α-amidoalkylating agents from N-acyl-α-amino acids: 1-(N-acylamino)alkyltriphenylphosphonium salts

Article abstract of DOI:10.1021/jo202534u

N-Acyl-α-amino acids were efficiently transformed in a two-step procedure into 1-N-(acylamino)alkyltriphenylphosphonium salts, new powerful α-amidoalkylating agents. The effect of the α-amino acid structure, the base used [MeONa or a silica gel-supported piperidine (SiO ₂-Pip)], and the main electrolysis parameters (current density, charge consumption) on the yield and selectivity of the electrochemical decarboxylative α-methoxylation of N-acyl-α-amino acids (Hofer-Moest reaction) was investigated. For most proteinogenic and all studied unproteinogenic α-amino acids, very good results were obtained using a substoichiometric amount of SiO₂-Pip as the base. Only in the cases of N-acylated cysteine, methionine, and tryptophan, attempts to carry out the Hofer-Moest reaction in the applied conditions failed, probably because of the susceptibility of these α-amino acids to an electrochemical oxidation on the side chain. The methoxy group of N-(1-methoxyalkyl)amides was effectively displaced with the triphenylphosphonium group by dissolving an equimolar amount of N-(1-methoxyalkyl)amide and triphenylphosphonium tetrafluoroborate in CH ₂Cl₂ at room temperature for 30 min, followed by the precipitation of 1-N-(acylamino)alkyltriphenylphosphonium salt with Et ₂O.

Full text of DOI:10.1021/jo202534u

Article
pubs.acs.org/joc
α-Amidoalkylating Agents from N-Acyl-α-amino Acids:
1-(N-Acylamino)alkyltriphenylphosphonium Salts
Roman Mazurkiewicz,*,† Jakub Adamek,*,† Agnieszka Pazdzierniok-Holewa,† Katarzyna Zielinska,†
́
́
Wojciech Simka,‡ Anna Gajos,† and Karol Szymura†
†Department of Organic Chemistry, Biochemistry and Biotechnology, Silesian University of Technology, B. Krzywoustego 4,
44-100 Gliwice, Poland
‡Department of Chemistry, Inorganic Technology and Fuels, Silesian University of Technology, B. Krzywoustego 6, 44-100 Gliwice,
Poland
S
* Supporting Information
ABSTRACT: N-Acyl-α-amino acids were efficiently transformed in a
two-step procedure into 1-N-(acylamino)alkyltriphenylphosphonium
salts, new powerful α-amidoalkylating agents. The effect of the α-
amino acid structure, the base used [MeONa or a silica gel-supported
piperidine (SiO2−Pip)], and the main electrolysis parameters (current
density, charge consumption) on the yield and selectivity of the
electrochemical decarboxylative α-methoxylation of N-acyl-α-amino
acids (Hofer−Moest reaction) was investigated. For most proteino-
genic and all studied unproteinogenic α-amino acids, very good results
were obtained using a substoichiometric amount of SiO2−Pip as the
base. Only in the cases of N-acylated cysteine, methionine, and try-
ptophan, attempts to carry out the Hofer−Moest reaction in the applied conditions failed, probably because of the susceptibility
of these α-amino acids to an electrochemical oxidation on the side chain. The methoxy group of N-(1-methoxyalkyl)amides was
effectively displaced with the triphenylphosphonium group by dissolving an equimolar amount of N-(1-methoxyalkyl)amide and
triphenylphosphonium tetrafluoroborate in CH2Cl2 at room temperature for 30 min, followed by the precipitation of 1-N-
(acylamino)alkyltriphenylphosphonium salt with Et2O.
properties in the presence of organic bases such as DBU or
INTRODUCTION
■
(i-Pr) EtN (Hunig’s base).14 They react smoothly with nitro-
̈
2
α-Amidoalkylation reactions play an important role in organic
synthesis as a valuable extension of the Mannich reaction.1−4
Numerous α-amidoalkylating reagents of a general structure 1
have been reported, where X represents some nucleofugal leav-
ing group, usually OH, OR, OCOR, Cl, Br, I, NHCOR, SO2Ar,
or 1-benzotriazolyl (Scheme 1).3,5−8
gen, sulfur, and oxygen nucleophiles in the presence of Hunig’s
̈
base to afford the expected amidoalkylation products usually in
good or very good yields.14
α-Amidoalkylation of dialkyl malonates or acetylacetates re-
quires the use of a much stronger base (DBU) and provides the
best results under the influence of microwave irradiation.14 α-
Amidoalkylation of enamines with 1-(N-acylamino)alkyltri-
Scheme 1. α-Amidoalkylating Agents and Their Reaction
with Nucleophiles
phenylphosphonium salts in the presence of Hunig’s base in a
̈
microwave reactor, followed by the hydrolysis of the cor-
responding iminium salt, produces the expected α-[1-
(N-acylamino)alkyl]ketones in good yields.14 α-Amidoalkyla-
tion of trialkylphosphites or dialkyl phosphonites with 1-
(N-acylamino)alkyltriphenylphosphonium salts followed by a
Michaelis−Arbuzov-like rearrangement offers a convenient and
effective way to synthesize important α-(N-acylamino)alkane-
phosphonic or α-(N-acylamino)alkanephosphinic acid esters,
respectively.17
Limitations and disadvantages of most of the above-
mentioned amidoalkylating agents have been reviewed by
Katritzky et al.3,9−11
Recently, we described a simple and efficient synthesis of 1-
(N-acylamino)alkyltriphenylphosphonium salts 4 by hydrolysis
and decarboxylation of 4-phosphoranylidene-5(4H)-oxazolones 2
or their alkylation products 3 (Scheme 2).12,13 We have also demon-
strated that phosphonium salts 4 display strong amidoalkylating
As we have demonstrated, the deprotonation and elimina-
tion of triphenylphosphine from the phosphonium salts 4 leads
to the corresponding highly reactive N-acylimines 5, which are
Received: December 15, 2011
Published: January 16, 2012
© 2012 American Chemical Society
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a
Scheme 2. Synthesis of 1-(N-Acylamino)alkyltriphenylphosphonium Salts 4 and Their Amidoalkylating Properties
a
(i) (a) DCC, (b) Ph3PBr2, Et3N;15 (ii) R2I or R2Br;16 (iii) H2O, HBF4;12 (iv) H2O;12 (v) NuH, (i-Pr)2EtN, or DBU.14
responsible for the strong amidoalkylating properties of this
reaction system.14,18,19
Kardasis et al.29 to 2,5-piperazinediones derived from amino-
malonic acid. The Hofer−Moest reactions were typically carried
out in MeOH, in the presence of sodium methanolate,20,23−27
organic bases (Et3N, (i-Pr)2EtN, or pyridine),28,30 or inorganic
bases (NaOAc,20,29 LiH, KOH, Cs2CO3).24 Recently, Tajima
et al. described the decarboxylative methoxylation of alanine and
proline derivatives using 3-(1-piperidino)propyl functionalized
silica gel (SiO2−Pip) as the base, ionizing the N-acyl-α-amino
acid into the corresponding carboxylate ion.23
In our studies, the Hofer−Moest decarboxylative α-methoxylation
of N-acyl-α-amino acids was carried out in methanol, in an
undivided cylindrical glass electrolyzer with a thermostatic
jacket, a magnetic stirrer, and a cylindrical Pt mesh anode, at a
constant current density (Figure 1).
In contrast to many other known amidoalkylating reagents,
α-(N-acylamino)alkyltriphenylphosphonium salts are stable,
usually crystalline, easy-to-use compounds that can be stored
for prolonged time under laboratory conditions and can be
easily activated with organic bases, which is much more advan-
tageous than the alternative usage of Lewis acids, usually re-
commended as catalysts for amidoalkylation reactions.
In this contribution, we report a new, convenient, very
efficient, two-stage method for the synthesis of these powerful
amidoalkylating agents from the N-acylated α-amino acids as
starting materials (Scheme 3).
Scheme 3. Transformation of N-Acyl-α-amino Acids into
1-(N-Acylamino)alkyltriphenylphosphonium Salts
It is noteworthy that the possibility of employing in this syn-
thesis a large variety of natural α-amino acids (both proteinogenic
and unproteinogenic acids) as well as a nearly infinite array of
unnatural α-amino acids provides potential access to a wide
variety of structurally diverse amidoalkylating agents, which sig-
nificantly broadens the scope of possible synthetic applications of
1-(N-acylamino)alkyltriphenylphosphonium salts as α-amidoalky-
lating agents.
RESULTS AND DISCUSSION
■
The first step of the transformation of N-acyl-α-amino acids
into the corresponding 1-(N-acylamino)alkyltriphenyl-
phosphonium salts involves the electrochemical decarboxylative
α-methoxylation of N-acyl-α-amino acids 6 to N-(α-methoxyalkyl)-
amides 7 (the Hofer−Moest reaction). Since the pioneering works
of Linstead et al.20 on the electrolysis of N-acylamino acids, the
Hofer−Moest decarboxylative α-methoxylation of N-acyl-
α-amino acids has been studied by a number of authors.21,22
Most of those investigations, however, were limited to relatively
simple N-acylated α-amino acids such as glycine, sarcosine,
hydrophobic α-amino acids with a simple aliphatic substituent
at the α-position (alanine, valine, leucine, phenylalanine and
their homologues), or proline and its cyclic homologues.20,23
Matsumura et al.24−26 and Onomura27 also described the
Hofer−Moest decarboxylative α-methoxylation of N,O-acetals
derived from serine, whereas Steckhan applied this reaction to
oxazolidin-2-one-4-carboxylic acids derived from threonine28 and
Figure 1. Electrolytic cell for the Hofer−Moest decarboxylative α-
methoxylation of N-acyl-α-amino acids in the presence of SiO2−Pip.
The effect of the α-amino acid structure, applied base [MeONa
or a silica gel supported piperidine (SiO2−Pip)], and the main
electrolysis parameters (current density, charge consumption) on
the reaction yield and selectivity was investigated. The results
obtained are provided in Table 1.
The decarboxylative α-methoxylation of N-acyl-α-amino acids
in the presence of MeONa was performed at a relatively low
current density (1.1 A/dm2) to avoid undesirable side reactions,
e.g., the Kolbe reaction (Procedure A).22 Alternatively, reactions
were carried out in the presence of a substiochiometric amount
of SiO2−Pip (0.075 mol of piperidine per mol of substrate;
Procedure B).
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Table 1. Decarboxylative α-Methoxylation of N-Acyl-α-amino Acids 6 to N-(1-Methoxyalkyl)amides 7
entry
substrate 6
N-Ac-Gly-OH
base
charge [F/mol]
7
yield [%]
1
MeONa
SiO2−Pip
SiO2−Pip
MeONa
SiO2−Pip
MeONa
SiO2−Pip
SiO2−Pip
SiO2−Pip
MeONa
MeONa
MeONa
SiO2−Pip
SiO2−Pip
MeONa
SiO2−Pip
MeONa
SiO2−Pip
MeONa
SiO2−Pip
SiO2−Pip
MeONa
SiO2−Pip
MeONa
SiO2−Pip
MeONa
SiO2−Pip
MeONa
SiO2−Pip
MeONa
SiO2−Pip
MeONa
SiO2−Pip
SiO2−Pip
SiO2−Pip
SiO2−Pip
SiO2−Pip
MeONa
SiO2−Pip
SiO2−Pip
SiO2−Pip
MeONa
SiO2−Pip
3.5
7a
7a
7b
7c
7c
7d
7d
7d
7e
7f
59
96
93
97
94
90
94
94
82
93
92
88
93
98
94
97
81
92
93
86
91
91
93
63
93
74
95
93
94
96
79
97
88
80
74
91
2
N-Ac-Gly-OH
3.5
3
N-Ac-D,L-Ala-OH
3.75
3.0
4
N-Piv-D,L-Ala-OH
5
N-Piv-D,L-Ala-OH
3.75
3.0
6
N-Cbz-L-Ala-OH
7
N-Cbz-L-Ala-OH
3.75
3.75
3.75
3.3
8
N-Cbz-D,L-Ala-OH
N-For-D,L-Ala-OH
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
N-Cbz-Aib-OH
N-Cbz-L-Phe-OH
3.0
7g
7h
7h
7i
N-Ac-D,L-Phg-OH
3.0
N-Ac-D,L-Phg-OH
3.75
3.75
3.0
N-Cbz-L-Phg-OH
N-Cbz-D,L-Val-OH
N-Cbz-D,L-Val-OH
N-Boc-L-Val-OH
7j
3.5
7j
3.0
7k
7k
7l
N-Boc-L-Val-OH
3.75
3.0
N-Cbz-L-Leu-OH
N-Cbz-L-Leu-OH
3.5
7l
N-Cbz-D,L-Leu-OH
N-Cbz-L-Pro-OH
3.75
3.0
7l
7m
7m
7n
7n
7o
7o
7p
7p
7q
7q
7r
N-Cbz-L-Pro-OH
3.75
3.0
N-Cbz-L-Asn-OH
N-Cbz-L-Asn-OH
3.75
3.0
N-Cbz-L-Gln-OH
N-Cbz-L-Gln-OH
3.75
3.0
N-Cbz-L-Ser(O-t-Bu)-OH
N-Cbz-L-Ser(O-t-Bu)-OH
N-Cbz-L-Asp(O-t-Bu)-OH
N-Cbz-L-Asp(O-t-Bu)-OH
N-Cbz-L-Glu(O-t-Bu)-OH
N-Cbz-L-Glu(O-t-Bu)-OH
N-Cbz-L-Tyr(O-Bn)-OH
N-Cbz-L-Lys(N-Cbz)-OH
N-Boc-L-His(N-Bn)-OH
N-Fmoc-L-Thr(O-t-Bu)-OH
N-Boc-D,L-Met-OH
N-Boc-D,L-Met-OH
N-Cbz-L-Cys(S-Bn)-OH
N-Ac-D,L-Trp-OH
3.75
3.0
3.75
3.0
3.75
3.0
7r
7s
7t
3.75
2.4
7u
7v
7w
7w
7x
7y
7z
7z
a
3.75
3.0
68
b
−
b
b
b
b
b
3.75
3.75
3.75
3.0
−
−
−
−
−
N-Boc-L-Trp(N-Bn)-OH
N-Boc-L-Trp(N-Bn)-OH
3.75
a
b
A mixture of diasteroisomers in a molar ratio of 3:2. A multicomponent reaction mixture.
In the latter case, the relatively high resistance of the electro-
not yet explored in the Hofer−Moest reaction. It was demon-
strated that, apart from the hydrophobic aliphatic and aromatic
N-acyl-α-amino acids (alanine, valine, leucine, phenylalanine,
and tyrosine), most extensively studied in this reaction, most
other natural proteinogenic and unproteinogenic N-acyl-
α-amino acids undergo a facile and efficient decarboxylative
α-methoxylation, including those with a functionalized neutral-
polar side chain (asparagine, glutamine, serine, threonine), a
protected acidic side chain (aspartic acid, glutamic acid), or a
basic side chain (histidine, lysine). However, in the case of
N-acylated cysteine, methionine, and tryptophan, our attempts
lyte required the placement of electrodes as close to one an-
other as possible (see Figure 1) and the reduction of current
density to 0.3 A/dm2.
Upon the charge consumption of 3 F/mol, the substrate
1
conversion was monitored using H NMR spectroscopy. If
necessary, the electrolysis was continued until all of the starting
material was consumed (see Table 1).
The decarboxylative α-methoxylation of a variety of N-acyl-
α-amino acids was investigated including α-amino acid deriv-
atives with functionalized side chains at the α-position that were
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Article
to carry out the Hofer−Moest reaction failed; in all of these cases,
multicomponent reaction mixtures were obtained, probably
because of the susceptibility of these α-amino acids to electro-
chemical oxidation on the side chain. It appears that the nature
of the N-acyl group does not markedly affect the course of the
reaction.
Investigations on the effect of the base used in the reaction
led to the conclusion that, in the most cases, better results were
obtained using the silica gel supported piperidine. In a few cases
of particularly hydrophilic amino acids (N-Ac-Gly-OH, N-Cbz-
Asn-OH, N-Cbz-Gln-OH) the results were markedly improved.
The obtained reaction yields using SiO2−Pip were usually very
good or even excellent. The main advantage obtained when
SiO2−Pip was used involved the simple workup procedure that
eliminated the need to extract the product from an aqueous
solution. Aqueous workups were especially difficult and inef-
fective in the case of products derived from polar, hydrophilic
amino acids.
We also demonstrated that SiO2−Pip could be used afresh
many times after separation by filtration and washing with
methanol. Five successive runs using N-Cbz-L-Ala-OH and the
same portion of SiO2−Pip afforded the expected product in
yields 93.2%, 96.1%, 94.3%, 93.3%, and 93.9%, respectively.
The stereoselectivity of the Hofer−Moest reaction performed
in the presence of SiO2−Pip was studied, by comparing the
reaction products obtained from N-Cbz-L-Ala-OH and N-Cbz-D,L-
Ala-OH. Beforehand we stated that doublets at 1.30−1.31 ppm
of methyl groups of both enantiomers of the expected N-
(1-methoxyethyl)amide 7d were well separated in the 1H NMR
spectra performed in the presence of quinine as a chiral solvat-
ing agent. As was expected, in both cases we obtained racemic
mixtures of both enantiomers in a molar ratio of 1:1 (Figure 2).
The methoxy group of N-(1-methoxyalkyl)amides 7 was ef-
fectively displaced by the triphenylphosphonium group by heating
a homogeneous mixture of the amide with triphenylphosphonium
tetrafluoroborate at 45−70 °C under reduced pressure (0.1−
0.2 mmHg) for 2 h (Table 2, Procedure C). In many cases, how-
ever, a higher reaction yield could be achieved by simply dissolving
equimolar amounts of N-(1-methoxyalkyl)amide and triphenyl-
phosphonium tetrafluoroborate in CH2Cl2 at room temperature
for 30 min, followed by the precipitation of the product with Et2O
(Table 2, Procedure D).
The N-(1-methoxyalkyl)amide derived from histidine (7u)
was an exception; its reaction with an equimolar amount of tri-
phenylphosphonium tetrafluoroborate resulted in the protona-
tion of the imidazole moiety, without the displacement of the
methoxy group. However, this transformation was achieved using
two equivalents of triphenylphosphonium tetrafluoroborate per
one equivalent of the corresponding N-(1-methoxyalkyl)amide
affording a reaction mixture, which contained about 80% the ex-
pected phosphonium salt with the protonated imidazole moiety
(see Experimental). Attempts to isolate the pure protonated
phosphonium salt 4u by crystallization failed.
CONCLUSIONS
■
A new, convenient, efficient, two-stage transformation of N-
acylated α-amino acids into 1-(N-acylamino)alkyltriphenyl-
phosphonium salts has been developed. The first step of the
transformation consists in the electrochemical decarboxylative
α-methoxylation of N-acylated α-amino acids to the corre-
sponding N-(1-methoxyalkyl)amides (Hofer−Moest reaction)
in the presence of a base (MeONa or SiO2−Pip). For most pro-
teinogenic and all unproteinogenic α-amino acids studied, very
good results were obtained using a substoichiometric amount of
the SiO2−Pip as a base. A significant advantage of the appli-
cation of SiO2−Pip is the facile workup procedure of reaction
mixtures, which eliminates a difficult extraction of the hydro-
philic product from an aqueous solution. The Hofer−Moest
decarboxylative α-methoxylation of N-Cbz-L-Ala-OH in the
presence of SiO2−Pip gave a racemic mixture of the expected
benzyl N-(1-methoxyethyl)carbamate. The methoxy group of
N-(1-methoxyalkyl)amides was effectively displaced by the
triphenylphosphonium group by dissolving equimolar amounts
of N-(1-methoxyalkyl)amide and triphenylphosphonium tetra-
fluoroborate in CH2Cl2 at room temperature for 30 min,
followed by the precipitation of the product with Et2O or by
heating a homogeneous mixture of the amide with triphenyl-
phosphonium tetrafluoroborate at 45−70 °C under reduced
pressure. The possibility of employing in this synthesis a large
range of natural α-amino acids (both proteinogenic and un-
proteinogenic), as well as an unlimited number of unnatural
α-amino acids, potentially provided access to a wide variety of
structurally diverse amidoalkylating agents that significantly widen
the scope of possible synthetic applications of 1-(N-acylamino)-
alkyltriphenylphosphonium salts as α-amidoalkylating agents.
Figure 2. Doublets of methyl groups of both enantiomers of N-
(1-methoxyethyl)amide 7d obtained from N-Cbz-L-Ala-OH and N-
Cbz-D,L-Ala-OH at 1.30 ppm (J = 6.0 Hz) and 1.31 ppm (J = 6.0 Hz);
CDCl3, 7d:quinine molar ratio of 1:5.
EXPERIMENTAL SECTION
General Methods. Melting points were determined in capillaries
■
and are uncorrected. IR spectra were measured on a FT-IR spectro-
A similar racemization in a Hofer−Moest decarboxylative α-
methoxylation of N-acyl-α-amino acids carried out in the pre-
sence of sodium methoxide was reported by Matsumura et al.31
In the case of the threonine derivative 7v with the additional
stereogenic center in the side chain, a mixture of both diasteromers
was obtained.
1
photometer (ATR method). H and 13C NMR spectra were recorded
at operating frequencies of 300 and 75.5 MHz, respectively, using
TMS as the resonance shift standard. 31P NMR spectra were recorded
at operating frequencies of 121.5 or 242.8 MHz, with 80% ortho-
phosphoric acid as an external resonance shift standard. All chemical
shifts (δ) are reported in ppm, and coupling constants (J) are in Hz.
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Table 2. Transformation of N-(1-Methoxyalkyl)amides 7 to 1-(N-acylamino)alkyltriphenylphosphonium Salts 4
a
entry
7
R1
Me
R2
R3
procedure
temp [oC]
4
yield [%]
1
7a
7a
7b
7b
7c
7c
7d
7d
7e
7g
7h
7h
7i
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
H
C
D
C
D
C
D
C
D
D
C
C
D
D
C
D
C
D
C
C
C
D
C
D
C
D
D
C
D
D
D
D
60
60
45
25
70
25
45
25
25
45
70
25
25
45
25
45
25
45
45
45
25
45
25
70
25
25
45
25
25
25
25
4a
4a
4b
4b
4c
4c
4d
4d
4e
4g
4h
4h
4i
67
98
74
96
93
85
99
97
92
97
95
92
99
89
83
90
96
82
99
100
84
100
90
91
95
79
92
90
94
2
Me
H
3
Me
Me
Me
Me
Me
Me
Me
Me
Bn
4
Me
5
t-Bu
t-Bu
BnO
BnO
H
6
7
8
9
10
11
12
13
14
15
16
17
18
19
BnO
Me
Ph
Me
Ph
BnO
BnO
BnO
t-BuO
t-BuO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
BnO
t-BuO
Ph
7j
i-Pr
i-Pr
i-Pr
i-Pr
i-Bu
4j
7j
4j
7k
7k
7l
4k
4k
4l
7m
7n
7n
7o
7o
7p
7p
7q
7r
(CH2)3
4m
4n
4n
4o
4o
4p
4p
4q
4r
b
20
CH2CONH2
H
H
H
H
H
H
H
H
H
H
H
H
b
21
CH2CONH2
b
22
(CH2)2CONH2
(CH2)2CONH2
CH2O-t-Bu
b
23
24
25
26
27
28
29
30
31
CH2O-t-Bu
CH2CO2-t-Bu
(CH2)2CO2-t-Bu
(CH2)2CO2-t-Bu
p-CH2C6H4OBn
(CH2)4NHCbz
7r
4r
7s
7t
4s
4t
c
-
d
7u
(1-benzylimidazol-5yl)methyl
4u
-
a
b
c
Procedure C, reactions in a homogeneous melt; procedure D, reactions in a solution. Reactions carried out in acetonitrile. A multicomponent
d
reaction mixture. The reaction mixture contained about 80% of the expected phosphonium salt with the protonated imidazole moiety (see
Experimental Section). Attempts to isolate the pure phosphonium salt failed.
Electrochemical Decarboxylative α-Methoxylation of N-
Acyl-α-amino Acids 6; General Procedures. Procedure A. To
an undivided cylindrical glass electrolyzer (85 cm3) with a thermostatic
jacket, equipped with a cylindrical Pt mesh anode (47 cm2), a cathode
made of platinized titanium (plate, 8 cm2), and a magnetic stirrer,
methanol (30 cm3), N-acyl-α-amino acid 6 (3.0 mmol), and MeONa
(1.8 mmol, methanolic solution) were added. The electrolysis was
carried out while stirring at a current density of 1.1 A/dm2 at 0 °C
until 3−3.5 F/mol charge (Table 1) had passed. After evaporation of
methanol in vacuo, methylene chloride (20 cm3) was added to the
residue, and the mixture was washed with 5% hydrochloric acid solu-
tion (5 cm3) and water (10 cm3). The organic layer was dried with
MgSO4, the drying agent was filtered out, and methylene chloride was
evaporated under reduced pressure to obtain N-(1-methoxyalkyl)-
amide 7 (Table 1).
filtered out, and methanol was evaporated under reduced pressure to
obtain N-(1-methoxyalkyl)amide 7 (Table 1).
Transformation of N-(1-Methoxyalkyl)amides 7 to 1-(N-
Acylamino)alkyltriphenylphosphonium Salts 4; General Pro-
cedures. Procedure C. To a solution of N-(1-methoxyalkyl)amide 7
(1.25 mmol) in dichloromethane (2 cm3) was added triphenylphos-
phine tetrafluoroborate (438 mg, 1.25 mmol). After obtaining a homo-
geneous solution, the solvent was evaporated to dryness, and the
residue was heated at 45−70 °C (Table 2) under reduced pressure
(1−2 mmHg) for 1.5 h. Recrystallization of the residue using CH2Cl2/
Et2O (1:2, v/v), CH3CN/Et2O (1:2, v/v), or ethyl acetate yielded, in
most cases, 1-(N-acylamino)alkyltriphenylphosphonium salts 4 as
colorless crystals.
Procedure D. To a stirred solution of N-(1-methoxyalkyl)amide 7
(1.27 mmol) in dichloromethane (0.7 cm3) was added triphenylphos-
phine tetrafluoroborate (445 mg, 1.27 mmol). The homogeneous mixture
was allowed to react at 25 °C for 30 min, and 1-(N-acylamino)alkyltri-
phenylphosphonium salt 4 was precipitated with Et2O, separated by
filtration, and dried under reduced pressure.
Procedure B. To an undivided cylindrical glass electrolyzer (85 cm3)
with a thermostatic jacket, equipped with a magnetic stirrer, a
cylindrical Pt mesh anode (47 cm2), and a similar cathode (44 cm2),
arranged concentrically to one another at a distance of 2.5 0.5 mm
(Figure 1), methanol (30 cm3), N-acyl-α-amino acid 7 (3.0 mmol),
and SiO2−Pip (200 mg, 0.22 mmol) were added. The electrolysis was
carried out while stirring at a current density of 0.3 A/dm2 at 10 °C
until 2.4−3.75 F/mol charge had passed (Table 1). SiO2−Pip was
Reaction of tert-Butyl N-[2-(1-benzylimidazol-5-yl)-1-
methoxyethyl]carbamate 7u with Triphenylphosphonium
Tetrafluoroborate. To a solution of tert-butyl N-[2-(1-benzylimidazol-
5-yl)-1-methoxyethyl]carbamate (24.3 mg, 0.07 mmol) in deuterated
chloroforrm (0.7 cm3) was added triphenylphosphine tetrafluoroborate
1956
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The Journal of Organic Chemistry
Article
(25.7 mg, 0.07 mmol). The composition of the obtained mixture was
monitored using 1H NMR. After 10 min another portion of triphenyl-
phosphine tetrafluoroborate (25.7 mg, 0.07 mmol) was added. After
40 min the reaction mixture contained about 80% of the expected
phosphonium salt 4u with the protonated imidazole moiety. Attempts
to isolate the pure phosphonium salt by precipitation with Et2O
failed.
tert-Butyl N-(1-Methoxy-2-methylpropyl)carbamate40 (7k).
Colorless crystals, mp 29−30 °C; 1H NMR (300 MHz, CDCl3) δ 4.79
(d, J = 10.2 Hz, 1H), 4.57 (dd, J = 10.4, 5.6 Hz, 1H), 3.34 (s, 3H),
1.90−1.70 (m, 1H), 1.46 (s, 9H), 0.94 (d, J = 6.9 Hz, 3H), 0.92 (d, J =
6.6 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 155.8, 87.1, 79.5,
55.6, 33.0, 28.3, 17.8, 17.2 ppm; IR (ATR) 3268, 1682, 1530, 1364,
1248, 1172, 1154, 1084, 1012 cm−1.
N-(Methoxymethyl)acetamide20 (7a). Colorless oil. H NMR
Benzyl N-(1-Methoxy-3-methylbutyl)carbamate39 (7l). Color-
1
1
(300 MHz, CDCl3) δ 6.63 (br s, 1H), 4.66 (d, J = 9.0 Hz, 2H), 3.34
(s, 3H), 2.05 (s, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 171.0,
71.3, 55.8, 23.2 ppm; IR (ATR) 3300, 1664, 1538, 1369, 1280, 1127,
1060 cm−1.
less oil. H NMR (300 MHz, CDCl3) δ 7.40−7.26 (m, 5H), 5.12
(s, 2H), 5.06 (d, J = 10.5 Hz, 1H), 4.94 (ddd, J = 9.9, 6.5, 6.5 Hz, 1H),
3.35 (s, 3H), 1.80−1.63 (m, 1H), 1.60−1.51 (m, 1H), 1.42−1.33 (m,
1H), 0.92 (d, J = 6.6 Hz, 6H) ppm; 13C NMR (75.5 MHz, CDCl3) δ
156.0, 136.2, 128.5, 128.2, 128.0, 82.3, 66.8, 55.4, 44.5, 24.5, 22.6, 22.4
ppm; IR (ATR) 3320, 2955, 1700, 1523, 1224, 1088, 1046, 1026 cm−1.
N-(Benzyloxycarbonyl)-2-methoxypyrolidine41 (7m). Color-
N-(1-Methoxyethyl)acetamide20 (7b). Colorless oil. H NMR
1
(300 MHz, CDCl3) δ 6.10 (br s, 1H), 5.27 (dq, J = 9.0, 5.9 Hz, 1H),
3.33 (s, 3H), 2.03 (s, 3H), 1.33 (d, J = 5.7 Hz, 3H) ppm; 13C NMR
(75.5 MHz, CDCl3) δ 170.2, 77.6, 55.5, 23.3, 21.4 ppm; IR (ATR)
3278, 1656, 1537, 1374, 1129, 1090, 1051 cm−1.
1
less oil. H NMR (300 MHz, CDCl3)a δ 7.40−7.26b (m, 5H), 5.17c
and 5.16c (s, 2H), 5.26−5.20c and 5.17−5.16c (m, 1H), 3.57−3.48c
and 3.45−3.32c (m, 2H), 3.39c and 3.26c (s, 3H), 2.20−1.65b (m, 4H)
ppm; 13C NMR (75.5 MHz, CDCl3)a δ 155.7c and 154.8c, 136.6b,
128.4b, 127.9b, 127.7b, 89.1c and 88.5c, 67.0c and 66.8c, 55.9c and 55.3c,
45.8c and 45.7c, 32.5c and 31.9c, 22.6c and 21.6c ppm; IR (ATR) 2943,
N-(1-Methoxyethyl)pivaloylamide (7c). Colorless crystals, mp
65−66 °C; 1H NMR (300 MHz, CDCl3) δ 5.78 (br s, 1H), 5.34 (dq,
J = 9.6, 6.0 Hz, 1H), 3.31 (s, 3H), 1.34 (d, J = 6.0 Hz, 3H), 1.22
(s, 9H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 178.5, 77.7, 55.5, 38.8,
27.5, 21.6 ppm; IR (ATR) 3327, 2969, 2936, 1645, 1526, 1194, 1126,
1091 cm−1. Anal. Calcd for C8H17NO2: C, 60.35; H, 10.76; N, 8.80.
Found: C, 60.05; H, 11.03; N, 8.68.
a
1701, 1402, 1356, 1079 cm−1. Two diastereomers with stereogenic
centers at C and N. bOverlapping signals of both diastereomers.
α
cSeparate signals from both diasteromers.
Benzyl N-(1-Methoxyethyl)carbamate32 (7d). Orange oil. H
1
Benzyl N-(2-Carbamoyl-1-methoxyethyl)carbamate (7n).
1
NMR (300 MHz, CDCl3) δ 7.36−7.30 (m, 5H), 5.20 (d, J = 10.2 Hz,
1H), 5.11 (s, 2H), 5.04 (dq, J = 10.2, 5.6 Hz, 1H), 3.33 (s, 3H), 1.32
(d, J = 6.0 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 155.8,
136.2, 128.5, 128.2, 128.0, 80.1, 66.7, 55.2, 21.6 ppm; IR (ATR) 3316,
1700, 1526, 1239, 1070 cm−1.
Colorless crystals, mp 154−155 °C; H NMR (300 MHz, DMSO-
d6) δ 7.89 (d, J = 9.6 Hz, 1H), 7.40−7.26 (m, 5H), 7.36 (d, J = 9.6 Hz,
1H), 6.86 (br s, 1H), 5.09 (ddd, J = 9.4, 7.4, 5.3 Hz, 1H), 5.06 (s, 2H),
3.16 (s, 3H), 2.46 (dd, J = 14.4, 7.2 Hz, 1H), 2.29 (dd, J = 14.4,
5.1 Hz, 1H) ppm; 13C NMR (75.5 MHz, DMSO-d6) δ 170.6, 155.8,
136.9, 128.4, 127.9, 127.8, 80.7, 65.4, 54.4, 40.8 ppm; IR (ATR) 3382,
3324, 3189, 1687, 1653, 1527, 1277, 1218, 1102, 1041, 1016 cm−1.
Anal. Calcd for C12H16N2O4: C, 57.13; H, 6.39; N, 11.10. Found: C,
56.93; H, 6.11; N, 11.05.
N-(1-Methoxyethyl)formamide33,34 (7e). Colorless oil. 1H
NMR (300 MHz, CDCl3)a Major rotamer: δ 8.27 (d, J = 0.8 Hz,
1H), 6.27 (br s, 1H), 5.35 (ddq, J = 9.6, 0.7, 6.1 Hz, 1H), 3.35
(s, 3H), 1.36 (d, J = 6.0 Hz, 3H); minor rotamer: δ 8.21 (d, J = 11.7
Hz, 1H), 6.55 (br s, 1H), 4.64 (dq, J = 10.1, 5.8 Hz, 1H), 3.30 (s, 3H),
1.45 (d, J = 6.0 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3)a Major
rotamer: δ 161.1, 76.2, 55.7, 21.4 ppm; minor rotamer: δ 163.8, 81.5,
54.3, 21.8 ppm; IR (ATR) 3274, 2987, 1667, 1525, 1385, 1088, 1045
Benzyl N-(3-Carbamoyl-1-methoxypropyl)carbamate (7o).
1
Colorless crystals, mp 132−133 °C; H NMR (300 MHz, CD3CN)
δ 7.42−7.28 (m, 5H), 6.25 (d, J = 7.5 Hz, 1H), 6.15 (br s, 1H), 5.69
(br s, 1H), 5.08 (s, 2H), 4.79 (ddd, J = 9.6, 6.3, 6.3 Hz, 1H), 3.24
(s, 3H), 2.21 (ddd, J = 7.4, 7.4, 3.3 Hz, 2H), 1.91−1.70 (m, 2H) ppm;
13C NMR (75.5 MHz, CD3CN) δ 175.4, 157.2, 138.2, 129.5, 128.9,
128.6, 83.8, 67.0, 55.4, 31.2, 31.0 ppm; IR (ATR) 3406, 3308, 1683,
1661, 1533, 1270, 1054 cm−1. Anal. Calcd for C13H18N2O4: C, 58.63;
H, 6.81; N, 10.52. Found: C, 58.32; H, 6.53; N, 10.43.
a
cm−1. Two rotamers in a molar ratio of 63:37.
Benzyl N-(1-Methoxy-1-methylethyl)carbamate35 (7f). Or-
1
ange oil. H NMR (300 MHz, CDCl3) δ 7.36−7.30 (m, 5H), 5.14
(br s, 1H), 5.08 (s, 2H), 3.22 (s, 3H), 1.54 (s, 6H) ppm; 13C NMR
(75.5 MHz, CDCl3) δ 154.2, 136.4, 128.5, 128.1, 128.0, 84.5, 66.3,
49.3, 26.0 ppm; IR (ATR) 3331, 1713, 1530, 1264, 1072 cm−1.
Benzyl N-(1-Methoxy-2-phenylethyl)carbamate36 (7g). Col-
Benzyl N-(2-tert-Butoxy-1-methoxyethyl)carbamate (7p).
1
Colorless crystals, mp 36−38 °C; H NMR (300 MHz, CDCl3) δ
1
orless crystals, mp 85−86 °C; H NMR (300 MHz, CDCl3) δ 7.39−
7.38−7.26 (m, 5H), 5.64 (d, J = 9.3 Hz, 1H), 5.14 (s, 2H), 5.00 (ddd,
J = 9.9, 3.0, 3.0 Hz, 1H), 3.54 (dd, J = 9.6, 2.4 Hz, 1H), 3.43 (dd, J =
9.8, 3.8 Hz, 1H), 3.39 (s, 3H), 1.19 (s, 9H) ppm; 13C NMR (75.5
MHz, CDCl3) δ 156.2, 136.3, 128.5, 128.2, 128.0, 82.0, 73.5, 66.9,
63.4, 55.8, 27.3 ppm; IR (ATR) 3344, 1696, 1526, 1268, 1195, 1098,
1055 cm−1. Anal. Calcd for C15H23NO4: C, 64.03; H, 8.24; N, 4.98.
Found: C, 63.80; H, 8.47; N, 4.92.
7.18 (m, 10H), 5.14 (ddd, J = 10.8, 5.6, 5.6 Hz, 1H), 5.12 (d, J = 12.3
Hz, 1H), 5.08 (s, 2H), 3.33 (s, 3H), 2.93 (d, J = 5.4 Hz, 2H) ppm; 13C
NMR (75.5 MHz, CDCl3) δ 155.9, 136.2, 135.8, 129.6, 128.5, 128.4,
128.1, 128.0, 126.7, 84.5, 66.3, 49.3, 26.0 ppm; IR (ATR) 3329, 1689,
1523, 1247, 1088, 1028 cm−1.
N-(1-Methoxy-1-phenylmethyl)acetamide37 (7h). Colorless
1
crystals, mp 89−91 °C; H NMR (300 MHz, CDCl3) δ 7.45−7.29
Benzyl N-(2-tert-Butoxycarbonyl-1-methoxyethyl)-
1
(m, 5H), 6.18 (d, J = 9.3 Hz, 1H), 6.10 (d, J = 9.3 Hz, 1H), 3.44
(s, 3H), 2.03 (s, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 170.2,
139.2, 128.6, 128.5, 125.8, 81.3, 55.9, 23.3 ppm; IR (ATR) 3289, 1655,
1538, 1089, 1066 cm−1.
carbamate (7q). Colorless crystals, mp 48−50 °C; H NMR (300
MHz, CDCl3) δ 7.40−7.28 (m, 5H), 5.97 (d, J = 9.9 Hz, 1H), 5.20
(ddd, J = 9.9, 5.0, 5.0 Hz, 1H), 5.13 (s, 2H), 3.36 (s, 3H), 2.61 (dd, J =
15.3, 4.8 Hz, 1H), 2.55 (dd, J = 15.3, 4.8 Hz, 1H), 1.43 (s, 9H) ppm;
13C NMR (75.5 MHz, CDCl3) δ 169.2, 155.9, 136.2, 128.5, 128.2,
Benzyl N-(1-Methoxy-1-phenylmethyl)carbamate38 (7i). Col-
1
orless crystals, mp 77−79 °C; H NMR (300 MHz, CDCl3) δ 7.42−
128.1, 81.4, 80.1, 66.8, 55.7, 41.1, 28.0 ppm; IR (ATR) 3347, 1716,
1539, 1317, 1208, 1162, 1009 cm−1; HRMS (ESI) calcd for
C16H23NO5Na [M + Na]+ 332.1468, found 332.1471.
7.31 (m, 10H), 5.89 (d, J = 9.6 Hz, 1H), 5.33 (d, J = 8.4 Hz, 1H), 5.16
(s, 2H), 3.47 (s, 3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 155.9,
139.0, 136.1, 128.6, 128.6, 128.5, 128.2, 128.1, 125.8, 84.0, 67.1, 55.7
ppm; IR (ATR) 3288, 1693, 1537, 1250, 1086, 1048 cm−1.
Benzyl N-(3-tert-Butoxycarbonyl-1-methoxypropyl)-
carbamate (7r). Colorless oil. 1H NMR (300 MHz, CDCl3) δ
7.41−7.28 (m, 5H), 5.27 (d, J = 9.9 Hz, 1H), 5.12 (s, 2H), 5.20 (ddd,
J = 9.9, 6.2, 6.2 Hz, 1H), 3.34 (s, 3H), 2.41−2.22 (m, 2H), 1.99−1.81
(m, 2H), 1.43 (s, 9H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 172.3,
156.0, 136.2, 128.5, 128.2, 128.0, 82.9, 80.5, 66.8, 55.6, 30.9, 30.4, 28.0
ppm; IR (ATR) 3324, 2978, 1705, 1523, 1248, 1151, 1047 cm−1. Anal.
Calcd for C17H25NO5: C, 62.99; H, 8.05; N, 4.44. Found: C, 63.14;
H, 8.05; N, 4.33.
Benzyl N-(1-Methoxy-2-methylpropyl)carbamate39 (7j). Col-
1
orless crystals, mp 97−99 °C; H NMR (300 MHz, CDCl3) δ 7.40−
7.29 (m, 5H), 5.13 (s, 2H), 5.03 (d, J = 9.6 Hz, 1H), 4.64 (dd, J =
10.4, 5.9 Hz, 1H), 3.35 (s, 3H), 1.90−1.74 (m, 1H), 0.94 (d, J = 6.6
Hz, 3H), 0.91 (d, J = 6.6 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3)
δ 156.4, 136.3, 128.5, 128.2, 128.0, 87.8, 66.9, 55.7, 33.0, 17.7, 17.1
ppm; IR (ATR) 3292, 1688, 1535, 1245, 1099, 1025 cm−1.
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Benzyl N-[1-Methoxy-2-(4-benzyloxyphenyl)ethyl]-
carbamate (7s). Cream-colored crystals, mp 105−107 °C; 1H
NMR (300 MHz, CDCl3) δ 7.45−6.86 (m, 14H), 5.17−5.05 (m, 1H),
5.08 (s, 2H), 5.03 (s, 2H), 5.00 (d, J = 10.5 Hz, 1H), 3.34 (s, 3H), 2.87
(d, J = 5.1 Hz, 2H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 155.9,
137.7, 137.0, 136.2, 130.7, 128.6, 128.5, 128.2, 128.1, 128.0, 127.9,
127.4, 114.8, 83.5, 70.0, 66.8, 55.7, 40.7 ppm; IR (ATR) 3307, 1698,
1534, 1511, 1260, 1237, 1048, 1025 cm−1; HRMS (ESI) calcd for
C24H25NO4Na [M + Na]+ 414.1676, found 414.1679.
Benzyl N-[5-(Benzyloxycarbonylamino)-1-methoxypentyl]-
carbamate (7t). Colorless crystals, mp 108−109 °C; 1H NMR
(300 MHz, DMSO-d6) δ 7.75 (d, J = 9.3 Hz, 1H) 7.41−7.30
(m, 10H), 7.25 (d, J = 5.6 Hz, 1H), 5.06 (s, 2H), 5.01 (s, 2H), 4.69
(ddd, J = 9.3, 6.3, 6.3 Hz, 1H), 3.17 (s, 3H), 2.97 (ddd, J = 6.3, 6.3, 6.3
Hz, 2H) 1.61−1.25 (m, 6H) ppm; 13C NMR (75.5 MHz, DMSO-d6) δ
156.2, 156.1, 137.3, 137.0, 128.4, 128.3, 127.8, 127.8, 127.7, 127.7,
83.1, 65.3, 65.1, 54.1, 40.1, 33.8, 29.0, 22.0 ppm; IR (ATR) 3291,
1689, 1541, 1258, 1227, 1042 cm−1; HRMS (ESI) calcd for
C22H28N2O5Na [M + Na]+ 423.1890, found 423.1901.
1-(N-Benzyloxycarbonylamino)ethyltriphenylphosphonium
Tetrafluoroborate (4d). Colorless crystals, mp 140−142 °C; 1H
NMR (300 MHz, CDCl3) δ 7.80−7.19 (m, 20H), 6.86 (d, J = 9.0 Hz,
1H), 5.65 (ddq, J = 9.0, 6.6, 7.4 Hz, 1H), 4.97 (d, J = 12.3 Hz, 1H),
4.88 (d, J = 12.3 Hz, 1H), 1.72 (dd, J = 17.3, 7.4 Hz, 3H) ppm; 13C
NMR (75.5 MHz, CDCl3) δ 156.1, 135.8, 135.2 (d, J = 2.9 Hz), 134.2
(d, J = 9.2 Hz), 130.3 (d, J = 12.2 Hz), 128.4, 128.0, 127.9, 116.6 (d,
J = 81.2 Hz), 67.3, 46.7 (d, J = 55.0 Hz), 17.4 (d, J = 5.3 Hz) ppm; 31P
NMR (242.8 MHz, CDCl3) δ 27.2 ppm; IR (ATR) 3470, 1703, 1409,
1107 cm−1. Anal. Calcd for C28H27BF4NO2P: C, 63.78; H, 5.16; P,
5.87. Found: C, 63.35; H, 5.23; P, 5.91.
1-(N-Formylamino)ethyltriphenylphosphonium Tetrafluoro-
borate (4e). Colorless crystals, mp 121−122 °C; 1H NMR (300
MHz, CDCl3) δ 8.11 (s, 1H), 7.91−7.67 (m, 16H), 6.05 (ddq, J = 9.3,
7.5, 7.2 Hz, 1H), 1.65 (dd, J = 17.1, 7.2 Hz, 3H) ppm; 13C NMR
(75.5 MHz, CDCl3) δ 162.2, 135.5 (d, J = 2.8 Hz), 134.1 (d, J = 9.4
Hz), 130.6 (d, J = 12.4 Hz), 116.2 (d, J = 82.4 Hz), 41.2 (d, J =
57.7 Hz), 17.2 (d, J = 4.3 Hz) ppm; 31P NMR (121.5 MHz, CDCl3)
δ 27.6 ppm; IR (ATR) 3174, 3009, 1661, 1525, 1438, 1105,
1047 cm−1; HRMS (ESI) calcd for C21H21NOP [M+] 334.1355, found
334.1365.
tert-Butyl N-[2-(1-Benzylimidazol-5-yl)-1-methoxyethyl]-
1
carbamate (7u). Orange oil. H NMR (300 MHz, CDCl3) δ 7.46
1-(N-Benzyloxycarbonylamino)-2-phenylethyltriphenyl-
(br s, 1H), 7.40−7.10 (m, 5H), 6.74 (br s, 1H), 6.13 (d, J = 9.9 Hz, 1H),
5.14−5.05 (m, 1H), 5.05 (s, 2H), 3.34 (s, 3H), 2.89 (d, J = 4.2 Hz, 2H),
1.44 (s, 9H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 155.7, 137.6, 136.7,
136.0, 128.9, 128.2, 127.3, 117.3, 81.6, 79.3, 55.4, 50.8, 33.4, 28.3 ppm; IR
(ATR) 3341, 2981, 2925, 1683, 1519, 1365, 1159, 1091, 1047, 741 cm−1;
HRMS (ESI) calcd for C18H26N3O3 [M+] 332.1969, found 332.1981.
Fluorenylmethyl N-(2-tert-Butoxy-1-methoxypropyl)-
phosphonium Tetrafluoroborate (4g). Colorless crystals, mp
1
152−154 °C; H NMR (300 MHz, CDCl3) δ 7.82−7.09 (m, 25H),
7.03 (d, J = 9.3 Hz, 1H), 5.75−5.63 (m, 1H), 4.86 (d, J = 12.6 Hz,
1H), 4.78 (d, J = 12.6 Hz, 1H), 3.40 (ddd, J = 14.4, 11.1, 8.3 Hz, 1H),
3.14 (ddd, J = 14.0, 4.8, 4.0 Hz, 1H) ppm; 13C NMR (75.5 MHz,
CDCl3) δ 156.3 (d, J = 3.1 Hz), 135.9, 135.3 (d, J = 3.1 Hz), 134.2
(d, J = 9.4 Hz), 130.5 (d, J = 12.2 Hz), 129.1, 128.8, 128.3, 127.8,
127.7, 127.7, 127.5, 116.6 (d, J = 81.3 Hz), 67.1, 52.7 (d, J = 51.5 Hz),
37.0 (d, J = 7.2 Hz) ppm; 31P NMR (242.8 MHz, CDCl3) δ 26.5 ppm;
IR (ATR) 3329, 1720, 1522, 1439, 1236, 1109, 1061 cm−1. Anal. Calcd
for C34H31BF4NO2P: C, 67.68; H, 5.18; P, 5.13. Found: C, 67.49;
H, 5.61; P, 4.71.
carbamate (7v). Orange oil. 1H NMR (300 MHz, CDCl3)a
δ
7.80−7.28b (m, 8H), 5.57c (d, J = 9.6 Hz, 1H) and 5.45c (d, J = 10.5
Hz, 1H), 4.77c (dd, J = 10.2, 2.7 Hz, 1H) and 4.65c (dd, J = 9.8, 1.7
Hz, 1H), 4.60−4.38b (m, 3H), 4.27−4.20b (m, 1H), 3.34c and 3.32c
(s, 3H), 1.21c and 1.19c (s, 9H), 1.09b (d, J = 6.6 Hz, 3H) ppm; 13C
NMR (75.5 MHz, CDCl3) δ 156.6c and 156.1c, 143.9c, 143.8c, 142.9c,
141.3c, 127.6c, 127.2c, 127.0c, 127.0c, 125.0c, 124.7c, 120.1c, 120.0c,
86.0c and 85.0c, 74.1c and 74.0c, 69.0c and 68.1c, 66.7b, 56.0c and 55.4c,
47.2c and 47.1c, 28.5c and 28.4c, 19.5c and 18.1c ppm; IR (ATR) 2974,
2977, 1712, 1495, 1194, 1076, 738 cm−1; HRMS (ESI) calcd for
C23H29NO4Na [M + Na]+ 406.1989, found 406.1995. aTwo dia-
1-(N-Acetylamino)phenylmethyltriphenylphosphonium Tet-
1
rafluoroborate (4h). Colorless crystals, mp 221−222 °C; H NMR
(300 MHz, CDCl3) δ 8.40 (d, J = 9.3 Hz, 1H), 7.90−7.09 (m, 20H),
6.96 (dd, J = 9.8, 9.7 Hz, 1H), 1.99 (s, 3H) ppm; 13C NMR (75.5 MHz,
CDCl3) δ 171.5, 135.3 (d, J = 2.9 Hz), 134.5 (d, J = 9.1 Hz), 130.1 (d,
J = 12.3 Hz), 130.1, 130.0, 129.4, 129.3, 115.8 (d, J = 80.6 Hz), 53.9 (d,
J = 52.6 Hz), 22.2 ppm; 31P NMR (121.5 MHz, CDCl3) δ 24.7 ppm; IR
(ATR) 3341, 3291, 1690, 1520, 1438, 1097, 1054 cm−1; HRMS (ESI)
calcd for C27H25NOP [M+] 410.1668, found 410.1682.
b
stereomers in a molar ratio of 3:2. Overlapping signals of both dia-
c
stereomers. Separate signals from both diasteromers.
1-(N-Acetylamino)methyltriphenylphosphonium Tetrafluoro-
borate (4a). Colorless crystals, mp 169−170 °C; 1H NMR
(300 MHz, CDCl3) δ 7.88−7.66 (m, 16H), 5.06 (dd, J = 6.3, 3.3
Hz, 2H), 1.80 (d, J = 1.2 Hz, 3H) ppm; 13C NMR (75.5 MHz, CDCl3)
δ 171.7, 135.2 (d, J = 2.9 Hz), 133.9 (d, J = 9.8 Hz), 130.2 (d, J = 12.6
Hz), 116.9 (d, J = 84.3 Hz), 36.9 (d, J = 58.3 Hz), 21.9 ppm; 31P NMR
(121.5 MHz, CDCl3) δ 21.0 ppm; IR (ATR) 3383, 1685, 1519, 1438,
1260, 1056, 1017 cm−1. Anal. Calcd for C21H21BF4NOP: C, 59.89; H,
5.03; P, 7.35. Found: C, 59.86; H, 4.76; P, 7.46.
N-(1-Acetylamino)ethyltriphenylphosphonium Tetrafluoro-
borate (4b). Colorless crystals, mp 154−155 °C; 1H NMR (300
MHz, CDCl3) δ 7.87−7.62 (m, 16H), 5.92 (ddq, J = 9.0, 6.9, 7.2 Hz,
1H), 1.86 (d, J = 0.9 Hz, 3H), 1.66 (dd, J = 17.4, 7.2 Hz, 3H) ppm;
13C NMR (75.5 MHz, CDCl3) δ 171.6, 135.3 (d, J = 3.0 Hz), 134.1 (d,
1-(N-Benzyloxycarbonylamino)phenylmethyltriphenylphos-
phonium Tetrafluoroborate (4i). Colorless crystals, mp 177−
1
179 °C; H NMR (300 MHz, CDCl3) δ 7.82−7.04 (m, 26H), 6.64
(dd, J = 9.9, 9.9 Hz, 1H), 4.99 (d, J = 12.3 Hz, 1H), 4.90 (d, J = 12.6
Hz, 1H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 156.2, 135.7, 135.3 (d,
J = 2.9 Hz), 134.6 (d, J = 9.1 Hz), 130.2 (d, J = 12.3 Hz), 129.4, 129.4,
129.2, 129.1, 128.3, 127.9, 127.8, 115.8 (d, J = 80.8 Hz), 67.6, 56.5 (d,
J = 54.0 Hz) ppm; 31P NMR (121.5 MHz, CDCl3) δ 23.9 ppm; IR
(ATR) 3314, 1703, 1526, 1438, 1055, 1011 cm−1; HRMS (ESI) calcd
for C33H29NO2P [M+] 502.1930, found 502.1935.
1-(N-Benzyloxycarbonylamino)-2-methylpropyltriphenyl-
1
phosphonium Tetrafluoroborate (4j). Colorless resin. H NMR
(300 MHz, CDCl3) δ 7.80−7.15 (m, 20H), 7.01 (d, J = 8.7 Hz, 1H),
5.38−5.29 (m, 1H), 4.88 (d, J = 12.6 Hz, 1H), 4.78 (d, J = 12.6 Hz,
1H), 2.73−2.59 (m, 1H), 1.00 (d, J = 6.3 Hz, 3H), 0.89 (d, J = 6.6 Hz,
3H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 156.3, 135.7, 134.8 (d, J =
2.9 Hz), 134.4 (d, J = 9.4 Hz), 130.1 (d, J = 12.3 Hz), 128.3, 127.9,
127.7, 117.9 (d, J = 80.3 Hz), 67.1, 55.7 (d, J = 48.1 Hz), 29.6 (d, J =
6.2 Hz), 21.2 (d, J = 4.7 Hz), 19.2 (d, J = 7.7 Hz) ppm; 31P NMR
(121.5 MHz, CDCl3) δ 27.5 ppm; IR (ATR) 3332, 2970, 1713, 1518,
1438, 1233, 1054 cm−1. Anal. Calcd for C30H31BF4NO2P·H2O: C,
62.84; H, 5.80; P, 5.40. Found: C, 62.63; H, 5.82; P, 5.24.
1-(N-tert-Butoxycarbonylamino)-2-methylpropyltriphenyl-
phosphonium Tetrafluoroborate (4k). Colorless crystals, mp 116−
117 °C; 1H NMR (300 MHz, CDCl3) δ 7.85−7.62 (m, 15H), 6.59 (d,
J = 9.0 Hz, 1H), 5.31 (ddd, J = 8.8, 8.8, 8.8 Hz, 1H), 2.70−2.54 (m, 1H),
1.19 (s, 9H), 0.98 (d, J = 6.6 Hz, 3H), 0.90 (d, J = 6.9 Hz, 3H) ppm;
13C NMR (75.5 MHz, CDCl3) δ 155.5, 134.7, 134.6 (d, J = 9.1 Hz),
J = 9.4 Hz), 130.4 (d, J = 12.3 Hz), 116.7 (d, J = 82.0 Hz), 43.7 (d, J =
55.1 Hz), 22.2, 17.3 (d, J = 4.6 Hz) ppm; 31P NMR (121.5 MHz,
CDCl3) δ 28.1 ppm; IR (ATR) 3257, 3044, 1669, 1536, 1441, 1372,
1304, 1108, 1045 cm−1. Anal. Calcd for C22H23BF4NOP: C, 60.72; H,
5.33; P, 7.12. Found: C, 60.46; H, 5.18; P, 7.32.
1-(N-Pivaloylamino)ethyltriphenylphosphonium Tetrafluo-
1
roborate (4c). Colorless crystals, mp 163−164 °C; H NMR (300
MHz, CDCl3) δ 7.85−7.68 (m, 16H), 5.80 (ddq, J = 7.5, 7.5, 7.5 Hz,
1H), 1.72 (dd, J = 17.6, 7.4 Hz, 3H), 0.91 (s, 9H) ppm; 13C NMR
(75.5 MHz, CDCl3) δ 179.3 (d, J = 2.2 Hz), 134.8 (d, J = 2.9 Hz),
134.3 (d, J = 9.3 Hz), 130.0 (d, J = 12.4 Hz), 117.8 (d, J = 82.0 Hz),
45.1 (d, J = 53.5 Hz), 38.4, 26.6, 17.3 (d, J = 4.5 Hz) ppm; 31P NMR
(242.8 MHz, CDCl3) δ 29.8 ppm; IR (ATR) 3373, 1660, 1511, 1438,
1184, 1053 cm−1. Anal. Calcd for C25H29BF4NOP: C, 62.91; H, 6.12;
P, 6.49. Found: C, 62.88; H, 6.37; P, 6.22.
1958
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Article
130.0 (d, J = 12.2 Hz), 118.7 (d, J = 80.1 Hz), 80.8, 55.1 (d, J =
46.7 Hz), 29.5 (d, J = 6.7 Hz), 27.8, 21.2 (d, J = 4.3 Hz), 19.2 (d, J =
8.0 Hz) ppm; 31P NMR (242.8 MHz, CDCl3) δ 27.7 ppm; IR (ATR)
3346, 2976, 1702, 1508, 1438, 1250, 1154, 1054 cm . Anal. Calcd for
2C27H33BF4NO2P·H2O: C, 61.15; H, 6.46; P, 5.84. Found: C, 61.09;
Hz, 1H), 6.06 (m, 1H), 4.85 (d, J = 12.6 Hz, 1H), 4.76 (d, J = 12.3 Hz,
1H), 3.29−3.06 (m, 2H), 1.23 (s, 9H) ppm; 13C NMR (75.5 MHz,
CDCl3) δ 168.8 (d, J = 8.7 Hz), 156.0, 135.6, 134.8 (d, J = 2.8 Hz),
134.7 (d, J = 9.4 Hz), 130.0 (d, J = 12.4 Hz), 128.4, 128.0, 127.9, 117.3
(d, J = 82.1 Hz), 82.4, 67.2, 47.3 (d, J = 54.7 Hz), 37.1 (d, J = 6.7 Hz),
27.7 ppm; 31P NMR (121.5 MHz, CDCl3) δ 29.1 ppm; IR (ATR)
3329, 2981, 1721, 1523, 1439, 1232, 1051 cm−1; HRMS (FD) calcd for
C33H35NO4P [M+] 540.2304, found 540.2308.
−1
H, 6.30; P, 5.43.
1-(N-Benzyloxycarbonylamino)-3-methylbutyltriphenyl-
phosphonium Tetrafluoroborate (4l). Colorless crystals, mp 93−
94 °C; 1H NMR (300 MHz, CDCl3) δ 7.80−7.19 (m, 20H), 6.90 (d,
J = 9.3 Hz, 1H), 5.64−5.51 (m, 1H), 5.02 (d, J = 12.6 Hz, 1H), 4.87
(d, J = 12.6 Hz, 1H), 2.34−2.20 (m, 1H), 1.98−1.83 (m, 1H), 1.45−
1.32 (m, 1H), 0.95 (d, J = 6.9 Hz, 3H), 0.93 (d, J = 7.2 Hz, 3H) ppm;
13C NMR (75.5 MHz, CDCl3) δ 156.5 (d, J = 3.2 Hz), 135.9, 135.2
(d, J = 2.9 Hz), 134.0 (d, J = 9.2 Hz), 130.3 (d, J = 12.2 Hz), 128.3,
127.9, 127.8, 116.6 (d, J = 81.4 Hz), 67.3, 49.5 (d, J = 53.8 Hz), 39.5
(d, J = 4.3 Hz), 25.3 (d, J = 12.2 Hz), 22.2, 20.8 ppm; 31P NMR (242.8
MHz, CDCl3) δ 26.2 ppm; IR (ATR) 3315, 2957, 1698, 1525, 1344,
1223, 1045 cm−1. Anal. Calcd for 2C31H33BF4NO2P·H2O: C, 64.37;
H, 5.93. Found: C, 64.09; H, 5.96.
N-Benzyloxycarbonyl-2-pyrolidinyltriphenylphosphonium
Tetrafluoroborate (4m). Colorless crystals, mp 88−90 °C; 1H NMR
(300 MHz, CDCl3) δ 7.77−7.07 (m, 20H), 6.15−5.79 (m, 1H), 4.81
(d, J = 12.7 Hz, 1H), 4.73 (d, J = 12.6 Hz, 1H); 3.71−3.56 (m, 1H),
3.31−3.02 (m, 1H), 2.89−2.60 (m, 1H), 2.31−2.07 (m, 1H), 2.07−
1.84 (m, 1H), 1.71−1.40 (m, 1H) ppm; 13C NMR (75.5 MHz,
CDCl3) δ 154.7 (d, J = 1.4 Hz), 135.2, 134.7 (d, J = 2.9 Hz), 134.1 (d,
J = 9.2 Hz), 129.9 (d, J = 12.2 Hz), 128.4, 128.1, 128.0, 117.5 (d, J =
82.5 Hz), 67.7, 55.6 (d, J = 55.3 Hz), 47.9, 30.3, 24.2 ppm; 31P NMR
(242.8 MHz, CDCl3) δ 27.2 ppm; IR (ATR) 3064, 1698, 1485, 1439,
1357, 1191, 1109, 1058 cm−1. HRMS (ESI) calcd for C30H29NO2P
[M+] 466.1930, found 466.1940.
1-(N-Benzyloxycarbonylamino)-3-tert-butoxycarbonylpro-
pyltriphenylphosphonium Tetrafluoroborate (4r). Colorless
1
crystals, mp 84−86 °C; H NMR (300 MHz, CDCl3) δ 7.83−7.19
(m, 20H), 6.79 (d, J = 9.6 Hz, 1H), 5.89−5.75 (m, 1H), 5.01 (d, J =
12.6 Hz, 1H), 4.90 (d, J = 12.3 Hz, 1H), 2.67−2.42 (m, 2H), 2.25−
2.02 (m, 2H), 1.42 (s, 9H) ppm; 13C NMR (75.5 MHz, CDCl3) δ
171.9, 156.5 (d, J = 3.0 Hz), 136.0, 135.1 (d, J = 2.7 Hz), 134.1 (d, J =
9.4 Hz), 130.3 (d, J = 12.4 Hz), 128.3, 127.8, 127.7, 116.5 (d, J = 81.5
Hz), 81.2, 67.2, 48.8 (d, J = 56.8 Hz), 30.1 (d, J = 13.7 Hz), 27.9, 26.1
(d, J = 8.1 Hz) ppm; 31P NMR (121.5 MHz, CDCl3) δ 26.9 ppm; IR
(ATR) 3304, 1717, 1520, 1439, 1230, 1074 cm−1. Anal. Calcd for
C34H37BF4NO4P: C, 63.66; H, 5.81; P, 4.83. Found: C, 63.30; H, 6.14;
P, 5.11.
1-(N-Benzyloxycarbonylamino)-2-(4-benzyloxyphenyl)-
ethyltriphenylphosphonium Tetrafluoroborate (4s). Colorless
1
crystals, mp 139−140 °C; H NMR (300 MHz, CDCl3) δ 7.81−6.78
(m, 29H), 7.00 (d, J = 9.3 Hz, 1H), 5.64 (ddd, J = 19.0, 9.3, 3.2 Hz,
1H), 4.96 (s, 2H), 4.86 (d, J = 12.6 Hz, 1H), 4.78 (d, J = 12.6 Hz, 1H),
3.33 (ddd, J = 14.3, 10.7, 8.9 Hz, 1H), 3.10 (ddd, J = 14.4, 4.2, 4.2 Hz,
1H) ppm; 13C NMR (75.5 MHz, CDCl3) δ 158.1, 156.3 (d, J = 3.4
Hz), 136.8, 135.9, 135.2 (d, J = 2.7 Hz), 134.2 (d, J = 9.4 Hz), 130.4
(d, J = 12.0 Hz), 128.5, 128.3, 127.9, 127.8, 127.6, 127.4, 127.1, 127.0,
116.7 (d, J = 80.5 Hz), 115.2, 69.8, 67.0, 52.8 (d, J = 50.0 Hz), 36.2
(d, J = 7.8 Hz) ppm; 31P NMR (121.5 MHz, CDCl3) δ 26.2 ppm; IR
(ATR) 3139, 1709, 1511, 1439, 1331, 1246, 1057, 1036 cm−1. Anal.
Calcd for C41H37BF4NO3P: C, 69.40; H, 5.26; P, 4.37. Found: C,
69.00; H, 5.48; P, 4.21.
1-(N-Benzyloxycarbonylamino)-2-carbamoylethyltriphenyl-
phosphonium Tetrafluoroborate (4n). Colorless crystals, mp
1
151−152 °C; H NMR (300 MHz, CDCl3) δ 7.84−7.10 (m, 20H),
6.86 (d, J = 9.9 Hz, 1H), 6.85 (s, 1H), 6.11−5.98 (m, 1H), 5.49
(s, 1H), 4.92 (d, J = 12.3 Hz, 1H), 4.80 (d, J = 12.3 Hz, 1H), 3.21
(ddd, J = 15.3, 8.8, 5.8 Hz, 1H), 2.91−2.75 (m, 1H) ppm; 13C NMR
(75.5 MHz, CDCl3) δ 170.2, 155.7 (d, J = 4.2 Hz), 135.6, 135.3 (d, J =
2.9 Hz), 134.4 (d, J = 9.4 Hz), 130.4 (d, J = 12.4 Hz), 128.4, 128.2,
128.1, 116.4 (d, J = 81.7 Hz), 67.6, 48.8 (d, J = 56.9 Hz), 36.4 ppm;
31P NMR (242.8 MHz, CDCl3) δ 27.1 ppm; IR (ATR) 3361, 1722,
1-Benzyl-5-[2-(N-tert-butoxycarbonylamino)-2-triphenylphos-
phonioethyl]imidazolium Ditetrafluoroborate (4u). (Prepared
1
in situ) H NMR (300 MHz, CDCl3) δ 8.62 (br s, 1H), 7.84−7.26
(m, 21H), 6.38 (d, J = 9.0 Hz, 1H), 5.93−5.78 (m, 1H), 5.24 (s, 2H),
3.35−3.21 (m, 2H), 1.08 (s, 9H) ppm; 13C NMR (75.5 MHz, CDCl3)
δ 154.9 (d, J = 3.2 Hz), 135.4, 134.3 (d, J = 9.6 Hz), 132.8, 130.5 (d,
J = 12.4 Hz), 129.3, 129.2, 128.9, 128.7, 128.6, 122.1, 117.8 (d, J = 85.9
Hz), 81.5, 53.4, 48.3 (d, J = 55.1 Hz), 27.6, 26.2 (d, J = 11.2 Hz) ppm;
31P NMR (121.5 MHz, CDCl3) δ 26.2 ppm.
1682, 1525, 1439, 1255, 1108, 1058 cm−1. HRMS (FD) calcd for
C29H28N2O3P [M+] 483.1838, found 483.1814.
1-(N-Benzyloxycarbonylamino)-3-carbamoylpropyltriphe-
nylphosphonium Tetrafluoroborate (4o). Colorless crystals, mp
1
ASSOCIATED CONTENT
* Supporting Information
122−124 °C; H NMR (300 MHz, CD3CN) δ 7.91−7.19 (m, 20H),
■
6.30 (d, J = 9.9 Hz, 1H), 6.23 (s, 1H), 5.98−5.80 (m, 1H), 5.86
(s, 1H), 5.09 (d, J = 12.6 Hz, 1H), 4.97 (d, J = 12.3 Hz, 1H), 2.44−
2.35 (m, 2H), 2.35−2.25 (m, 1H), 1.82−1.67 (m, 1H) ppm; 13C NMR
(75.5 MHz, CD3CN) δ 174.3, 157.4 (d, J = 5.1 Hz), 137.4, 136.4 (d,
J = 3.0 Hz), 135.4 (d, J = 9.5 Hz), 131.1 (d, J = 12.3 Hz), 129.6, 129.2,
128.8, 117.6 (d, J = 82.7 Hz), 68.3, 49.0 (d, J = 60.6 Hz), 30.2, 27.0
ppm; 31P NMR (242.8 MHz, CDCl3) δ 26.3 ppm; IR (ATR) 3367,
S
NMR spectra of N-(1-methoxyalkyl)amides 7c, 7n−7v and 1-(N-
acylamino)alkyltriphenylphosphonium salts 4; IR spectra and 31P
NMR of selected 1-(N-acylamino)alkyltriphenylphosphonium
salts. This material is available free of charge via the Internet at
http://pubs.acs.org.
−1
1716, 1673, 1525, 1439, 1241, 1109, 1058 cm . Anal. Calcd for
AUTHOR INFORMATION
Corresponding Author
*E-mail: roman.mazurkiewicz@polsl.pl; jakub.adamek@polsl.pl.
C30H30BF4N2O3P: C, 61.66; H, 5.17. Found: C, 61.79; H, 5.49.
1-(N-Benzyloxycarbonylamino)-2-tert-butoxyethyltriphenyl-
phosphonium Tetrafluoroborate (4p). Colorless crystals, mp
■
1
146−147 °C; H NMR (300 MHz, CDCl3) δ 7.80−7.11 (m, 20H),
Notes
7.02 (d, J = 9.3 Hz, 1H), 5.83−5.63 (m, 1H), 4.89 (d, J = 12.3 Hz,
1H), 4.76 (d, J = 12.6 Hz, 1H), 4.05 (ddd, J = 10.4, 10.4, 10.4 Hz, 1H),
3.89 (ddd, J = 29.1, 9.0, 5.4 Hz, 1H), 0.78 (s, 9H) ppm; 13C NMR
(75.5 MHz, CDCl3) δ 156.0, 135.6, 134.7 (d, J = 9.5 Hz), 134.6, 129.7
(d, J = 12.5 Hz), 128.3, 128.0, 127.8, 117.9 (d, J = 82.4 Hz), 75.1, 67.2,
59.2, 51.9 (d, J = 51.8 Hz), 26.6 ppm; 31P NMR (242.8 MHz, CDCl3)
δ 32.0 ppm; IR (ATR) 3304, 2981, 1716, 1519, 1438, 1230, 1074
cm−1. Anal. Calcd for C32H35BF4NO3P: C, 64.12; H, 5.89; P, 5.17.
Found: C, 63.83; H, 5.87; P, 4.79.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The financial help of the Ministry of Science and Higher
Education of Poland (Grant No. N N204 165636) is gratefully
acknowledged.
REFERENCES
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■
(1) (a) Zaug, H. E. Synthesis 1970, 49−73. (b) Zaug, H. E. Synthesis
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