho to para isomer. cThe average microwave power that provides the desired reaction tem-
perature. d1-(2,4,6-trimethoxyphenyl)ethyltris(4-trifluoromethyl-phenyl)phosphonium tetrafluoroborate (10) was isolated from the reaction mixture in
73% yield as the main product. eN-Vinylphthalimide was also obtained as side product in 54% yield. fThe reaction was carried out in the presence of
an equimolar amount of tetrafluoroboric acid.
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Scheme 3: Reaction of imidophosphonium salt 5e with 1,3,5-trimethoxybenzene.
The imidoalkylation of anisole and toluene gave the expected equimolar amount of tetrafluoroboric acid to the reaction mix-
products as mixtures of ortho and para isomers in molar ratios ture effectively suppressed this side reaction.
ranging from 1.4:1.0 to 1.0:4.0 (Table 3). It seems that the steric
The solubility of phosphonium salts in some aromatic hydro-
carbons is limited. In such cases, to ensure an effective mass
transfer of reactants, sonification of the reaction mixture was
examined. The use of ultrasound reduced the reaction time and
afforded slightly higher yields in two out of the three investigat-
ed reactions (Table 3, entries 6, 11 and 19).
congestion is the main factor governing the molar ratio of the
regioisomers. Thus an excess of ortho isomers was obtained
only in the case of 1-imidoalkylphosphonium salts derived from
succinimide, with a relatively small imide ring (Table 3, entries
14 and 15). On the other hand, phosphonium salts derived from
phthalimide gave in all cases some excess of the para isomers.
Bulky phenyl or isobutyl substituents at the α-position favored
the formation of para isomers (cf. Table 3, entries 1, 8 and 12
as well as 3 and 13). Toluene, with the relatively rigid methyl
group gave a greater ratio of para isomers than anisole, with the
more flexible methoxy group.
Conclusion
A convenient method for the synthesis of 1-imidoalkylphos-
phonium salts as a new class of reactive α-imidoalkylating
agents was developed. The imidoalkylating properties of the
obtained 1-imidoalkylphosphonium salts were tested in the
The 1-imidocarbenium cation derived from succinimide should Tscherniac–Einhorn-type reaction with aromatic hydrocarbons
be a molecule of higher energy and reactivity compared to the as a model reaction. The generation of 1-imidocarbenium
corresponding cation derived from phthalimide, in which the cations through the thermal splitting of the Cα–P+ bond seems
positive charge is delocalized into the aryl ring that provides to be the crucial step in the imidoalkylation of relatively reac-
some additional resonance stability, but reduces its electrophi- tive hydrogen carbons such as anisole or 1,3-dimethoxyben-
licity. Consequently, the generation of the corresponding imido- zene. Reactions with imidoalkylphosphonium salts that
carbenium cation from 1-succinimidoalkylphosphonium salts in generate more stable carbenium cations, e.g., benzyl-type car-
the reaction with anisole started at a considerably higher tem- benium cations, started at a considerably lower temperature.
perature compared to the corresponding phthalimide deriva- The Cα–P+ bond strength can be considerably reduced and
tives (cf. Table 3, entry 14 against 1 and entry 15 against 5). consequently the generation of the corresponding 1-imido-
However, the reaction yields were lower, probably because of carbenium cations can be markedly facilitated using
the instability of phosphonium salt at these elevated tempera- 1-imidoalkylphosphonium salts derived from triarylphosphines
tures.
with electron-withdrawing substituents such as tris(m-
chorophenyl)phosphine, tris(p-chlorophenyl)phosphine and
To demonstrate the enhanced reactivity of 1-imidoalkylphos- tris[p-(trifluoromethyl)phenyl]phosphine. Phosphonium salts
phonium salts as imidoalkylating agents, we successfully with a reduced Cα–P+ bond strength react with aromatic hydro-
carried out their reactions with toluene (Table 3, entries 25–29), carbons at a much lower temperature. In addition,
which was shown to be unreactive toward the most commonly microwave irradiation considerably facilitates the splitting of
used amidoalkylating agents [9,10]. In the reaction of toluene the highly polar Cα–P+ bond. The enhanced reactivity of
with phosphonium salt 5e the elimination of triarylphospho- 1-imidoalkylphosphonium salts as imidoalkylating agents was
nium tetrafluoroborate with formation of N-vinylphthalimide as demonstrated by the successful imidoalkylation of the scarcely
a side product was observed. Fortunately, the addition of an reactive toluene. The 1-imidoalkylphosphonium salts derived
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from electron-withdrawing triarylphosphines can be considered Decarboxylative α-methoxylation of 2-imidoalkanecar-
a new interesting class of imidoalkylating agents of high reac- boxylic acids 6 to N-(1-methoxyalkyl)imides 7 [18]: To an
tivity without the need of a catalyst. Starting from a wide range undivided electrolyzer (100 cm3) with a thermostatic jacket
of amino acids they are easily synthesized and isolated by equipped with a magnetic stirrer, a cylindrical Pt mesh anode
simple work-up procedures as crystalline and stable com- (47 cm2) and cathode (44 cm2), methanol (30 cm3), 2-(N-
pounds.
imido)alkanecarboxylic acids 6 (3.0 mmol) and silica gel-sup-
ported piperidine (SiO2-Pip; 200 mg, 0.22 mmol) were added.
The electrolysis was carried out under stirring at a current den-
Experimental
General methods: Melting points were determined in capil- sity of 0.3 A/dm2 at 0 °C until a 2.7–3.75 F/mol charge had
laries and are uncorrected. IR spectra were measured on an FT passed. Solid SiO2-Pip was filtered off, methanol was evaporat-
IR spectrophotometer (ATR method). 1H and 13C NMR spectra ed under reduced pressure, and the product was isolated by
were recorded at operating frequencies of 400 and 100 MHz, re- column chromatography (CH2Cl2/MeOH/Et3N 80:1:1, v/v/v).
spectively, using TMS as internal standard. 31P and 19F NMR The crystalline crude compounds 7a, 7b and 7h were recrystal-
spectra were recorded at operating frequencies of 161.9 and lized from toluene.
376 MHz, respectively, without the resonance shift standard,
with respect to H3PO4 and CFCl3, respectively, as zero ppm. Transformation of N-(1-methoxyalkyl)imides 7 to phos-
All chemical shifts (δ) are reported in ppm, and coupling con- phonium salts 5; general procedure: To a solution of
stants (J) are given in hertz (Hz). High-resolution mass spec- triarylphosphine (1 mmol) in DCM, tetrafluoroboric acid
trometry (HRMS) analyses were performed on a Waters Xevo diethyl ether complex (136 µL, 161.9 mg, 1 mmol) was added
G2 Q-TOF mass spectrometer equipped with an ESI source at 0 °C. After 2 h of stirring at room temperature, N-(1-
operating in the positive ion mode. The accurate mass and methoxyalkyl)imides 7 (1 mmol) and sodium bromide
composition for the molecular ion adducts were calculated (15.4 mg, 0.15 mmol) were added to the reaction mixture and
using the MassLynx software incorporated within the the solvent was evaporated to dryness under reduced pressure.
instrument. Spectroscopic properties of all synthesized com- The residue was then heated at 85–140 °C under reduced pres-
pounds as well as 1H NMR, 13C NMR, 31P NMR and 19F NMR sure for the time given in Table 2. The crude product
spectra of all new compounds are given in Supporting Informa- was dissolved in DCM, sodium bromide was removed by
tion File 1.
decantation and phosphonium salt 5 was precipitated with
Et2O, which was separated by filtration and dried under reduced
Synthesis of 2-imidoalkanecarboxylic acids 6 from α-amino pressure.
acids: The synthesis of 2-imidoalkanecarboxylic acids 6 was
carried out based on the modified procedure described by Transformation of 1-(N-imido)alkyltriarylphosphonium
McKenzie and Walker [32]. The corresponding α-amino acid salts 5 to N-(1-arylalkyl)imides 9; general procedure: A
(10 mmol) was heated with phthalic or succinic anhydride suspension of 1-(N-imido)alkyltriarylphosphonium salt 5
(11 mmol) at 170 °C or 140 °C under reduced pressure for the (0.1 mmol) in an aromatic compound (1 cm3) was placed in a
time given in Table 1. The crude product was recrystallized glass vial sealed with a screw-cap. To improve the solubility of
from toluene.
the phosphonium salts in some cases an additional solvent was
added (Table 3). In the reaction of toluene with phosphonium
Synthesis of 2-(1,8-naphthalimido)propionic acid: The syn- salt 5e the addition of tetrafluoroboric acid diethyl ether com-
thesis of 2-(1,8-naphthalimido)propionic acid was carried out plex (HBF4·Et2O, 13.6 µL, 16.2 mg, 0.1 mmol) to the reaction
based on the procedure described by Reger [35]. To a stirred mixture was necessary to suppress the side reaction of
aqueous solution of L-alanine (1.96 g, 22 mmol) potassium N-vinylphthalimide formation. The reaction mixture was vigor-
hydroxide (1.12 g, 20 mmol) was added. After 20 min of stir- ously stirred and heated under the conditions given in Table 3.
ring, 1,8-naphthalic anhydride (3.96 g, 20 mmol) and ethanol The reaction mixture was evaporated to dryness under reduced
(75 mmol) were added to the amino acid solution. The reaction pressure and the product was isolated by column chromatogra-
mixture was heated under reflux for 5 h. Then a solution of phy (toluene/ethyl acetate 10:1, v/v). The crude crystalline com-
1 M HCl (20 cm3, 20 mmol) was added. The precipitated pounds 9aa, 9ab, 9bb, 9db, 9e, 9f, 9g, 9ia were recrystallized
product was filtered and washed with distilled water from toluene or toluene/hexane 1:1, v/v.
(4 × 50 cm3) and ice-cold absolute ethanol (50 cm3). The
obtained solid was dried under reduced pressure to Microwave assisted synthesis of N-(1-arylalkyl)imides 9: A
give analytically pure 2-(1,8-naphthalimido)propionic acid in suspension of the 1-(N-imido)alkyltriarylphosphonium salt 5
84% yield.
(0.25 mmol) in an aromatic compound (2.5 cm3) was placed in
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Beilstein J. Org. Chem. 2017, 13, 1446–1455.
a glass vial sealed with a screw-cap. To improve the solubility Acknowledgements
of the phosphonium salts, in some cases an additional solvent The financial support of the National Science Centre, Poland
was added (Table 3). In the reaction of toluene with phos- (NCN) Grant No. 2015/19/D/ST5/00733 is gratefully acknowl-
phonium salt 5e the addition of tetrafluoroboric acid diethyl edged
ether complex (HBF4·Et2O, 17.0 µL, 20.3 mg, 0.125 mmol) to
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