Metal-free phosphonation of heteroarene N-oxides with trialkyl phosphite at room temperature

Article abstract of DOI:10.1039/C7OB00402H

A new protocol is described for the conversion of heteroarene N-oxides to heteroarylphosphonates through in situ activation with bromotrichloromethane. The N-oxides of isoquinoline, quinoline, quinoxaline and 1,10-phenanthroline were fast transformed into the corresponding heteroarylphosphonates in up to 92% yield under mild conditions in the absence of solvent and metal catalysts. The good functional group tolerance, low cost, feasibility of scale up, and wide availability of reagents make this method a prominent complement to the Hirao coupling.

Full text of DOI:10.1039/C7OB00402H

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Takeharu Haino et al.
Solvent-induced emission of organogels based on tris(phenylisoxazolyl)
benzene
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DOI: 10.1039/C7OB00402H
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Metal-free phosphonation of heteroarene N-oxides with trialkyl
phosphite at room temperature †
Received 00th January 20xx,
Accepted 00th January 20xx
Ming-Tao Chen, Xia You, Li-Gang Bai and Qun-Li Luo*
DOI: 10.1039/x0xx00000x
www.rsc.org/
A new protocol is described for the conversion of heteroarene N- 1, A2), in which toxic or moisture-sensitive regents were
oxides to heteroarylphosphonates through in situ activation with required.6 Recently, the strategy of C-H bond functionalization
bromotrichloromethane. The N-oxides of isoquinoline, quinoline, successfully
facilitated
the
synthesis
of
quinoxaline and 1,10-phenanthroline were fast transformed into heteroarylphosphonates.7, 8 Typically, Huang et al developed a
the corresponding heteroarylphosphonates in up to 92% yield dehydrogenative coupling reaction of heteroarenes with
under mild conditions in the absence of solvent and metal dialkyl hydrophosphonates by the use of a noble metal and
catalysts. The good functional group tolerance, the low cost, the excess of stoichiometric amount of oxidants (Scheme 1, B1).7a
feasibility of scale up, and the wide availability of reagents make In addition, Wu and co-workers reported a method via C-H
the method a prominent complement to the Hirao coupling.
functionalization of heteroaryl N-oxides that worked at an
elevated temperature for dozens of hours (Scheme 1, B2).8
Normally, heteroarene N-oxides are highly polar molecules,
but they are not so active. It requires to be at an elevated
temperature for the direct reactions between heteroarene N-
oxides with P(III) nucleophiles, such as hydrophosphonates.8
Accordingly, activation of the substrate is an alternative for
allowing such reactions to work under mild conditions.
Phosphonic acid derivatives have various applications in many
fields, such as organic synthesis, medicinal chemistry, and
materials chemistry.1, 2 Among them, arylphosphonates are
widely used as passive coating agents to inhibit the corrosion
of ferrous metals, as antistatic agents in the textile and
polymer industry, as emulsifiers for insecticides and
agricultural chemical mixtures, and as surface modification
reagents in material sciences.3 A reliable palladium-catalyzed
method for the synthesis of arylphosphonates from haloarenes
ArX (X = Br, I) was disclosed by Hirao and co-workers in the
1980s because of its high efficiency and good tolerance to
functionalities.4 However, the process of developing methods
for preparing heteroarylphosphonates has lagged behind. The
first general approach is based on the nucleophilic reactions of
N-alkoxypyridinium salts with alkali metal derivatives of dialkyl
hydrogenphosphonate (Scheme 1, A1). These reactions were
In situ activation highlights high step economy and the ease
of operation. However, in situ activation of heteroarene N-
oxides is theoretically challenging when
a phosphorous
nucleophile is present because the activating agents possibly
prefer the nucleophile rather than the weakly nucleophilic N-
oxide substrate. In continuation of our work on activating
agents in situ formed from the reagent combination of
phosphine derivatives with additives,9 we found that CBrCl3 is
able to activate the reactions of heteroarene N-oxides with
trialkyl
phosphites,
allowing
the
synthesis
of
o
conducted under water-free conditions below –15 C due to
heteroarylphosphonates under very mild conditions in the
absence of solvents, metal catalysts and extra common
activating agents (Scheme 1, C).
decomposition of the unstable reactants, and formed dialkyl
heteroarylphosphonates in only low to moderate yields.5 A few
reactions on the variants of N-alkoxypyridinium salts such as
At the outset of the investigation, isoquinoline N-oxide (1a
)
N-trifluoromethane
sulphonyl
pyridinium
and
N-
was chosen as the substrate in the model reaction (Table 1). It
was previously disclosed that the reaction of P(OMe)3 with
iodine quickly formed dimethoxyphosphoryl iodide, an active
intermediate capable of activating the carboxyl group.9a On
the other hand, it is well known that the deoxygenative
chlorination of pyridine N-oxides can be achieved with POCl3.10
We hoped that in situ formed dimethoxyphosphoryl iodide
could be used as an activator of N-oxides, similar to POCl3.
Therefore, we firstly tried the reagent combination of P(OMe)3
(alkoxycarbonyl)oxy pyridinium, were then developed (Scheme
Key Laboratory of Applied Chemistry of Chongqing Municipality, College of
Chemistry and Chemical Engineering, Southwest University, Chongqing 400715,
China. E-mail: qlluo@swu.edu.cn
†
Electronic Supplementary Information (ESI) available: Experimental procedures;
characterization data; 1H , 13C and 31P NMR HRMS spectra for new compounds. See
DOI: 10.1039/x0xx00000x
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and I2 for the deoxygenative phosphonation of 1a
Journal Name
.
equiv.) and CBrCl3 (3 equiv.) at room temperatuVrieewuAnrtdicleerOntlhinee
DOI: 10.1039/C7OB00402H
Unfortunately, no desired product formed despite the fact that ambient atmosphere in the absence of solvent.
1a was completely converted (entries 1 & 2). We then tried
CCl4 and CCl3CN since the combinations of PPh3/CCl4 and
Table 1 Optimization of the reaction conditionsa
PPh3/CCl3CN were capable of deoxygenative chlorination of
alcohols and heteroarene N-oxides, respectively.11 When
CCl3CN was employed as the additive in CCl4, the
deoxygenative phosphonation took place, but the yield was
Entry
1b
R (equiv.)
I2 (2)
I2 (2)
CCl3CN (2)
CCl3CN (2)
-
CBrCl3 (2)
CBrCl3 (3)
CBrCl3 (3)
CBrCl3 (3)
CBrCl3 (3)
CBrCl3 (3)
CBrCl3 (3)
CBrCl3 (3)
CBrCl3 (3)
CBrCl3 (2)
CBrCl3 (2)
CBrCl3 (3)
CBrCl3 (3)
CBrCl3 (3)
Solvent
DCM
CCl4
DCM
CCl4
CCl4
CCl4
CCl4
Toluene
CH3CN
DCM
Et2O
THF
2a
Yield
0
0
very low. A control experiment indicated that it was not CCl4
but CCl3CN promoted the reaction (entries 3 5).
–
2b
3
trace
19%
N.R.
56%
60%
29%
trace
35%
40%
41%
75%
81%
44%
46%
54%
N.R.
N.R.
4
5c
6
7
8
9
10
11
12
13d
14
15e
16
17e
18f
19g
-
-
-
-
-
-
a
Reaction conditions: 1a (1 mmol), 2a (350 μL, 3 mmol), solvent (1 mL) at room
temperature (r.t.) for 8 h unless otherwise stated. For entries 13 – 17, the
reaction time was 1 h. Yield of isolated product. N.R. = no reaction, which means
b
1a was unchanging as monitored by thin-layer chromatography (TLC). 2 mL of
solvent was used. TLC indicated that 1a was completely transformed into a
c
complicated mixture, and no confirmed compound was identified. The reaction
was performed from r.t. to 75 oC. d 0.5 mL of 2a (4.3 mmol) was used. e 230 L of
2a (2 mmol) was used. f The reaction was performed at 0 oC. g conditions as entry
14, but with dimethyl hydrogenphosphonate (275 μL, 3 mmol) rather than 2a.
Scheme 1 Different strategies for the synthesis of heteroarylphosphonate derivatives.
To assess the scope of the present protocol, various
heteroarene substrates were examined. The results,
summarized in Table 2, showed that the heteroarene N-oxides
produced the expected phosphonation products very fast
under mild conditions. For most of the tested substrates,
dimethyl heteroarylphosphonates were isolated in acceptable
More recently, Thiemann and co-workers noted the use of
CBrCl3 as a surrogate of CCl4 in Appel type transformations.11a,
12
We then turned to CBrCl3, a preferred reagent over CCl4
because of environmental concern.13 The transformations
worked, but good results could not be obtained despite
yields (3a
excellent yields. Generally, isoquinoline N-oxides gave better
results than quinoline N-oxides (3a 3g vs 3h 3o), while
–3q), and many of them were isolated in good to
attempting several optimization experiments (entries 6
–12).
Fortunately, when P(OMe)3 2a) was used as solvent, the
(
–
–
desired product was isolated in good yield (entry 13). Further
screening the amounts of reagents relative to N-oxide 1a
suggested that the best result was achieved with 3 equivalents
of 2a and CBrCl3 in the absence of solvent (entry 14). The
reaction did not occur at the temperature as low as ice point
(entry 18). When 2a was replaced with dimethyl
hydrogenphosphonate, the phosphonation did not work (entry
19). Therefore, we established optimized conditions for the
deoxygenative phosphonation of heteroarene N-oxides via in
situ activation for the preparation of heteroarylphosphonates.
The reaction was complete within one hour using P(OMe)3 (3
quinoxaline N-oxides better than 1,10-phenanthroline N-
oxides (3p vs 3q). The comparison of the substrate structures
reveales that the N-O bond in quinoline and 1,10-
phenanthroline N-oxides suffers from more steric hindrances
than that in isoquinoline and quinoxaline N-oxides,
respectively. Thus, the results suggest that the steric hindrance
around the N-O bond significantly impacted the deoxygenative
phosphonation.
Remarkably, most halogenated substrates, whether bromo
or iodo, gave the expected heteroarylphosphonates in good to
excellent yields (3b–3d, 3g, 3i). The outcomes are important
due to the fact that halo groups at aryl ring are desired in the
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extensive applications of cross-couplings, but they are often
incapable of tolerating the conditions of Hirao coupling.4
Therefore, the present protocol, as a prominent complement
to the Hirao coupling, is beneficial to the synthesis of halo-
substituted heteroarylphosphonates for their post-
transformations.
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DOI: 10.1039/C7OB00402H
To establish the mechanism of the deoxygenative
phosphonation, NMR spectroscopy was used to monitor the
progress of the reaction. As shown in Figure 1, the main
byproducts in the final mixture of the neat reactions were
Table 2 Substrate scope of deoxygenative phosphonation of heteroarene N-oxides a
trimethyl phosphate (
and tetramethyl diphosphate (
4
), dimethyl hydrogenphosphonate (
5),
6
). We then used 31P NMR
spectroscopy to monitor the progress of the reaction that was
conducted in a deuterated solvent. It was observed that the
phosphorus-containing compounds were formed in the
following sequence: firstly
and dimethyl (trichloromethyl)phosphonate (
(Figures S1 and S2).16 To elucidate the formation of these
4
and
5
, then the desired product
7
),14, 15 and finally
6
compounds in the neat reactions, two control experiments
were conducted (Equations 2 and 3).
a
Reaction conditions: N-oxide (1a–1q, 1 mmol), 2 (3 mmol) and CBrCl3 (3 mmol)
under the ambient atmosphere at room temperature. Yield of isolated product.
The substrates containing electron-donating substituents
Figure 1. 31P {1H} NMR spectrum recorded for the final mixture of deoxygenative
phosphonation in the absence of solvent. The bold codes above the peaks denote the
assignment of each peak to the related molecule in the inserted box.
gave the products in much lower yields than others (3l
–3o vs
3a–3k) due to their low activities. Better results of these
substrates were unsuccessful despite several attempts via
extension of reaction time and change of reaction temperature.
Moreover, the phosphite reagents bearing larger alkyls than
In principle, the Arbuzov reaction will possibly take place
when an alkyl halide mixes with a trialkyl phosphite.17 The
methyl decreased the yields sharply (3r, 3s & 3u vs 3a, 3b &
3h). No products were identified when P(OBu)3 was employed
(results not shown). In addition, pyridine N-oxide failed to
realize the transformation under the current conditions.
Notably, the gram-scale preparation of deoxygenative
phosphonation was feasible. The reaction efficiency affected
little when 1g was employed on a 10 mmol scale (Equation 1).
reaction of CCl4 with P(OMe)3 (2a) produced 7 14
.
Unexpectedly,
the neat reaction between CBrCl3 and 2a at room temperature
gave and prior to
(Figure S3),16 as shown in Equation 2.
4
5
7
Meanwhile, the reaction of
5 with CBrCl3 slowly generated 6
(Equation 3, Figure S4).16 These results indicated that the
reaction of CBrCl3 with P(OMe)3 (2a) was much faster than that
with dimethyl hydrogenphosphonate (
5
). The intermediate of
(Equation
2a with CBrCl3 was inferred to be phosphonium
A
4).9a, 11, 17 The reaction of
A
with trace of water from the
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reagents and ambient atmosphere possibly releases
Hydrogen halides are capable of decomposing trialkyl 3-position is less than that of the 1D-pOoI:s1it0i.o10n39(/SCc7hOeBm00e4022H).
phosphites.18 Accordingly, 2a could be transformed into
However, the phosphonations exclusively took place at the 1-
(Equation 5). Similar to water, ), both
is able to accelerate the position.8 In the activated form of substrates (
, and gives tetramethyl diphosphate (Equation positions 1 and 3 are theoretically electrophilic due to the fact
that the resonance structures and are relatively stable
(Scheme 3). In the resonance contributor , the 1-position that
4 and HBr. isoquinoline N-oxides (e.g., 3a), and the steric hindrance at the
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5
5
B
inactivation of
6).
A
B
D
B
represents the carbon center of the iminium moiety is more
electrophilic than the 3-position where the carbon atom
adjacent to the nitrogen atom in an enamine moiety is located.
When a nucleophile attacks on the 1-position, the aromaticity
of the benzene ring in
the 3-position in would give the dearomatized structure (
If the aromaticity of the benzene ring in is reserved via
resonance, the resonance contributors would be present as
B
is reserved. By contrast, the attack on
D
E).
E
the forms
F and G that are predicted to be relatively unstable
Based on the experimental observations, a mechanism is
proposed for the deoxygenative phosphonation (Scheme 2).
The reaction is initiated as the formation of phosphonium
due to the separated charges.22 Therefore, the 1-position in
is more favorable than the 3- position.
B
intermediate
biscation ion pair
biscation ion pair
A
. An N-oxide (1a) is activated by
A
, and forms
. The nucleophilic attack of 2a on gives
C. C is fragmentized into the desired product
B
B
(3a), accompanying with the byproducts that include trimethyl
phosphate (4), chloroform and bromomethane.
Scheme 3 The regioselectivity of the deoxygenative phosphonation.
In conclusion, a facile synthesis of heteroarylphosphonates
from heteroarene N-oxides is described. It represents the first
example of deoxygenative phosphonation of heteroarene N-
oxides via the strategy of in situ activation. The reactions were
employed under very mild conditions in the absence of
solvents, metal catalysts and extra common activating agents.
The N-oxides of isoquinoline, quinoline, quinoxaline and 1,10-
phenanthroline were successfully transformed into the
corresponding heteroarylphosphonates in a short time. The
reaction can be scaled up to produce grams of
heteroarylphosphonates under mild conditions. The control
experiments demonstrated that the reaction of trimethyl
phosphite with bromotrichloromethane did not pass through
the classic Arbuzov rearrangement under the present
conditions. The broad generality, the good functional group
tolerance, the low cost, the wide availability of reagents, and
the ease of use make the method a prominent complement to
the Hirao coupling.
Scheme 2 Proposed mechanism for the deoxygenative phosphonation.
The proposed mechanism features the in situ activation by
phosphonium intermediate
ion pairs and
is active, 9a, 11 and could be inactivated by a
nucleophile with little steric hindrance (e.g., H2O). will
partially convert to via the Arbuzov rearrangement in a
relatively dilute solution where is separated away from the
A, and the formation of biscation
B
C. A
A
7
A
nucleophilic N-oxide by solvent molecules (Figures S1 and
S2).16 Comparatively, the reaction system of high
concentration facilitates the deoxygenative phosphonation.
Consequently, the neat reactions become efficient due to the
fact that the number of collision between
(e.g., 1a) increases. The formation of biscation ion pairs
A
and the N-oxide
and
B
C
was supported in some extent by a few examples of similar
biscation ion pairs reported in literatures.19 The SNAr reactions
of pyridine N-oxides that were efficiently promoted by
phosphonium salt PyBroP rationalized the present
mechanism.20
The authors thank the financial support from the National
Natural Science Foundation of China (20971105) and the
Experimental Technology Foundation of Southwest University
(SYJ2016019).
The mechanism provides a reasonable explanation for the
regioselectivity of the phosphonation in case of isoquinoline N-
oxides.21 The reaction could occur at the 1- or 3-position of
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20 (a) A. T. Londregan, S. Jennings and L. Wei, Org.VLieewttA.r,ti2cl0e1O0nl,ine
12, 5254; (b) A. T. Londregan, K. BurfoDrdO,I:E1.0L.1.0C3o9n/Cn7,OKB.0D0.402H
Hesp. Org. Lett., 2014, 16, 3336; (c) Y. Lian, S. B. Coffey, Q. Li
and A. T. Londregan, Org. Lett., 2016, 18, 1362.
Notes and references
1
(a) L. D. Quin, eds., A Guide to Organophosphorus Chemistry,
John Wiley & Sons, Toronto, 2000; (b) F. H. Hartley, eds. The
Chemistry of Organophosphorus Compounds, Wiley, New
York, 1996.
21 The 31P NMR spectra indicated that the transformations of
P(OBu)3 with CBrCl3 were similar to that of P(OMe)3, but no
desired products were identified when P(OBu)3 was
2
(a) J.-L. Montchamp, Acc. Chem. Res., 2014, 47, 77; (b) X.
Chen, D. J. Kopecky, J. Mihalic, S. Jeffries, X. Min, J. Heath, J.
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Johnstone, S. Thibault, H. Xu, M. Cardozo, W. Shen, N.
employed in the deoxygenative phosphonation. These
results implied that the steric hindrance of a phosphite had a
significant impact on the nucleophilic attack of the phosphite
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in Scheme 2.
22 Pyridine N-oxide failed to realize the deoxygenative
B to C
3837; (c) S. A. Paniagua, A. J. Giordano, O. L. Smith, S. Barlow,
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oxide had been fully converted into a complicated mixture,
but the desired compound did not yield (Figure S5).16 The
result is probably attributed to the instability of the
pyridinium salt intermediate, a species corresponding to B.
Similarly, pyridine N-oxide was not workable in the
deoxygenative amination of heteroarene N-oxides. See: X.
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15 The main byproducts included
4
–
7
, CHCl3 and MeBr. They
were identified by NMR spectroscopy. Dimethyl
(trichloromethyl)phosphonate (
according to the literature.14a
7) was parallelly prepared
16 See the Supplementary Information (ESI).
17 A. K. Bhattacharya, G. Thyagarajan, Chem. Rev., 1981, 81
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Table of contents entry
Heteroarene N-oxides successfully converted to heteroarylphosphonates in a very
short time under mild conditions through in situ activation with CBrCl3.