Synthesis of 2-pyridylphosphinate and thiophosphinate derivatives by nucleophilic aromatic substitution of N-methoxypyridinium tosylates

Article abstract of DOI:10.1246/cl.2012.1630

We developed a straightforward and cost-effective method for the synthesis of 2-pyridylphosphinate derivatives based on a nucleophilic aromatic substitution of N-methoxypyridinium salts. The method proved to be useful for synthesizing various 2-pyridylphosphinates and thiophosphinates, including an optically active compound, from H-phosphinate precursors.

Full text of DOI:10.1246/cl.2012.1630

doi:10.1246/cl.2012.1630
1630
Published on the web December 1, 2012
Synthesis of 2-Pyridylphosphinate and Thiophosphinate Derivatives
by Nucleophilic Aromatic Substitution of N-Methoxypyridinium Tosylates
Natsuhisa Oka,* Kousuke Ito, Futoshi Tomita, and Kaori Ando
Department of Chemistry, Faculty of Engineering, Gifu University, 1-1 Yanagido, Gifu 501-1193
(Received September 15, 2012; CL-120955; E-mail: oka@gifu-u.ac.jp)
We developed a straightforward and cost-effective method
it was difficult to separate compounds 3a and 5 by silica gel
column chromatography, compound 3a was isolated in only
46%.
for the synthesis of 2-pyridylphosphinate derivatives based on a
nucleophilic aromatic substitution of N-methoxypyridinium
salts. The method proved to be useful for synthesizing various
2-pyridylphosphinates and thiophosphinates, including an opti-
cally active compound, from H-phosphinate precursors.
It has been reported that such P-hydroxymethylation
reactions are attributed to the base-promoted decomposition of
N-methoxypyridinium salts (e.g., compound 2), which generates
formaldehyde.4a,10 However, the addition of a base is necessary
for the SNAr reaction. In addition, it has been reported that the
decomposition of N-methoxypyridinium salts is promoted even
by a weak base.4a We speculated that the decomposition of 2
might be suppressed by lowering the reaction temperature
because we found that the reaction was extremely exothermic. In
fact, the formation of compound 5 was reduced at 0 °C (Entry 2)
and completely suppressed at ¹40 °C (Entry 3). Practically the
same result was obtained when the reaction was conducted in
CH2Cl2 (Entry 4). The formation of 4 was not as temperature
dependent as that of 5; it was minimized at ¹40 °C (Entries 3
and 4) and was not further improved at ¹78 °C (Entry 5).
Although the formation of 4 was not completely suppressed,
compound 3a was easily isolated in excellent yield (Entry 3).
We also found that the relatively strong base DBU was necessary
for the reaction; the conversion of 1a was reduced from >99%
to 41% and 14% when DBU was replaced by Et3N and i-Pr2NEt,
respectively, even with an extended reaction time (Entries 3 vs.
6, 7).
With the optimized conditions in Table 1, Entry 3, we
examined the scope of the reaction by using various substrates.
First, ethyl and isopropyl phenylphosphinates 1b and 1c were
used in place of the methyl ester 1a (Table 2). Compounds 1b
and 1c were synthesized according to the literature with minor
modifications.8,11 The results were rather surprising; although
the desired products 3b and 3c were formed in 90-93%, they
were both contaminated with compound 3a. Although the
mechanism of this side reaction is not clear yet, it is most likely
derived from the N-methoxy group of compound 2. Because of
this undesired transesterification, we carried out the following
investigations by using methyl esters as starting materials.
Compound 1a was allowed to react with 2- and 4-
methylpyridinium salts 6a and 6b, which were expected to be
less reactive than compound 2 owing to the electron-donating
methyl group (Table 3). In fact, compound 6a was significantly
less reactive than compound 2. Thus, only 68% of the starting
material 1a was consumed under the optimized conditions and
the isolated yield of compound 7a was less than 40% (Entry 1).
The result was not practically improved by increasing the
amounts of compound 6a and DBU (Entry 2) and also extending
the reaction time (Entry 3). In contrast, compound 6b having
a methyl group at the 4-position showed greater reactivity than
the 2-methyl reagent 6a, although still less reactive than the
unsubstituted 2, and the desired product 7b was isolated in good
yields (Entries 4 and 5).
2-Pyridylphosphine oxides and 2-pyridylphosphonates have
been used as ligands for many applications such as the extraction
of lanthanide ions,1 preparation of luminescent metal com-
plexes,2 and transition-metal-catalyzed reactions.3 Biological
activities of these compounds have also attracted attention.4 In
contrast, 2-pyridylphosphinates categorized “in between” have
attracted little attention,5 and only a few studies on their
application have been reported to date.5e,5f
2-Pyridylphosphinates in the literature have been synthe-
sized by Pd-catalyzed cross-coupling between the corresponding
H-phosphinates and 2-halopyridines exclusively.5 However, 2-
halopyridines are generally less reactive than other aryl halides,
and thus, high catalyst loadings or highly reactive but expensive
catalysts are essential. Therefore, the development of a cost-
effective alternative method is required. For this purpose, we
sought to develop a new method based on a nucleophilic
aromatic substitution (SNAr) of N-methoxypyridinium salts,
which would not require an expensive transition-metal catalyst.
This type of reaction has been used to synthesize 2-pyridyl-
phosphonates.3a,4,6 However, to the best of our knowledge, it has
not been applied to the synthesis of 2-pyridylphosphinate
derivatives. Therefore, we first investigated the reaction between
methyl phenylphosphinate (1a) and N-methoxypyridinium tosy-
late (2) to verify the applicability of this reaction to the synthesis
of 2-pyridylphosphinates (Table 1). Compound 2 can be easily
synthesized from inexpensive pyridine N-oxide and methyl p-
toluenesulfonate.7
When the reaction between compounds 1a and 2 was carried
out in the presence of 1,8-diazabicyclo[5.4.0]undec-7-ene
(DBU) at rt under similar conditions used for the synthesis of
dialkyl 2-pyridylphosphonates by Stawinski et al.,4 compound
1a was completely consumed within 5 min and the desired 2-
pyridylphosphinate 3a as well as two by-products 4 and 5 were
formed (Table 1, Entry 1). 31P NMR analysis of the crude
mixture showed that the ratio of compounds 3a:4:5 was 80:4:16.
1
By-products 4 and 5 were identified by comparing the H and
31P NMR spectra with those of an authentic sample synthesized
by Pd-catalyzed cross-coupling between compound 1a and 4-
iodopyridine8 and with those in the literature,9 respectively.
Concomitant formation of 2- and 4-pyridyl derivatives is
common in the syntheses of pyridylphosphonates.6 P-Hydroxy-
methylation has also been reported by Stawinski et al. in the
reaction of diethyl H-phosphonate with compound 2.4a Because
Chem. Lett. 2012, 41, 1630-1632
© 2012 The Chemical Society of Japan
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1631
Table 1. Optimization of reaction conditions for the synthesis of phenyl(2-pyridyl)phosphinates 3a
N
base
(1.5 equiv)
N
OH
H
P
O
TsO−
OMe
+
N+
Ph
OMe
+
+
Ph
P
O
OMe
Ph
P
O
5
OMe
Ph
P
O
4
OMe
(1.5 equiv)
1a
3a
2
Entry
Base
Conditions
Conversiona/%
3a:4:5a
Yield of 3ab/%
1
2
3
4
5
6
7
DBU
DBU
DBU
DBU
DBU
Et3N
MeCN, rt, 5 min
MeCN, 0 °C, 5 min
MeCN, ¹40 °C, 5 min
CH2Cl2, ¹40 °C, 5 min
CH2Cl2, ¹78 °C, 5 min
MeCN, ¹40 °C, 2 h
MeCN, ¹40 °C, 2 h
b
>99
>99
>99
>99
>99
41
80:4:16
90:4:6
98:2:0
98:2:0
98:2:0
®
46
®
93
®
®
®
®
i-Pr2NEt
14
®
aDetermined by 31P NMR analysis of crude mixture. Isolated yield.
Table 2. Transesterification during the synthesis of phenyl(2-
pyridyl)phosphinates 3b and 3c
OMe
MgBr (1.3 equiv)
OMe
P
Cl
P
Ni-Pr2
2 (1.5 equiv)
DBU (1.5 equiv)
Ni-Pr2
THF, 0 °C, then rt, 1 h
H
P
N
N
9
8
Ph
OR
+
MeCN
−40 °C, 5 min
Ph
P
OR
Ph
P
OMe
1 M HCl aq., rt
O
O
O
2 (1.5 equiv)
DBU (1.5 equiv)
N
1b (R = Et)
3b (R = Et)
3a
H
P
1c (R = i-Pr)
3c (R = i-Pr)
OMe
P
OMe
Conversiona/%
3b,c:3aa
MeCN, −40 °C, 3 h
Entry
1
O
O
1
2
1b
1c
>99
>99
90:10
93:7
10
82%
11
66%
aDetermined by 31P NMR.
Scheme 1. Synthesis of methyl cyclohexyl(2-pyridyl)phosphi-
nate (11).
Table 3. Synthesis of methyl phenyl(methyl-2-pyridyl)phos-
phinates 7a and 7b
the 2-pyridylphosphinate 11 in good yield, though the reaction
required a longer reaction time than that for compound 1a
(Scheme 1).
R2
R1
TsO−
OMe
N+
R2
R1
Oxygen to sulfur exchange has been one of the major
transformations in organophosphorus chemistry, which can
dramatically change properties of molecules such as coordina-
tion ability to metal ions and biological activity.12 Synthesis of
2-pyridylthiophosphinates from the 2-pyridylphosphinates we
already obtained would therefore significantly extend the scope
of the reaction. For this reason, we sought to develop a method
to synthesize 2-pyridylthiophosphinates. First, we attempted to
convert compound 3a to the corresponding thiophosphinate by
treatment with Lawesson’s reagent (1.5 equiv) for 6 h at rt.13
However, the reaction did not give the desired product and
multiple unidentified by-products were formed instead.
Therefore, we next conducted the O to S exchange prior to
the introduction of the 2-pyridyl group (Scheme 2) and found
that compound 1a was successfully converted into the corre-
sponding thiophosphinate 12 in contrast to compound 3a.
0.5 equiv of Lawesson’s reagent was sufficient for the complete
consumption of compound 1a. It was also found that the optimal
reaction time was ca. 1-2 h and a prolonged treatment of 1a with
Lawesson’s reagent resulted in the formation of some highly
polar by-products, which were probably derived from the over-
sulfurization of 12. The reaction of compounds 12 and 2 under
DBU
6a (R1 = Me, R2 = H)
6b (R1 = H, R2 = Me)
N
H
P
O
Ph
OMe
Ph
P
OMe
MeCN, −40 °C
O
7a (R1 = Me, R2 = H)
7b (R1 = H, R2 = Me)
1a
Equiv of Reaction
Conversiona
/%
Entry 6 (equiv)
7
DBU
time
1
2
3
4
5
6a (1.5)
6a (2.0)
6a (2.0)
6b (1.5)
6b (2.0)
1.5
2.0
2.0
1.5
2.0
5 min
5 min
3 h
5 min
5 min
7a
7a
7a
7b
7b
68 (37)b
75 (35)b
68 (33)b
89 (69)b
93 (61)b
b
aDetermined by 31P NMR. Isolated yields of 7 are given in
parentheses.
We found that the reaction was also applicable to the
synthesis of an alkyl(2-pyridyl)phosphinate. Thus, the reaction
of methyl cyclohexylphosphinate (10), which was synthesized
from the chlorophosphoramidite 8, with compound 2 afforded
Chem. Lett. 2012, 41, 1630-1632
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/

1632
H
P
H
P
S
The authors thank Katayama Chemical Industries Co., Ltd.
for kindly providing optically active (RP)-14. This research was
partially supported by a Grant-in-Aid for Scientific Research on
Innovative Areas “Advanced Molecular Transformations by
Organocatalysts” from MEXT, Japan, and a research grant from
the SEI Group CSR Foundation.
Lawesson's reagent (0.5 equiv)
toluene, rt, 1.5 h
Ph
OMe
Ph
OMe
O
1a
12
77%
R
TsO −
(1.5 equiv)
N+
R
OMe
2 (R = H)
6b (R = Me)
N
OMe
References and Notes
DBU (1.5 equiv)
1
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Ph
P
MeCN, −40 °C, 10 min
S
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13b (R = Me), 66%
Scheme 2. Synthesis of phenyl(2-pyridyl)thiophosphinate es-
ters 13a and 13b via methyl phenylthiophosphinate (12).
i-Pr
O
2 (1.5 equiv)
i-Pr
O
P
P
DBU (1.5 equiv)
Ph
Me
O
3
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−40 °C, 30 min
Ph
Me
O
N
H
(RP)-14 (d.r. = 95:5)
(SP)-15, 71% (d.r. = 95:5)
4
5
Scheme 3. Synthesis of optically active 2-pyridylphosphinate
derivative (SP)-15.
similar conditions as above gave the desired 2-pyridylthiophos-
phinate 13a in good yield. The reaction with 4-methyl reagent
6b was also successful, producing the corresponding thiophos-
phinate 13b.
The 2-pyridylphosphinate derivatives produced by this
method are P-chiral. Considering the potential applications of
these compounds, i.e., ligands for transition-metal catalysts and
biologically active compounds, it is important to open a way to
the synthesis of these compounds in optically active forms.14 We
also envisage that optically active 2-pyridylphosphinate deriv-
atives would work as Lewis basic organocatalysts for asym-
metric reactions in analogy with bidentate phosphine oxides and
pyridine derivatives.15 As a preliminary study in this pursuit, we
conducted the reaction of (RP)-1416 (RP:SP = 95:5) (Scheme 3)
and found that the reaction proceeded smoothly to afford the
desired product 15 in good yield, though taking a little longer
time than the methyl ester 1a. The reaction was completely
stereospecific. In analogy with the reaction of dialkyl H-
phosphonates reported by Stawinski et al.,4 we speculate that
the reaction proceeded with retention of configuration at the
phosphorus atom. Although the transesterification described
above (Table 2) also occurred in this case and a small amount of
the methyl ester 3a (3% by 31P NMR) was observed in the crude
mixture, it was easily removed from the desired product (SP)-15
by silica gel column chromatography.
6
7
8
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In conclusion, we developed a straightforward method for
the synthesis of 2-pyridylphosphinates and thiophosphinates
using the SNAr reaction of N-methoxypyridinium salts. This
method would be a cost-effective alternative for the synthesis of
various 2-pyridylphosphinate derivatives, which are currently
synthesized by rather costly Pd-catalyzed cross-coupling. Fur-
ther extension of this study, particularly on the synthesis of
optically active compounds, is in progress.
Chem. Lett. 2012, 41, 1630-1632
© 2012 The Chemical Society of Japan
www.csj.jp/journals/chem-lett/