P-Triazinylphosphonium chlorides as a new group of coupling reagents

Article abstract of DOI:10.2478/s11532-012-0190-3

Tertiary phosphines in reaction with 2-chloro-4,6-dialkoxy-1,3,5-triazines gave unstable quaternary P-triazinylphosphonium chlorides, which readily decomposed with a departure of the alkyl group of the triazine ring substituent. Stable quaternary P-triazinylphosphonium chlorides were obtained only in reaction of 2-chloro-4,6-diphenoxy-1,3,5-triazine. Both, stable quaternary P-triazinylphosphonium chlorides as well unstable analogues prepared in situ activated carboxylic acid yielding "superactive" triazine esters, useful as highly efficient reagents in peptide bond synthesis.

Full text of DOI:10.2478/s11532-012-0190-3

Cent. Eur. J. Chem. • 11(4) • 2013 • 569-583
DOI: 10.2478/s11532-012-0190-3
Central European Journal of Chemistry
P-Triazinylphosphonium chlorides
as a new group of coupling reagents
Research Article
Beata Kolesinska1*, Agnieszka Mrozek2,
Justyna Fraczyk1, Zbigniew J. Kaminski1
1Institute of Organic Chemistry,
Lodz University of Technology,
90-924 Lodz, Poland
2Institute of General and Environmental Chemistry,
Lodz University of Technology,
90-924 Lodz, Poland
Received 19 May 2012; Accepted 30 November 2012
Abstract:
Tertiary phosphines in reaction with 2-chloro-4,6-dialkoxy-1,3,5-triazines gave unstable quaternary P-triazinylphosphonium chlorides,
which readily decomposed with a departure of the alkyl group of the triazine ring substituent. Stable quaternary P-triazinylphosphonium
chlorides were obtained only in reaction of 2-chloro-4,6-diphenoxy-1,3,5-triazine. Both, stable quaternary P-triazinylphosphonium
chlorides as well unstable analogues prepared in situ activated carboxylic acid yielding “superactive” triazine esters, useful as highly
efficient reagents in peptide bond synthesis.
Keywords: P-triazinylphosphonium chlorides • Dealkylation • Coupling Reagents • 1,3,5-Triazine • Phosphine
© Versita Sp. z o.o.
prepared using unnatural building blocks such as non-
1. Introduction
coded amino acids. In most cases, these advantageous
effects of the incorporation of unnatural moieties into the
peptide chain entail the impossibility of the application
of biological approaches for their preparation, which
need to be replaced with successful chemical synthetic
strategies. Consequently, there is a strong need for
the development of new coupling reagents and more
advanced synthetic strategies. The most promising
approach to rational design of new reagents is based
on reducing size of the fragment participating in the rate
determining step. So far, only a few reagents have been
designed in line with this idea. One of the first and most
promising responses to this problem was the design
of coupling reagents based on the compact, strongly
electron-withdrawing 1,3,5-triazine nucleus. Due to
the presence of a hydrogen bond acceptor fragment
favoring the formation of a cyclic transition state, the
transfer of the acyl group on the amino component is
greatly facilitated even in the case of extremely sterically
hindered substrates. This spectacular increase of the
The arsenal of recently available reagents and coupling
strategies suffices for the successful incorporation of
20 proteinogenic amino acids into the peptide chain
in solution and on a solid support [1]. However, in the
case of their unnatural analogues, or so-called difficult
sequences, the known reagents are often found
insufficient or even fail completely. The most demanding
in this respect is the coincidence of poor reactivity and
steric hindrance in one building block, because the
application of stronger activation and prolonged coupling
time may severely deteriorate the yield and purity of the
final peptide. At present, the main reasons for practicing
this frustrating approach are an expected increase in
the resistance of the unnatural structures to metabolic
degradation, prolonged activity, reduced dosage, and a
more convenient application of peptides showing a broad
range of activity. Many of those employed as insecticides,
contraceptives,
growth
promoters,
metabolism
regulators, agents combating various diseases, etc. are
* E-mail: beata.kolesinska@p.lodz.pl
569

P-Triazinylphosphonium chlorides
as a new group of coupling reagents
Scheme 1. Condensation involving “superactive“ triazine ester 7 via N-triazinylammonium 5 or P-triazinylphosphonium 3 salts.
efficiency of the coupling procedure has been inspiring 4-(4-nitrobenzyl)pyridine (NBP). Melting points were
for the further improvement of triazine-based coupling determined on a Buchi apparatus, model 510. IR
reagents.
spectra were recorded as KBr pellets or film on a Bruker
The crucial transformations in the process of ALPHA spectrometer or a PerkinElmer Spectrum
activation of the carboxylic component with classic 100. 1H-NMR, 13C-NMR and 31P-NMR spectra were
triazine-based reagents are the formation of
a
recorded on a Bruker Avance DPX 250 (250 MHz)
N-triazinylammonium salt followed by the substitution spectrometer. Chemical shifts (ppm) are relative to
of the ammonium leaving group with a carboxylic acid TMS used as an internal standard. The multiplicity
moiety yielding a “superactive” triazine ester [2]. The were marked: s-singlet, d-doublet, t-triplet, q-quartet,
process of developing a new N-triazinylammonium qu-quintet, m-multiplet. Electrospray ionization mass
salt is, however, severely restricted by the sensitivity spectra (ESI-MS) were acquired on a LCQ-Advantage
of the precursors to the steric hindrance effect of the ESI ion trap spectrometer (ThermoFinnigan) for positive
tertiary amine. This in practice reduces the scope of the and negative ions detection. HPLC-ESI-MS (ESI Ion
preparative procedure to aliphatic N,N-dimethylamines Trap LCQ Advantage ThermoFinnigan; equipped
and/or N-methylated cyclic aliphatic amines. One can with a diode array detector) using a Phenomenex
expect that the exchange of the ammonium fragment Aqua C18 column (5 µ m, 150×2.0 mm) (flow rate:
with a phosphonium analogue [3] will provide an 200 µL min-1) with a gradient of 5-95% CH3CN/H2O.
advantageous modification to the reagent structure Analytical HPLC were performed by a Waters 600S
because the lengths of the C-P+ bonds directly engaged instrument using a Phenomenex Jupiter column 5µ
in the activation process are substantially longer than C18 300 Å (250×4.6 mm). The solvent systems used
the C-N+ bonds (see Scheme 1).
were: A (0.1% TFA in H2O) and B (0.1% TFA in CH3CN).
The longer (weaker) C-P+ bond should facilitate the In all experiments, in order to protect oxygen-sensitive
activation of the less reactive carboxylic components, phosphines, reactions were carried out under an inert
leaving intact the benefits of the accelerated acylation of atmosphere (argon). In all cases the used solvents were
the amino-component with “superactive” triazine esters. dried by standard procedures and then by 3 Å molecular
Thus, herein we initiated research on the reaction sieves [4].
of phosphines with 2-chloro-4,6-disubstituted-1,3,5-
triazines.
2.1. Synthesis of tributyl-(4-oxy-6-methoxy-
1,3,5-triazin-2-yl)-phosphonium
(11a). Typical procedure A
salt
2. Experimental procedure
The vigorously stirred and cooled to 0ºC solution of
CDMT (1a) (0.175 g, 1 mmol) in chloroform (5 mL) was
Thin layer chromatographies (TLC) were carried out treated with Bu3P (2a) (0.202 g, 1 mmol). Solution was
on SiO2 (Merck; 60 Å F254) and spots were located stirred at room temperature for 5 days until all CDMT
with: UV light (254 and 366 nm) and 1% ethanolic was consumed (according to TLC disappearing of spot
570

B. Kolesinska et al.
colored with 0.5% solution of NBP in ethanol). Solvent calcd.: C 68.21%, H 4.68%, N 10.85%, P 8.00%: found:
was evaporated under reduced pressure. To the solid C 68.42%, H 4.55%, N 10.80%, P 7.95%.
residue was added hexane (5 mL) and the mixture
2.4. Synthesis of triphenyl-(4-oxy-6-methoxy-
was stirred using a magnetic bar for 30 min, after
1,3,5-triazin-2-yl)-phosphonium
salt
which the hexane layer was removed. The procedure
was repeated three times yielding tributyl-(4-oxy-6-
methoxy-1,3,5-triazin-2-yl)-phosphonium salt (11a)
(0.108 g, 33%), mp = 127-131ºC, lit. mp = 166-168ºC
[5]. 31P-NMR (CDCl3): δ = 32.27 [ppm]. 1H-NMR (CDCl3):
δ = 0.79 (t, 3 x 3H, J = 7 Hz, -CH2-CH3); 1.32-1.54 (m,
3 x 4H, -CH2-CH2-CH3); 2.00-2.76 (t, 3 x 2H, J = 6.5 Hz,
-P-CH2-); 3.83 (s, 3H, -OCH3) [ppm]. 13C-NMR (CDCl3):
δ =12.9, 23.2, 26.4. 27.4. 55.7, 149.3, 170.4, 171.4
[ppm]. IR (film): ν = 3206.0, 2957.5, 2933.0, 2872.3,
2801.5, 1752.4, 1710.0, 1562.0. 1464.5, 1414.7,
1360.8, 1230.3, 1139.4, 1043.8, 969.5, 902, 808.9,
768.6 [cm-1]. ESI-MS m/z: 329.4 [M+H]+. Analysis: for
C16H30N3O2P (327.41): calcd.: C 58.70%, H 9.24%, N
12.83%, P 9.46%; found: C 56.33%, H 9.30%, N 12.82%,
P 9.42%.
(11b) in CHCl3 according to procedure B
Starting materials: CDMT (0.175 g, 1 mmol), PPh3 (2b)
(0.262 g, 1 mmol), CHCl3 (5 mL). After 4 hours triphenyl-
(4-oxy-6-methoxy-1,3,5-triazin-2-yl)-phosphonium salt
(11b) was obtained (0.306 g, 79%). Spectroscopically
product was identical with described above.
2.5. Synthesis of tributyl-(4-oxy-6-benzyloxy-
1,3,5-triazin-2-yl)-phosphonium
salt
(11c) in CHCl3 according to procedure A
Starting materials: 2-chloro-4,6-dibenzyloxy-1,3,5-
triazine (1b) (6.560 g, 20 mmol), Bu3P (2a) (4.040 g,
20 mmol), CHCl3 (50 mL). After 7 days tributyl-(4-oxy-
6-benzyloxy-1,3,5-triazin-2-yl)-phosphonium salt (11c)
(2.100 g, 26%) was obtained, mp = 136-138ºC, lit. mp
= 166-169ºC [5]. 31P-NMR (CDCl3): δ = 26.91 [ppm]. 1H-
NMR (CDCl3): δ = 0.91 (t, 3 x 3H, J = 7.8 Hz, -CH2-CH3);
1.34-1.57 (m, 3 x 4H, -CH2-CH2-CH2-); 3.00 (t, 3 x 2H, J
= 6.6 Hz, -CH2-CH2-); 5.53 (s, 2H, -O-CH2-); 7.23-7.50
(m, 5H, -CH2-C6H5) [ppm]. 13C-NMR (CDCl3): δ = 13.6,
23.4, 26.4, 27.1, 68.8, 127.3, 130.3, 131.2, 135.2, 169.7,
170.8, 173.0 [ppm]. IR (film): ν = 2957.8, 2932.9, 2871.8,
2802.2, 1752.3, 1711.4, 1557.9, 1455.6, 1410.0, 1339.3,
1229.7, 1132.4, 1046.9, 1027.7, 969.1, 902.9, 820.8,
767.0, 733.7, 697.4 [cm-1]. ESI-MS m/z: 405.0 [M+H]+.
Analysis: for C22H34N3O2P (403.51): calcd.: C 65.49%, H
8.49%, N 10.41%, P 7.68%; found: C 65.32%, H 8.41%,
N 10.38%, P 7.72%.
2.2. Synthesis of tributyl-(4-oxy-6-methoxy-
1,3,5-triazin-2-yl)-phosphonium
salt
(11a) in CHCl3. Typical procedure B
To the vigorously stirred solution of CDMT (1a)
(0.175 g, 1 mmol) in chloroform (5 mL) Bu3P (2a)
(0.202 g, 1 mmol) was added and the solution was
refluxed until all CDMT was consumed (according to
TLC disappearing of spot colored with 0.5% solution of
NBP in ethanol). Solvent was evaporated under reduced
pressure. To the solid residue was added hexane (5 mL)
and the mixture was stirred using a magnetic bar for
30 min after which the hexane layer was removed. The
procedure was repeated three times, yielding tributyl-
(4-oxy-6-methoxy-1,3,5- triazin-2-yl)-phosphonium salt
(11a) (0.209 g, 64%) spectroscopically identical with
product described above.
Isolation of benzyl chloride
The hexane extract were collected and washed with
water, 1M aqueous KHSO4, and water, dried with CaCl2,
filtered and solvent was evaporated under reduced
pressure. The remaining liquid was distilled yielding
benzyl chloride (1.723 g, 68%); b.p = 176°C [6] b.p. =
174°C; nD20 = 1.5390 [7] nD20 = 1.3910. 1H-NMR (CDCl3):
δ = 4.55 (2H, s, H2C); 7.33 (5H, br s, C6H5) [ppm]. ESI-
MS m/z: 127.8 [M+H]+.
2.3. Synthesis of triphenyl-(4-oxy-6-methoxy-
1,3,5-triazin-2-yl)-phosphonium
salt
(11b) in THF according to procedure A
Starting materials: CDMT (0.175 g, 1 mmol), PPh3 (2b)
(0.262 g, 1 mmol), THF (5 mL). After 5 days triphenyl-
(4-oxy-6-methoxy-1,3,5-triazin-2-yl)-phosphonium salt
(11b) was obtained (0.159 g, 41%), mp = 83-87ºC, lit.
mp. 247-260ºC [5]. 31P-NMR (CD3CN): δ = 13.7 [ppm].
1H-NMR (CD3CN): δ = 3.91 (s, 3H, -OCH3); 7.45-7.96
(m, 15H, -P-(C6H5)3) [ppm]. 13C-NMR (CD3CN): δ = 55.1,
116.5, 117.9, 120.1, 129.8, 156.9, 157.9, 159.2 [ppm].
IR (film): ν = 3057.2, 2922.4, 2853.3, 1682.4, 1617.5,
1470.3, 1435.7, 1393.3, 1361.3, 1187.8, 1114.9, 996.4,
899.7, 791.0, 747.2, 719.0, 690.7 [cm-1]. ESI-MS m/z:
389.4 [M+H]+. Analysis: for C22H18N3O2P (387.38):
2.6. Synthesis of tributyl-(4-oxy-6-benzyloxy-
1,3,5-triazin-2-yl)-phosphonium
salt
(11c) in CHCl3 according to procedure B
Starting materials: 2-chloro-4,6-dibenzyloxy-1,3,5-
triazine (1b) (0.328 g, 1 mmol), Bu3P (2a) (0.202 g,
1 mmol), CHCl3 (5 mL). After 20 hours tributyl-(4-
oxy-6-benzyloxy-1,3,5-triazin-2-yl)-phosphonium
salt (11c) (0.294 g, 73%) was obtained. Product was
spectroscopically identical with the sample described
above.
571

P-Triazinylphosphonium chlorides
as a new group of coupling reagents
10.63%, P 7.83%; found: C 51.66%, H 7.41%, F 14.40%,
N 10.65%, P 7.85%.
2.7. Synthesis of triphenyl-(4-oxy-6-benzyloxy-
1,3,5-triazin-2-yl)-phosphonium salt (11d)
in CHCl3 according to procedure A
2.10.
Synthesis of triphenyl-(4-oxy-6-(2,2,2-
trifluoro-ethoxy)-1,3,5-triazin-2-yl)-
phosphonium salt (11f) in CH2Cl2
according to procedure A
Starting materials: 2-chloro-4,6-dibenzyloxy-1,3,5-
triazine (1b) (0.328 g, 1 mmol), PPh3 (2b) (0.262 g,
1 mmol), CHCl3 (5 mL). After 7 days triphenyl-(4-oxy-
6-benzyloxy-1,3,5-triazin-2-yl)-phosphonium salt (11d)
(0.283 g, 61%) was obtained, mp = 224-225ºC, lit. mp
= 224-227ºC [5]. 31P-NMR (CD3CN): δ = 23.01 [ppm].
1H-NMR (CD3CN): δ = 5.49 (s, 2H, -O-CH2-Ph); 7.10-
7.84 (m, 20H, -(CH2-C6H5) + -P(C6H5)3) [ppm]. 13C-NMR
(CD3CN): δ = 71.1, 126.8, 127.8, 129.5, 131.2, 131.5,
131.8, 133.4, 134.8, 163.0, 170.0, 170.9 [ppm]. IR (film):
ν = 3059.6, 3032.1, 2785.8, 1694.2, 1568.7, 1541.4,
1434.9, 1339.8, 1309.1, 1177.3, 1115.9, 1089.7, 995.6,
821.4, 749.0, 719.1, 691.6 [cm-1]. ESI-MS m/z: 464.5
[M+H]+. Analysis: for C28H22N3O2P (463.48): calcd.: C
72.56%, H 4.78%, N 9.07%, P 6.68%; found: C 72.48%,
H 4.80%, N 9.09%, P 6.70%.
Starting materials: 2-chloro-4,6-bis-(2,2,2-trifluoro-
ethoxy)-1,3,5-triazine (1c) (0.312 g, 1 mmol), PPh3 (2b)
(0.262 g, 1 mmol), CH2Cl2 (5 mL). After 2 days triphenyl-
(4-oxy-6-(2,2,2-trifluoro-ethoxy)-1,3,5-triazin-2-yl)-
phosphonium salt (11f) (0.320 g, 70%) was obtained
as a colorless oil. 31P-NMR (CD3CN): δ = 13.7 [ppm].
1H-NMR (CD3CN): δ = 5.06 (q, J3H-F = 8.5 Hz, 4H, CF3-
CH2) 7.45-8.26 (m, 15H, -P-(C6H5)3) [ppm]. 13C-NMR
(CD3CN) δ = 64.5, 122.3, 125.6, 127.8, 129.5, 131.2,
171.9, 173.5, 175.1 [ppm]. IR (film): ν = 3057.1, 3030.6,
2788.9, 1697.1, 1569.5, 1542.8, 1433.8, 1337.1, 1312.7,
1179.1, 1116.0, 1088.2, 996.8, 823.6, 748.9, 717.8,
691.3 [cm-1]. ESI-MS m/z: 456.4 [M+H]+. Analysis: for
C23H17F3N3O2P (455.38): calcd.: C 60.67%, H 3.76%, F
12.52%, N 9.23%, P 6.80%; found: C 60.63%, H 3.79%,
F 12.50%, N 9.19%, P 6.82%.
2.8. Synthesis of triphenyl-(4-oxy-6-benzyloxy-
1,3,5-triazin-2-yl)-phosphonium salt (11d)
in CHCl3 according to procedure B
Starting materials: 2-chloro-4,6-dibenzyloxy-1,3,5-
triazine (1b) (0.328 g, 1 mmol), PPh3 (2b) (0.262 g,
1 mmol), CHCl3 (5 mL). After 8 hours triphenyl-(4-
oxy-6-benzyloxy-1,3,5-triazin-2-yl)-phosphonium
2.11.
Synthesis of tributyl-(4-oxy-6-(2-ethoxy-
ethoxy)-1,3,5-triazin-2-yl)-phosphonium
salt (11g) in CH2Cl2 according to
procedure A
salt (11d) (0.459 g, 99%) was obtained as
a
product spectroscopically identical with described
above.
Starting materials: 2-chloro-4,6-bis-(2-ethoxy-ethoxy)-
1,3,5-triazine (1d) (5.840 g, 20 mmol), Bu3P (2a)
(4.040 g, 20 mmol), CH2Cl2 (50 mL). After 2 days
tributyl-(4-oxy-6-(2-ethoxy-ethoxy)-1,3,5-triazin-2-yl)-
phosphonium salt (11g) (5.480 g, 71%) was obtained
as a colorless oil. 31P-NMR (CDCl3): δ = 29.27 [ppm].
1H-NMR (CDCl3): δ = 0.91 (t, 3 x 3H, J = 7 Hz, -CH3);
1.05 (t, 3H, J = 7.5 Hz, CH3-CH2O); 1.36-1.54 (m, 3 x
4H, -CH2-CH2-); 2.98 (t, 3 x 2H, J = 6.5 Hz, -P-CH2-);
3.45 (q, 2H, J = 7.5 Hz, –O-CH2-); 3.61 (t, 2H, J = 5.8 Hz,
–CH2-O-); 4.21 (t, 2H, J = 5.8 Hz, -O-CH2-) [ppm]. 13C-
NMR (CDCl3): δ = 13.3, 14.9. 22.5, 23.4, 27.1, 65.5, 66.5,
67.9, 140.0, 171.0, 171.7 [ppm]. IR (film): ν = 3203.7,
3054.0, 2960.1, 2873.9, 2831.2, 2779.7, 1777.3, 1753.7,
1688.8, 1455.9, 1414.0, 1060.0, 1049.9, 838.2, 776.3,
756.6, 737.5, 690.2 [cm-1]. ESI-MS m/z: 388 [M+H]+.
Analysis: for C19H36N3O3P (385.49): calcd.: C 59.20%, H
9.41%, N 10.90%, P 8.03%; found: C 59.15%, H 9.45%,
N 10.88%, P 8.05%.
2.9.
Synthesis of tributyl-(4-oxy-6-(2,2,2-
trifluoro-ethoxy)-1,3,5-triazin-2-yl)-
phosphoniumsalt(11e)inCH2Cl2according
to procedure A
Starting materials: 2-chloro-4,6-bis-(2,2,2-trifluoro-
ethoxy)-1,3,5-triazine (1c) (0.312 g, 1 mmol), Bu3P (2a)
(0.202 g, 1 mmol), CH2Cl2 (5 mL). After 2 days tributyl-
(4-oxy-6-(2,2,2-trifluoro-ethoxy)-1,3,5-triazin-2-yl)-
phosphonium salt (11e) (0.301 g, 76%) was obtained
as a colorless oil. 31P-NMR (CDCl3): δ = 32.27 [ppm].
1H-NMR (CDCl3): δ = 0.91 (t, 3 x 3H, J = 7 Hz, -CH3);
1.42-1.54 (m, 3×4, -CH2-CH2-); 2.97 (7, 3 x 2H,
J = 7.2 Hz, -P-CH2-) 4.46-4.51 (m, 2H, CH2); 5.07 (q,
J3H-F =8.4 Hz, 4H, CF3-CH2) [ppm]. 13C-NMR (CD3CN)
δ = 12.9, 23.2, 26.4. 27.4, 64.5, 122.3, 171.3, 173.7
[ppm]. IR (film): ν = 3044.1, 3030.0, 2781.8, 1695.7,
1569.1, 1545.7, 1438.1, 1336.8, 1304.9, 1175.2, 1114.9,
1087.9, 992.1, 828.0, 749.0, 716.2, 691.8 [cm-1]. ESI-
MS m/z: 396.5 [M+H]+. Analysis: for C17H29F3N3O2P
(455.38): calcd.: C 51.64%, H 7.39%, F 14.41%, N
Isolation of 2-chloroethyl-ethyl ether
The hexane extract were collected and washed with
water, 1 M aqueous KHSO4, and water, dried with CaCl2,
filtrated and solvent was evaporated under reduced
572

B. Kolesinska et al.
pressure. The remaining liquid was distilled yielding
2-chloroethyl-ethyl ether
2.14. Synthesis of of bis-triphenyl-(2-oxo-
1,3,5-triazin-4,6-di-yl) phosphonium salt
(11l) in CH2Cl2 according to procedure A
(1.194 g, 55%); b.p = 106°C, lit. [8] b.p. = 107°C;
20
20
nD = 1.392, lit. [8] nD = 1.411. 1H-NMR (CDCl3):
δ = 1.71 (3H, t, J = 6.5 Hz, CH3-CH2-O); 3.45 (2H, q, J
= 6.5 Hz, CH3-CH2-O); 3.66 (2H, t, J = 7.0 Hz, Cl-CH2-
CH2-O); 3.91 (2H, t, J = 7.0 Hz, Cl-CH2-CH2-O) [ppm].
ESI-MS m/z: 109.6 [M+H]+.
Starting materials: 2,4-dichloro-6-methoxy-1,3,5-triazine
(1e) (0.180 g, 1 mmol), PPh3 (2b) (0.524 g, 2 mmol),
CH2Cl2 (5 mL). After 1 day bis-triphenyl-(2-oxo-1,3,5-
triazin-4,6-di-yl)-phosphonium salt (11l) was obtained,
(0.230 g, 37%) mp = 210 - 215ºC. 31P-NMR (CDCl3):
1
δ = 12.15 [ppm]. H-NMR (CDCl3): δ = 7.90-7.32 (m,
2.12.
Synthesis of triphenyl-(4-oxy-6-(2-
ethoxy-ethoxy)-1,3,5-triazin-2-yl)-
phosphonium salt (11h) in CH2Cl2
according to procedure A
30H, (C6H5)3P)2-) [ppm]. 13C-NMR (CDCl3): δ = 118.1,
128.3, 130.6, 134.5, 149.4, 156.3 [ppm]. IR (film):
ν = 3213.3, 3056.6, 2831.7, 1777.7, 1698.8, 1617.0,
1589.7, 1483.7, 1436.6, 1400.8, 1359.6, 1310.8, 1181.6,
1117.5, 1070.5, 995.6, 899.1, 856.3, 846.7, 790.1,
747.1, 718.9, 691.1 [cm-1]. ESI-MS m/z: 620.1 [M+H]+.
Analysis: for C39H30N3OP2 (618.64): calcd C 75.72%,
H 4.89%, N 6.79%, P 10.01%; found: C 75.74%, H
4.90%, N 6.78%, P 10.03%.
Starting materials: 2-chloro-4,6-bis-(2-ethoxy-ethoxy)-
1,3,5-triazine (1d) (0.292 g, 1 mmol), PPh3 (2b)
(0.262 g, 1 mmol), CH2Cl2 (5 mL). After 2 days
triphenyl-(4-oxy-6-(2-ethoxy-ethoxy)-1,3,5-triazin-2-yl)-
phosphoniumsalt(11h)(0.304g, 68%)wasobtainedasa
colorless oil. 31P-NMR (CDCl3): δ = 34.27 [ppm]. 1H-NMR
(CDCl3): δ = 1.07 (t, 3H, J = 7.5 Hz, -CH3); 3.48 (q, 2H,
J = 7.5 Hz, –O-CH2-); 3.62 (t, 2H, J = 5.8 Hz, –CH2-O-);
4.25 (t, 2H, J = 5.8 Hz, -O-CH2-); 7.45-8.26 (m, 15H,
-P-(C6H5)3) [ppm]. 13C-NMR (CDCl3): δ = 14.9, 63.5,
65.5, 70.7, 125.5, 127.8, 129.5, 131.2, 171.9, 173.5,
175.1 [ppm]. IR (film): ν = 3214.8, 3057.2, 2975.7,
288.3, 1704.6, 1589.8, 1483.8, 1436.2, 1406.6, 1156.5,
1117.5, 1069.6, 996.6, 747.2, 720.1, 691.1 [cm-1]. ESI-
MS m/z: 447 [M+H]+. Analysis: for C25H24N3O3P (445.46):
calcd.: C 67.41%, H 5.43%, N 9.43%, P 6.95%; found:
C 67.43%, H 5.42%, N 9.44%, P 6.97%.
2.15.
Synthesis of tributyl-(4,6-diphenoxy-
1,3,5-triazin-2-yl)-phosphonium chloride
(3k)
To the vigorously stirred solution of 2-chloro-4,6-
diphenoxy-1,3,5-triazine (1f) (0.300 g, 1 mmol) in DCM
(5 mL) at room temperature was added Bu3P (2a)
(0.202 g, 1 mmol). The solution was stirred until
2-chloro-4,6-diphenoxy-1,3,5-triazine was consumed
(according to TLC disappearing of spot developed
with 0.5% solution of NBP in ethanol). Solvent was
evaporated under reduced pressure. To the solid residue
was added hexane (5 mL) and the mixture was stirred
using a magnetic bar for 30 min, after which the hexane
layer was removed. The procedure was repeated three
times, yielding tributyl-(4,6-diphenoxy-1,3,5-triazin-
2-yl)-phosphonium chloride (3k) (0.342 g, 68%) as a
2.13.
Synthesis of bis-tributyl-(2-oxo-1,3,5-
triazin-4,6-di-yl) phosphonium salt (11k)
in CH2Cl2 according to procedure A
Starting
materials:
2,4-dichloro-6-methoxy-1,3,5-
1
colorless oil. 31P-NMR (CD3CN): δ = 35.20 [ppm]. H-
triazine (1e) (0.180 g, 1 mmol), Bu3P (2a) (0.404 g,
2 mmol), CH2Cl2 (5 mL). After 1 day bis-tributyl-(2-
oxo-1,3,5-triazin-4,6-di-yl) phosphonium salt (11k)
(0.446 g, 89%) was obtained as a colorless oil. 31P-NMR
(CDCl3): δ = 11.10 [ppm]. 1H (CDCl3): δ = 0.83 (t, 18 H,
J = 5 Hz, -CH2-CH3); 1.03-1.20 (m, 24 H, -CH2-CH2-
CH3); 2.32 (broad t, 12H, -P-CH2-) [ppm]. 13C (CDCl3):
δ = 13.7, 23.7, 25.7, 27.4, 146.8, 149.7 [ppm]. IR (film):
ν = 3207.3, 3056.0, 2959.7, 2933.2, 2872.0, 2831.6,
1979.7, 1754.7, 1709.3, 1621.6, 1589.5, 1482.7, 1463.8,
1436.0, 1400.9, 1309.6, 1189.8, 1180.3, 1117.8, 1068.5,
996.2, 749.5, 718.6, 691.4 [cm-1]. ESI-MS m/z: 501.2
[M+H]+. Analysis: for C27H54N3OP2 (498.70): calcd.:
C 65.03%, H 10.91%, N 8.43%, P 12.42%; found:
C 65.04%, H 10.90%, N 8.44%, P 12.43%.
NMR (CD3CN ): δ = 0.95 (t, 3 x 3H, J = 7.5 Hz, -CH2-
CH3); 1.33-1.55 (m, 3 x 4H, -CH2-CH2-CH2-); 2.31 (t, 3 x
2H, J = 6.8 Hz, -CH2-CH2-); 7.28-7.49 (m, 10H, -O-C6H5)
[ppm]. 13C-NMR (CD3CN ): δ = 13.6, 23.5, 25.6, 27.3,
122.2, 126.8; 129.7, 130.0, 165.6, 172.3 [ppm]. ESI-MS
m/z: 468.5 [M+H]+.
2.16.
Synthesis of triphenyl-(4,6-diphenoxy-
1,3,5-triazin-2-yl)-phosphonium chloride
(3l)
To the vigorously stirred solution of 2-chloro-4,6-
diphenoxy-1,3,5-triazine (1f) (0.300 g, 1 mmol) in CH2Cl2
(5 mL) at room temperature was added Ph3P (2b)
(0.262 g, 1 mmol). Solution was stirred until 2-chloro-
573

P-Triazinylphosphonium chlorides
as a new group of coupling reagents
4,6-diphenoxy-1,3,5-triazine was consumed. Solvent solution was diluted with CH2Cl2 (5 mL) and washed
was evaporated under reduced pressure. To the solid successively with water, 0.5 M aqueous NaHSO4, water,
residue was added hexane (5 mL) and the mixture was 0.5 M aqueous NaHCO3, and water again. The organic
stirred using a magnetic bar for 30 min, after which layer was dried with MgSO4, filtered, and concentrated
the hexane layer was removed. The procedure was to dryness. The residue was dried under vacuum
repeated three times, yielding triphenyl-(4,6-diphenoxy- with P2O5 and KOH to constant weight yielding 2-(4-
1,3,5-triazin-2-yl)-phosphonium chloride (3l) (0.275 g, methoxybenzoyloxy)-4,6-diphenoxy-1,3,5-triazine (7f)
49%) as a colorless oil. 31P-NMR (CDCl3): δ = 22.45 (0.291 g, 70%). 1H-NMR (CDCl3): δ = 3.91 (s, 3H, CH3O-
1
[ppm]. H-NMR (CDCl3): δ = 6.40-7.79 (m, 25H, (C6H5- C6H4-); 6.98 (d, 2H, J = 8 Hz, CH-CCOO-); 7.17-7.68
O-)2 + (C6H5)3-P) [ppm]. 13C-NMR (CDCl3): δ = 116.1, (m, 10 H, C6H5-O-); 7.71 (d, 2H, J = 8 Hz, CH3OC-CH-)
120.9, 122.2, 126.8; 129.7, 130.0, 131.4, 133,0, 165.6, [ppm]. 13C-NMR (CDCl3): δ = 55.3, 113.3, 120.2, 125.7;
172.3 [ppm]. ESI-MS m/z: 550.4 [M+Na]+.
128.7, 130.1, 132.9, 133.3, 134.7, 164.4, 170.6, 172.9
[ppm]. IR (film/NaCl): ν = 3015, 2975, 2860, 1790, 1745,
1666, 1555, 1544, 1511, 1455, 1444, 1343, 1301, 1229,
1201, 1188, 1173, 1133, 1102, 1080, 1031, 1010 [cm-1].
ESI-MS m/z: 438.4 [M+Na]+.
2.17.
Synthesis of 2-(4-methoxybenzoyloxy)-
4,6-dimethoxy-1,3,5-triazine
Typical Procedure
(7a).
Solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (1a)
(0.175 g, 1 mmol) and Bu3P (2a) (0.202 g, 1 mmol)
in CH2Cl2 (5 mL) was stirred at room temperature.
After 60 minutes 4-methoxybenzoic acid (6a) (0.152 g,
1 mmol) and DIPEA (0.16 mL, 1 mmol) were added and
stirringwascontinuedovernight.Thesolutionwasdiluted
with CH2Cl2 (5 mL), and then washed successively with
water, 0.5 M aqueous KHSO4, water, 0.5 M aqueous
NaHCO3, and water again. The organic layer was dried
with MgSO4, filtered and concentrated to dryness. The
residue was dried under vacuum with P2O5 and KOH
to constant weight yielding 2-(4-methoxybenzoyloxy)-
4,6-dimethoxy-1,3,5-triazine (7a) (0.250 g, 86%),
2.19. Synthesis of 4-methoxybenzoic acid 4,6-
diphenoxy-1,3,5-triazin-2-yl ester (7f)
using (4,6-diphenoxy-1,3,5-triazin-2-yl)-
triphenyl-phosphonium chloride (3l)
Strating
materials:
(4,6-diphenoxy-1,3,5-triazin-2-
yl)-triphenylphosphonium chloride (3l) (0.562 g,
1 mmol), 4-methoxybenzoic acid (9) (0.152 g, 1 mmol),
DIPEA (0.16 mL, 1 mmol), DCM (5 mL). Product: 2-(4-
methoxybenzoyloxy)-4,6-diphenoxy-1,3,5-triazine (7f)
(0.237 g, 57%). Product was spectroscopically identical
with described above.
1
2.20.
mp = 86-88ºC, lit. mp = 83-85ºC [2]. H-NMR (CDCl3):
Synthesis
of
4-methoxy-N-p-
δ = 3.85 (s, 3H, OCH3); 4.00 (s, 6H, OCH3); 6.99 (d,
2H, J = 7.5 Hz, C6H4-); 8.09 (d, 2H, J = 7.5 Hz, C6H4-)
[ppm]. 13C-NMR (CDCl3): δ = 55.6, 55.9, 113.9, 120.1,
132.8, 161.9, 164.4, 170.8, 173.1 [ppm]. IR (film/NaCl):
ν = 3009, 2955, 2871, 1788, 1750, 1678, 1556, 1541,
1516, 1466, 1449, 1353, 1307, 1225, 1202, 1189, 1171,
1130, 1107, 1082, 1036, 1010 [cm-1]. ESI-MS m/z: 314.0
[M+Na]+.
tolylbenzamide (9a) by using in situ
prepared (4,6-dimethoxy-1,3,5-triazin-2-
yl)-triphenyl-phosphonium chloride (3b).
Typical procedure
Solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (1a)
(0.175 g, 1 mmol) and PPh3 (2b) (0.262 g, 1mmol) in
CH2Cl2 (5 mL) was stirred at room temperature. After
60 minutes 4-methoxybenzoic acid (6a) (0.152 g,
1 mmol) and DIPEA (0.16 mL, 1 mmol) were added
and stirring was continued 6 hours. According to TLC
spot of (4,6-dimethoxy-1,3,5-triazin-2-yl)-triphenyl-
phosphonium chloride disappeared and spot of 2-(4-
methoxybenzoyloxy)-4,6-dimethoxy-1,3,5-triazine
developed (Rf = 0.2). p-Toluidine (0.107 g, 1 mmol) (8a)
was added, and the mixture was stirred overnight at
room temperature. The solution was diluted with CH2Cl2
(5 mL) and then washed successively with water, 0.5 M
aqueous NaHSO4, water, 0.5 M aqueous NaHCO3, and
water again. The organic layer was dried with MgSO4,
filtered, and concentrated to dryness. The residue was
dried under vacuum with P2O5 and KOH to constant
2.18.
Synthesis of 4-methoxybenzoic acid
4,6-diphenoxy-1,3,5-triazin-2-yl ester
(7f) using tributyl-(4,6-diphenoxy-1,3,5-
triazin-2-yl)-phosphonium chloride (3k)
Tostirredsolutionoftributyl-(4,6-diphenoxy-1,3,5-triazin-
2-yl)-phosphonium chloride (3k) (0.502 g, 1 mmol),
in CH2Cl2 (5 mL) 4-methoxybenzoic acid (9) (0.304 g,
2 mmol) and DIPEA (0.16 mL, 1 mmol) were added.
Stirring was continued until all (4,6-diphenoxy-1,3,5-
triazin-2-yl)-triphenyl-phosphonium
chloride
was
consumed (disappearing of spot of 4,6-diphenoxy-
1,3,5-triazin-2-yl)-triphenyl-phosphonium chloride). The
574

B. Kolesinska et al.
weight yielding 4-methoxy-N-p-tolyl-benzamide (9a) solution was diluted with CH2Cl2 (5 mL) and was washed
(0.174 g, 72%), mp 143-145ºC, lit. mp 145-148ºC successively with water, 0.5 M aqueous NaHSO4, water,
[9]. HPLC: gradient 50-100%B, 20 min: Rt = 10.92 0.5 M aqueous NaHCO3, and water again. The organic
min, 79%. IR (NaCl/film):ν = 3344, 2960, 1648, 1604, layer was dried with MgSO4, filtered, and concentrated
1524,1248,1032, 760, 656 [cm-1]. 1H-NMR (CDCl3): to dryness. The residue was dried under vacuum with
δ = 2.34 (s, 3H, CH3C6H4-); 3.87 (s, 3H, -COO-CH3); P2O5 and KOH to constant weight yielding 4-methoxy-N-
6.94-6.99 (d, 2H, J = 8 Hz, C6H4-); 7.17 (d, 2H, J = 7.5 p-tolylbenzamide (9a) (0.070 g, 29%) spectroscopically
Hz, C6H4-); 7.51 (d, 2H, J = 7.5 Hz, C6H4-); 7,81-7.87 (t, identical with described above. HPLC: gradient 50-
2H, J = 8 Hz, C6H4-) [ppm].
100%B, 20 min: Rt = 10.93 min, 85%.
2.21.
Synthesis
of
4-methoxy-N-p-
2.23.
Synthesis
of
4-methoxy-N-p-
tolylbenzamide (9a) by using in situ
prepared tributyl-(4,6-dimethoxy-1,3,5-
triazin-2-yl)-phosphonium chloride (3a).
Typical procedure
tolylbenzamide (9a) by using tributyl-
(4,6-diphenoxy-1,3,5-triazin-2-yl)-
phosphonium chloride (3k)
Starting
materials:
tributyl-(4,6-diphenoxy-1,3,5-
Solution of 2-chloro-4,6-dimethoxy-1,3,5-triazine (1a) triazin-2-yl)-phosphonium chloride (3k) (0.502 g,
(0.175 g, 1 mmol) and Bu3P (2a) (0.202 g, 1 mmol) 1 mmol), 4-methoxybenzoic acid (6a) (0.152 g, 1 mmol),
in CH2Cl2 (5 mL) was stirred at room temperature. p-toluidine (8a) (0.214 g, 2 mmol), DIPEA (0.32 mL,
After 60 minutes 4-methoxybenzoic acid (0.152 g,
2
mmol). Product: 4-methoxy-N-p-tolyl-benzamide
1 mmol) (6a) and DIPEA (0.16 mL, 1 mmol) were added (9a) (0.099 g, 41%) spectroscopically identical with
and stirring was continued for 6 hours. According to described above. HPLC: gradient 50-100%B, 20 min:
TLC spot of tributyl-(4,6-dimethoxy-1,3,5-triazin-2-yl)- Rt = 10.92 min, 84%.
phosphonium chloride disappeared and spot of 2-(4-
methoxybenzoyloxy)-4,6-dimethoxy-1,3,5-triazine
3. Results and discussion
developed (Rf = 0.2). p-Toluidine (0.107 g, 1 mmol) (8a)
was added, and the mixture was stirred overnight at
In order to compare the geometry of ammonium and
phosphonium moieties, which play crucial role in the
activation process, we have searched Cambridge
Structural Database (CSD) [10] for fragments depicted
in Fig. 1. We were especially interested in bond lengths
marked as d1 (P+-Car) and d2 (N+-Car).
Review of CSD (CSD, ver. 5.32 of November, 2011)
gave us 16 structures which contain phosphonium salt
and 122 structures containing ammonium salt. During
the search procedure structures without 3D coordinates
and with the r factor exceeding 5% were eliminated.
The length of most of the N+-C bonds (112 of 122)
are between 1.490-1.519Å while for most of the P+-C
bonds (10 of 14) the lengths are between 1.780 and
1.799Å. Such significant elongation should facilitate the
quaternization process due to increased polarizability of
the phosphorus atom and reduce steric requirements of
intermolecular reactions.
room temperature. The solution was diluted with CH2Cl2
(5 mL) and then washed successively with water, 0.5 M
aqueous NaHSO4, water, 0.5 M aqueous NaHCO3, and
water again. The organic layer was dried with MgSO4,
filtered, and concentrated to dryness. The residue was
dried under vacuum with P2O5 and KOH to constant
weight yielding 4-methoxy-N-p-tolylbenzamide (9a)
(0.183 g, 76%) which was spectroscopically identical
with described above. HPLC: gradient 50-100%B,
20 min: Rt = 10.90 min, 88%.
2.22.
Synthesis
of
4-methoxy-N-p-
tolylbenzamide (9a) by using (4,6-
diphenoxy-1,3,5-triazin-2-yl)-triphenyl-
phosphonium chloride (3l)
To a stirred solution of (4,6-diphenoxy-1,3,5-triazin-
2-yl)-triphenylphosphonium chloride (3l) (0.562 g,
1 mmol) in CH2Cl2 (5 mL) 4-methoxybenzoic acid (6a)
(0.152 g, 1 mmol) and DIPEA (0.16 mL, 1 mmol) were
added. Stirring was continued until all (4,6-diphenoxy-
1,3,5-triazin-2-yl)-triphenylphosphonium chloride was
consumed (disappearing of spot of 4,6-diphenoxy-
d2
d1
R
R
Car N+
R
Car P+
R
R
R
1,3,5-triazin-2-yl)-triphenylphosphonium
chloride).
p-Toluidine (8a) (0.107 g, 1 mmol) was added, and the
mixture was stirred overnight at room temperature. The
Figure 1. The structure’s fragments for which the searching of CSD
was made.
575

P-Triazinylphosphonium chlorides
as a new group of coupling reagents
(a)
O
Cl
R
P
R
R
+
R
R
+
R
R3P
P
N
N
Cl-
2a-b
+ CH3-Cl
N
N
N
N
N
O
O
N
O
O
N
O
1a
3a-b
11a-b
R3P = Bu3P (a) or Ph3P (b)
a: R = Bu
b: R = Ph
(b)
Bu
N
Bu
Bu
Bu
+
Bu
N
N
N
Cl-
+ Bu-Cl
N
Bu3N
N
N
Cl
4a
O
O
O
N
O
12
N
N
5a
O
N
O
Ph
+
N
Ph3N
4b
1a
Ph
Ph
Cl-
N
N
O
N
O
5b
(a) Synthesis of P-triazinylphosphonium chlorides 3a–b, by using CDMT (1a) and teritiary phosphines (2a-b) with subsequent
O-dealkylation leading to tributyl-(4-oxy-6-methoxy-1,3,5-triazin-2-yl)-phosphonium salt 11a and triphenyl-(4-oxy-6-methoxy-1,3,5-
triazin-2-yl)-phosphonium salt 11b, (b) synthesis of N-triazinylammonium chloride 6a, by using CDMT (1a) and tributhylamine (4a)
with subsequent N-dealkylation leading to 2-(N,N-dibutylamino-)4,6-dimethoxy-1,3,5-triazine 12. Reaction 1a with triphenylamine
(4b) was not observed.
Scheme 2.
Asexpected,thetreatmentof2-chloro-4,6-dimethoxy- NMR spectra of degradation products. Any attempts
1,3,5-triazine (1a) with tertiary phosphines 2a–b gave to prevent this degradation by modification of reaction
P-triazinylphosphonium chlorides 3a–b, which was conditions and to isolate the expected product 11a-b
confirmed by a positive test with 4-(4-nitrobenzyl) were ineffective (see Table 1).
pyridine (NBP) [11]. The quaternization of Bu3P and
The most intensive degradation (74% and 72%
Ph3P with 1a, proceeding relatively slowly at 0ºC, was yields, Table 1, entries 7 and 13) was observed in
accelerated at elevated temperatures. The increased reaction of CDMT (1a) with Bu3P in propan-2-ol and
polarity of the solvent had a negligible effect on dichloromethane at 0ºC and under reflux in ethyl
the reaction rate. Unfortunately, 3a–b were found acetate used as a solvent (78% yield, Table 1, entry 5).
extremely unstable and easily decomposed yielding In a more polar acetonitrile solution, only trace amounts
demethylated products 11a–b (a negative test with NBP, of products 11a–b were formed. In the case of Ph3P,
see Scheme 2a). Products 11a–b were isolated and the highest yields were obtained in CH2Cl2 (68% yield,
their structures were unequivocally confirmed by the Table 1, entry 14) and at elevated temperature in toluene
decreased intensity of the singlet methoxy group from and/or acetonitrile (81% and 86% yields, Table 1, entries
6H to 3H in 1H-NMR strongly suggesting a degradation 10 and 12). Comparison of analytic data of crude 11a-c
proceeding with the participation of a triazine substituent. showed in several cases divergences. This variation
This
pathway
of
decomposition
3a–b,
of effect was dependent on tiny modifications of synthetic
which procedure, but was eliminated by recrystallisation of
P-triazinylphosphonium
chlorides
was different from that of N-dealkylation of 11a-c. The most notable divergences were found in
N-triazinylammonium chloride (see Scheme 2b) the case of melting points and chemical shift of the
1
[12b,13,14] has been confirmed by H-NMR and 31P- phosphonium group in 31P-NMR. Therefore, analytical
576

B. Kolesinska et al.
Table 1. Tributyl-(4-oxy-6-methoxy-1,3,5-triazin-2-yl)-phosphonium salt 11a and triphenyl-(4-oxy-6-methoxy-1,3,5-triazin-2-yl)-phosphonium
salt 11b prepared by the treatment of 2-chloro-4,6-dimethoxy-1,3,5-triazine (1a) with Bu3P (2a) and PPh3 (2b).
room temp.
Yield [%]
reflux
Entry
phosphine
solvent
time
time
Yield [%]
1
Bu3P
PPh3
Bu3P
PPh3
Bu3P
PPh3
Bu3P
PPh3
Bu3P
PPh3
Bu3P
PPh3
Bu3P
PPh3
CHCl3
CHCl3
5 days
7 days
5 days
5 days
3 days
3 days
3 days
7 days
4 days
7 days
7 days
7 days
3 days
3 days
33
0
14 h
4 h
64
79
52
17
78
37
47
0
2
3
THF
49
41
55
14
74
0
14 h
3 days
7 h
4
THF
5
AcOEt
6
AcOEt
12 h
14 h
2 h
7
propan-2-ol
propan-2-ol
toluene
toluene
CH3CN
CH3CN
CH2Cl2
CH2Cl2
8
9
67
0
4 h
59
81
0
10
11
12
13
14
3 h
0
20 h
3 h
0
86
-
72
68
-
-
-
R
P
R
P
+
Cl
R
R
+
R
R
+
R3P
2a-b
-
N
N
Cl
R'
Cl
N
N
N
N
R'
X
N
O
-
N
OR'
X
X
N
O
1b-e
3c-j
11c-j
R3P = Bu3P or Ph3P
3c: R' = CH2C6H5, X = OCH2C6H5, R = Bu; 3d: R' = CH2C6H5, X = OCH2C6H5,R = Ph;
3e: R' = CH2CF3, X = OCH2CF3, R = Bu; 3f: R' = CH2CF3, X = OCH2CF3, R = Bu;
3g: R' = CH2CH2OCH2CH3, X = OCH2CH2OCH2CH3, R = Bu; 3h: R' = CH2CH2OCH2CH3, X = OCH2CH2OCH2CH3, R = Ph;
3i: X = Cl, R' = Me, R = Bu; 3j: X = Cl, R' = Me, R = Ph
Scheme 3. Synthesis of (4-oxy-6-alkyloxy-1,3,5-triazin-2-yl) phosphonium salts 11c–j by treatment of 2-chloro-4,6-dialkoxy-1,3,5-triazines
1b–e with 2a-b.
characterization of already known [5] 11a-d was of reaction conditions. In order to further elucidate
completed as required for the brand new products.
this phenomenon, the structure of the dealkylation
Inordertoverifywhethertheobserveddealkylationisa product was studied by the X-ray method, calculation
generalprocessoronespecificfortriazinesubstitutedwith of charge distribution in the zwitterionic product, and the
amethoxygroup, experimentsweremadeinvolvingother comparison of results with experimental data collected
triazineswithabroadrangeofsubstituentsinthering,e.g. in the Cambridge Structural Database.
2-chloro-4,6-dibenzyloxy-1,3,5-triazine (1b), 2-chloro-
It was found that crystallization from methanol-
4,6-bis-(2,2,2-trifluoroethoxy)-1,3,5-triazine (1c), water mixture promoted further demethylation of 11a,
2-chloro-4,6-bis-(2-ethoxy-ethoxy)-1,3,5-triazine finally leading to tributyl-(4-hydroxy-6-oxy-1,3,5-triazin-
(1d), and 2,4-dichloro-6-methoxy-1,3,5-triazine (1e). 2-yl)-phosphonium salt (12) (the deposition number
Unfortunately, it was found again that in all of these CCDC 879925 ) (see Scheme 4). The structure of
cases, the treatment of 1b–e with phosphines 2a–b 8 was confirmed by X-ray analysis. It forms a dimer
gave dealkylation products 11c–j (see Scheme 3).
with hydrogen bonds between N1–H and O2 atoms
All attempts to use dealkylated products 11c–j (see Fig. 2).
as coupling reagents were fruitless. None of 11c–j
To arrive at a rational description of the structure
activated 4-methoxybenzoic acid under a broad range of 12, we divided the molecule into two parts:
577

P-Triazinylphosphonium chlorides
as a new group of coupling reagents
the aromatic moiety of the triazine ring and the
To calculate the HOMA index based on geometrical
tributyl substituent around the phosphorus atom. parameters, we needed precise information concerning
The stability of the aromatic ring can be described the molecular geometry of the 1,3,5-triazine ring.
using the HOMA index—a quantitative measure of Therefore, we used crystallographic data for 12 as well
aromaticity. The HOMA index is defined as follows
Bu
Bu
+
[15]:
Bu
Bu
+
Bu
Bu
P
P
MeOH/H2O
HOMA = 1 - α(Ropt - Rav)2 - α/n∑(Rav - Ri)2
N
N
N
N
crystallization
-
where n is the number of bonds taken into summation; α
is an empirical constant fixed to give HOMA = 0 for the
hypothetical Kekule structures of aromatic systems and
1 for systems with all bonds equal to the optimal value
Ropt, Rav is the average bond length; and Ri reflects the
lengths of individual bonds.
O
N
O
O
N
H
O
11a
12
Scheme 4. Demethylation
of 11a to tributyl-(4-hydroxy-6-oxy-
1,3,5-triazin-2-yl)-phosphonium salt (12) in aqueous
methanol.
Figure 2. Structure of tributyl-(4-hydroxy-6-oxy-1,3,5-triazin-2-yl)-phosphonium salt (12).
578

B. Kolesinska et al.
as data collected in the Cambridge Structural Database based on crystallographic coordinates, showed that
for unsubstituted triazine rings [16]. We calculated the the negative partial charge is located mainly on carbon
aromaticity of unsubstituted triazine and compared atoms, closest to P1 in the n-butane chains (C4, C14,
it to 12. For triazine, this index equals 0.99, which is C24) as well as on both oxygens O2 and O3. Calculation
very close to the ideal aromatic ring (HOMA = 1) with of partial charges was performed using Gaussian 09
all bonds conjugated. A significant lowering of the by the following methods, classified by Cramer dipole
aromaticity of the triazine ring is observed following the derivative charges, also called atomic polar tensor
transformation of the moiety into a phosphonium salt and derived charges (APT in Table 2), electrostatic potential
substitution with two oxygens. The HOMA index is thus (ESP), and natural population analysis (NPA).
decreased from 0.99 to 0.88. The C–N bonds lengths in
Crystallographic and computational data show that
the aromatic ring of 12 vary from 1.322 to 1.335 Å and the positive charge is not located exclusively on the
are much more alternated than in unsubstituted triazine. phosphorus and C1 atoms, but is diffused in the triazine
In the investigated compound, N1–C2, N1–C3, N3–C3, ring and neutralized by the partial negative charge
and N2–C2 are between 1.371 and 1.381 Å and close to located on the C4, C14, and C24 carbons of the butyl
formal single bonds, while C1–N3 and C1–N2 are 1.323 groups surrounding the P1 phosphorus. Such a charge
and 1.317 Å, respectively, and there are about 0.2 Å distribution does not favor SNAr substitution involving an
longer than formal double bonds.
attack of the carboxylate anion and a departure of tertiary
Theformal+1chargelocatedonthephosphorusatom phosphine, which is the crucial stage in the process of
is not balanced by the other −1 point charge. Quantum “superactive” ester formation [12]. Therefore, in further
chemistry calculation for the investigated structure, research, an attempt was made to use 2-chloro-4,6-
diphenoxy-1,3,5-triazine 1f to verify whether the
Table 2. Charge distribution, electrostatic potential (ESP), and
application of starting materials resistant to nucleophilic
substitution facilitates the formation of P-quaternization
products. As expected, it was found that in this case
the treatment of 1f with tertiary phosphine gave final
P-triazinylphosphonium salts (see Scheme 5).
Salts 3k–l were obtained with satisfactory
yield, but the disadvantage of the procedure was
the preactivation time prolonged to 10–14 days,
necessary for the completion of the reaction. With
access to stable salts 3k–l, we were able to prove
that that the activation of 4-methoxybenzoic acid (6a)
yielded the same intermediate “superactive” ester 7f
(Scheme 6) as condensation mediated by means of
a classic N-triazinylammonium salt DPhT/NMM/BF4
[12a,17].
natural population analysis (NPA) in 12.
Charges
Atom
APT
ESP (MSK)
NPA
P1
1.220739
-0.735926
-0.966057
-1.005213
-0.915898
-0.919325
0.752618
1.351001
1.357554
-0.282714
-0.277681
-0.277669
0.661411
-0.909375
-0.959469
-0.947613
-0.661645
-0.660679
0.811111
1.130305
1.110678
-0.516990
-0.539896
-0.539907
1.56662
-0.70463
-0.62605
-0.64464
-0.62235
-0.62579
0.11434
0.78658
0.78801
-1.04799
-1.04553
-1.04552
N1
N2
N3
O2
O3
C1
C2
C3
C4
C14
C24
Anticipating that the primary products of the
reaction of tertiary phosphines 2a–b with triazines
1a–e were unstable quaternary P-triazinylphosphonium
salts 3a–j, attempts were made to prepare them in
Ph
+
P
Bu
+
Bu
Ph
Ph
Cl-
Bu
P
Cl
N
Cl-
N
N
N
N
N
N
Bu3P
Ph3P
O
O
O
N
O
O
N
O
3k, 68%
1f
3l, 49%
Scheme 5. Stable P-triazinylphosphonium 2-chloro-4,6-diphenoxy-1,3,5-triazines 3k-l.
579

P-Triazinylphosphonium chlorides
as a new group of coupling reagents
O
N
R
P
+
O
OH
R
R
O
N
Cl
CH2Cl2 / 0'C
N
N
OMe
N
+
DIPEA
7 h
O
N
O
O
O
OMe
6a
3k-l
R = Ph, Bu
7f
yield = 57% (R = Ph)
yield = 70% (R = Bu)
6a CH2Cl2 / 0'C
2 h
O
-
N+
BF4
N
N
O
N
O
DPhT/NMM/BF4
Scheme 6. Synthesis of active triazine ester 7f using phosphonium salts 3k-l and classic coupling reagent DPhT/NMM/BF4.
CO2H
O
R
+
Cl
R
R
O
P
R3P
2a-b
OMe
6a
OMe
-
N
N
Cl
N
N
N
N
R'
R'
R'
X
N
O
N
O
X
X
N
O
1a-e
3a-j
in situ
7a-f
in situ
NH2
Me
O
N
H
8a
9a
Me
MeO
R3P = Bu3P or Ph3P
3a: R' = CH3, X = OCH3, R = Bu; 3b: R' = CH3, X = OCH3, R = Ph;
3c: R' = CH2C6H5, X = OCH2C6H5, R = Bu; 3d: R' = CH2C6H5, X = OCH2C6H5,R = Ph;
3e: R' = CH2CF3, X = OCH2CF3, R = Bu; 3f: R' = CH2CF3, X = OCH2CF3, R = Bu;
3g: R' = CH2CH2OCH2CH3, X = OCH2CH2OCH2CH3, R = Bu; 3h: R' = CH2CH2OCH2CH3, X = OCH2CH2OCH2CH3, R = Ph;
3i: X = Cl, R' = Me, R = Bu; 3j: X = Cl, R' = Me, R = Ph
Scheme 7. Synthesis of 4-methoxy-N-p-tolyl-benzamide 9a with in situ prepared P-triazinylphosphonium chlorides 3.
580

B. Kolesinska et al.
Table 3. Synthesis of 2-acyloxy-4,6-disubstituted-1,3,5-triazines 7a–e.
P-triazinyl-phosphonium
chloride (prepared in situ)
Product
Yield
[%]
IR [2,18]
[cm-1
]
Bu
O
O
+
P
Bu
Bu
-
Cl
N
N
86
85
1750
OMe
N
N
O
N
O
O
N
7a
O
3a
Bu
O
+
P
Bu
Bu
O
-
Cl
N
N
O
N
N
1750
O
N
O
O
N
O
3c
7b
Bu
O
+
P
Bu
Bu
O
-
Cl
N
N
77
75
1760
1755
OMe
CF3
N
N
F3C
O
N
O
CF3
F3C
O
N
7c
O
3e
Bu
O
N
+
P
Bu
Bu
-
O
Cl
N
N
OMe
N
O
O
N
O
O
3g
O
O
O
N
7d
O
O
Bu
+
P
Bu
Bu
O
-
2Cl
N
N
OMe
N
N
MeO
71
1745
Bu
P+
N
O
O
N
7e
O
3i
Bu Bu
O
situ and consume immediately for the activation of and gave the product of condensation with moderate
4-methoxybenzoic acid to appropriate “superactive” yield (see Table 4, entries 6 and 12).
esters. As expected, this procedure was found very
effective and the anticipated products of activation were
isolated in 75%–86% yield. All of them were identical
with the authentic samples obtained with classic
4. Conclusions
N-triazinylammonium salts and identified as 7a–e based
on the characteristic carbonyl IR band at 1750–1760 cm-1
(see Table 3).
Tertiary phosphines in reaction with 2-chloro-4,6-
dialkoxy-1,3,5-triazines gave unstable quaternary
P-triazinylphosphonium chlorides, which readily
decomposed with a departure of the alkyl group of the
triazine ring substituent. The dealkylation products are
useless as reagents for the activation of carboxylic
acids. Nevertheless, in accord with expectations, the
activation of the carboxylic function, even in the presence
of spatially expanded tributyl- or triphenylphosphine,
was enhanced so significantly that the in situ procedure
gave appropriate “superactive” esters and products
of condensation with good yield. This means that the
Moreover,
it
has
been
proven
that
P-triazinylphosphonium chlorides 3a–j prepared in
situ are very efficient coupling reagents, useful in the
synthesis of amides (see Scheme 7 and Table 4).
Inallcases,theapplicationofP-triazinylphosphonium
salts
3
prepared in situ gave 4-methoxy-N-p-
tolylbenzamide isolated with acceptable yield and purity.
Only 3k–l derived from 2-chloro-4,6-diphenoxy-1,3,5-
triazine were less efficient in the coupling procedure,
581

P-Triazinylphosphonium chlorides
as a new group of coupling reagents
Table 4. 4-Methoxy-N-p-tolyl-benzamide 9a obtained by using in situ prepared P-triazinylphosphonium chlorides 3.
Entry
Coupling reagent
prepared in situ
Yielda [%]
4-Methoxy-N-p-tolyl-benzamide
Puritya
[%]
Ph
+
Ph
O
Ph
Cl-
P
1
2
72
91
79
81
N
N
N
O
3b
Ph
+
P
Ph
O
Ph
Cl-
N
N
N
O
3d
Ph
+
Ph
O
Ph
Cl-
P
3
4
80
89
83
80
N
N
F3C
N
O
CF3
3f
Ph
+
P
Ph
O
Ph
Cl-
N
N
O
N
O
O
3h
Ph
+
P
Ph
Ph
Cl-
N
N
Cl-
5
91
78
Ph
N
O
P
+
3j
Ph
Ph
Ph
+
Ph
O
Ph
Cl-
P
6
7
29b)
85
88
N
N
N
N
N
O
3l
Bu
+
Bu
O
Bu
Cl-
P
76
N
N
O
3a
Bu
+
P
Bu
O
Bu
Cl-
N
8
97
84
N
O
3c
Bu
+
Bu
O
Bu
Cl-
P
9
88
83
82
83
N
N
F3C
N
O
CF3
3e
Bu
+
P
Bu
O
Bu
Cl-
10
N
N
O
N
O
O
3g
Bu
+
P
Bu
Bu
Cl-
N
N
Cl-
11
12
95
80
84
Bu
N
O
P
+
3i
Bu
Bu
Bu
+
P
Bu
Bu
Cl-
41b)
N
N
O
N
O
3k
a) isolated crude product, purity determined by HPLC, b) using stable, isolated chlorides 3l, 3k.
582

B. Kolesinska et al.
replacement of tertiary amines by tertiary phosphines
paved the road to a new family of coupling reagents.
The most interesting finding is the possible application
of configurationally stable chiral phosphines bearing the
stereogeniccenteronthephosphorusinenantioselective
condensations.
Supplementary Material
Supporting
Information Available:
Experimental
procedures, characterization data.
Acknowledgements
This work was supported by MSHE Grant N N204
228734.
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