Copper(II) Acetate-Catalyzed Synthesis of Phosphorylated Pyridines via Denitrogenative C?P Coupling between Pyridotriazoles and P(O)H Compounds

Article abstract of DOI:10.1002/adsc.201800909

A new inexpensive copper-catalyzed denitrogenative C?P coupling reaction of pyridotriazoles with P(O)H compounds has been developed. The reaction proceeds via a process of copper-catalyzed P(O)?H insertion into the pyridyl carbene intermediates generated in situ from pyridotriazoles. This reaction provides a new and effective method for the synthesis of a variety of 2-picolylphosphoryl compounds. (Figure presented.).

Full text of DOI:10.1002/adsc.201800909

Title: Copper(II) Acetate-Catalyzed Synthesis of Phosphorylated
Pyridines via Denitrogenative C-P Coupling between
Pyridotriazoles and P(O)H Compounds
Authors: Ruwei Shen, Chao Dong, Jianlin Yang, and Li-Biao Han
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800909
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10.1002/adsc.201800909
Advanced Synthesis & Catalysis
UPDATE
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Copper(II) Acetate-Catalyzed Synthesis of Phosphorylated
Pyridines via Denitrogenative C-P Coupling between
Pyridotriazoles and P(O)H Compounds
Ruwei Shen,a, * Chao Dong,a Jianlin Yang,a Li-Biao Hanb
a State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech
University, Nanjing 210009, China. E-mail: shenrw@njtech.edu.cn
b National Institute of Advanced Industrial Science & Technology (AIST), Tsukuba, Ibaraki, 305-8565, Japan
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract.
A
new
inexpensive
copper-catalyzed
denitrogenative CP coupling reaction of pyridotriazoles
with P(O)H compounds has been developed. The reaction
proceeds via a process of copper-catalyzed P(O)H
insertion into the pyridyl carbene intermediates generated
in situ from pyridotriazoles. This reaction provides a new
and effective method for the synthesis of a variety of 2-
picolylphosphoryl compounds.
Keywords: Copper catalysis; Pyridotriazoles; C-P
coupling; 2-Picolylphosphoryl compounds
Functionalized pyridines are not only valuable
building blocks in organic synthesis, but also widely
occurring in bioactive reagents, pharmaceuticals,
natural products and functional materials.[1,2]
Amongst phosphorus-functionalized pyridines, 2-
picolylphosphorus compounds have been found to
Scheme 1. E-H insertion of pyridyl carbenes derived from
pyridotriazoles
display
various
biological
activities
and
pharmacological properties such as antibacterial and
antimalaria activities.[3] Particularly, a recent study
also revealed that a few types of these compounds
inhibit a range of metallo-β-lactamase (MBL) targets,
indicative of their promising use against medicinally
relevant antibiotic resistant pathogens.[4] In addition,
2-picolylphosphinyl derivatives have been widely
used as important bidentate ligands in transition metal
catalysis,[5] and significantly as extracting reagents in
the processing of nuclear material solutions
containing f-block element ions, due to their good
coordinating ability.[6] Although this type of products
can be accessed by the classic Arbuzov reaction or
Michaelis-Becker reaction using picolyl halides with
R2POM (M=Na, Li, Mg),[3-7] the methods suffer from
drawbacks such as limited reaction scope, low yields,
tedious procedures and a lack of diversity. Thus, the
development of more effective and flexible methods
is highly desired.
On the other hand, pyridotriazoles 1 represent a
valuable class of synthetic intermediates which have
recently received numerous attentions due to their
interesting properties and easy availability.[8-13]
Particularly, the existence of the equilibrium between
1 and the diazo form 1A[13] in solution renders them
convenient precursors of carbene species (Scheme
1a). Based on this reactivity, the transition metal-
catalyzed denitrogenative cyclizations between
pyridotriazoles and alkynes or nitriles have been
developed to provide effective entries to many valued
azacyclic compounds.[8,9] The insertion of a EH
bond (E heteroatom) into pyridyl carbenes can offer
attractive synthetic methods towards functional
pyridines.[10] However, this chemistry is less explored.
Previously, Gevorgyan reported the Rh-catalyzed
NH insertion reaction of pyridyl carbenes derived
from pyridotriaoles to produce valuable picolylamine
derivatives (Scheme 1b).[11] They also revealed in a
pioneer work[8a] one example of Rh-catalyzed SiH
1
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10.1002/adsc.201800909
Advanced Synthesis & Catalysis
insertion in which 7-chloro-substituted pyridotriazole
was the competent precursor. H-phosphonates, H-
phosphinates and H-phosphine oxides (P(O)H
compounds) are stable and easily available. They
have been used as versatile reagents for introducing
phosphoryl or phosphonyl functionalities into organic
molecules via CP bond forming reactions.[14] As part
of our recent interest, we have reported several CP
coupling reactions based on the utility of P(O)H
compounds and copper catalysts, providing effective
methods for the synthesis of a lot of phosphorylated
unsaturated compounds and heterocycles.[15] As a
continued exploration, we propose here that the
Cu(OTf)2 afforded 3a in yields of ≤ 50% (Table 1,
entries 2-5). No reaction took place in a blank
experiment, indicative of the necessity of a catalyst
for the reaction (Table 1, entry 8). The screening of
solvents revealed that dioxane was the best. The
reactions conducted in other solvents such as DCE,
THF, toluene and DMF all gave low yields (20-60%,
Table 1, entry 8-11), and only a trace amount of the
product was detected in case of DMSO as a solvent
(Table 1, entry 12). We also examined the influence
of the reaction temperature. The reaction performed
o
at an elevated temperature (120 C) in a sealed
Schlenk tube produced 3a in 80% yield in 3 h (Table
1, entry 13). However, the decrease in reaction
temperature led to a considerable loss of reaction
efficiency and product yield. When the reaction was
performed at 80 oC, for example, the reaction gave 3a
only in 46% yield after 48 h (Table 1, entry 14). The
significant temperature effect may be partially
explained in terms of the favorable equilibrium shift
to the diazo form at high temperature.[13] Finally the
influence of the catalyst loading was also investigated.
The reaction still proceeded well when Cu(OAc)2 was
reduced from 15 mol% to 10 mol%, furnishing 3a in
82% yield in 6 h (Table 1, entry 15). However, a
prolonged reaction time to 10 h was required to
achieve a comparable yield with 5 mol% of
Cu(OAc)2 (Table 1, entry 16). We therefore defined
the conditions listed in entry 15 of Table 1 as the
standard conditions for the following study.
reactive
carbene
species
generated
from
pydidotriazole 1 may be trapped by a phospho-
nucleophile to form new CP bond based on an
inexpensive copper catalyst. Such a denitrogenative
CP coupling would thereby provide a new method
towards phosphorylated pyridines from these readily
available materials (Scheme 1c).
Our study began with the investigation on the
reaction of pyridotriazole 1a and diphenylphosphine
oxide (2a). Table 1 shows the results for optimization
study. Among the various copper salts we checked,
Cu(OAc)2 was found as the most effective catalyst to
give the expected 2-picolyldiphenylphosphine oxide
o
(3a) in 81% yield in dioxane at 100 C after 6 h
(Table 1, entry 6). CuI was least effective and gave
3a only in 10% yield (Table 1, entry 1). Other copper
salts such as CuCl, Cu(MeCN)4PF6, CuSO4 and
Table 1. Optimization on the copper-catalyzed reaction of 1a and 2a[a]
Entry
Catalyst
Loading (%)
solvent
Tempt (oC)
Time (h)
Yield (%)[b]
15
15
15
15
15
15
15
15
15
15
15
15
15
15
10
5
6
6
1
2
CuI
CuCl
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
dioxane
DCE
100
100
100
100
100
100
100
100
100
100
100
100
120
80
10
50
47
28
50
81
0
6
3
Cu(MeCN)4PF6
Cu(OTf)2
CuSO4
6
4
12
6
5
6
Cu(OAc)2
No catalyst
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
Cu(OAc)2
6
7
6
8
43
60
20
56
trace
80
46
82
80
12
12
12
6
9
THF
10
11
12
13
14
15
16
toluene
DMF
DMSO
dioxane
dioxane
dioxane
dioxane
3
48
6
100
100
10
[a] Unless otherwise noted, 1a (0.2 mmol), 2a (1.5 equiv), [Cu] (5-15 mol%), solvent (1 mL) was heated in a Schlenk tube.
[b] Isolated yields.
2
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10.1002/adsc.201800909
Advanced Synthesis & Catalysis
Table 2. Copper-catalyzed denitrogenative C-P coupling of pyridotriazoles 1 with P(O)H compounds 2[a]
[a]
Unless otherwise noted, 1 (0.2 mmol), 2 (1.5 equiv), Cu(OAc)2 (10 mol%), 1,4-dioxane (1 mL) was heated at 100 oC for
6 h. Isolated yields are given.
[b] Reaction time: 10 h.
3
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10.1002/adsc.201800909
Advanced Synthesis & Catalysis
Table 2 shows some typical 2-picolylphosphoryl
Some control experiments were conducted to gain
insights into the mechanism (Scheme 3). The reaction
of the D-labelled substrate 2a-D and 1a afforded 3a-
D in 79% yield under the standard conditions (eq.1).
About 89% of D atom was observed in the methenyl
group of 3a-D. Interestingly, the reaction of 1a and
2a under aerobic conditions did not produce 3a,
instead 2-picolyl diphenylphosphinate (6) was
obtained in 36% yield (eq. 2). We reason that 6 may
be formed via several consecutive steps: 2a may be
oxidized to diphenylphosphinic acid (7) in the
presence of the copper catalyst under the aerobic
conditions, which reacts with 1a to produce 6. This
assumption was supported by the result of a separate
experiment that the treatment of a mixture of 1a and
7 under similar conditions led to the formation of 6 in
75% yield (eq. 3).
compounds prepared by taking advantage of the
present method. The pyridotriazole 1b which bears a
methyl group at C6 position reacted smoothly with 2a
to furnish the expected product 3b in 84% yield
(Table 2, entry 2). 7- or 4-methyl substituted
pyridotriazoles 1c and 1d gave the corresponding
products 3c and 3d in 70% and 75% yield,
respectively (Table 2, entries 3 and 4). The aryl
substituted pyridotriazoles 1e and 1f participated well
in the reactions, yielding 3e and 3f in 85% and 83%
yields (Table 2, entries 5 and 6). It was also possible
to employ bromo-substituted pyridotriazole in this
transformation, as exemplified by the successful
preparation of 3g in good yield (Table 2, entry 7).
However, the reaction of the quinoline-derived
triazole 1h took place slowly and gave the product 3h
in moderate yield (Table 2, entry 8). The reaction of
7-pyrydinyl pyridotriazole 1i delivered the
phosphinyl bipyrydine 3i in a low yield probably due
to the poison of the copper catalyst by the bipyridine
unit (Table 2, entry 9). Indeed, a separate experiment
revealed that the reaction of 1a and 2a catalyzed by a
combination of 10 mol% Cu(OAc)2 and 10 mol%
2,2'-bipyridine gave 3a in a decreased yield (55%).
This result may support our assumption. Fortunately,
pyridotriazoles 1j-1l bearing a methyl or a phenyl
substituent (R2 = Me or Ph) at the C3 position, could
successfully couple with 2a to afford the products in
moderate to good yields (Table 2, entries 7, 10, 11
and 12). As for P(O)H compounds, a lot of H-
phosphine oxides (2b-2j) including a thiophene-
substituted substrate (2i) can engage in the reaction to
deliver the corresponding products in good to high
yields (Table 2, entries 13-21). The reactions were
generally complete in 6 h, except for 2g and 2h
bearing ortho-substituted phenyl groups. A prolonged
reaction time to 10 h was needed for the full
consumption of the starting materials probably due to
the steric effect (Table 2, entries 18 and 19). In
addition, H-phosphonate 2k and H-phosphinate 2l are
also applicable to this transformation, yielding 3v-3x
in moderate yields (Table 2, entries 22-24).
Synthetic transformations of the products are
illustrated in Scheme 2. The treatment of 3a with
LiHMDS at –20 oC followed by the addition of allylic
bromide gave the bisallylation product 4 in 96% yield
in one operation. The cyclization of 3a with 2-
bromoacetophenone in the presence of K2CO3
afforded the phosphinyl indolizine 5 in 60% yield.
Scheme 3.The control experiments
To probe the possibility of a radical process, we
performed the reaction of 1a and 2a in the presence
of a free radical scavenger butylated hydroxytoluene
Scheme 2. Synthetic transformations of 3a
4
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10.1002/adsc.201800909
Advanced Synthesis & Catalysis
(BHT). The reaction of 1a, 2a and BHT in an equal
amount gave 3a in 64% yield (eq. 4). In addition, we
also conducted the reaction of 1a with pent-4-en-1-
yl(phenyl)phosphine oxide (2m) under the standard
conditions (eq. 5). The reaction produced 3y in 79%
yield, yet the possible cyclized product from a radical
process was not formed. These results exclude a
radical mechanism although the copper catalyst is
known as initiator for the formation of phosphoryl
radicals in some reactions.[16]
In summary, we have reported a Cu(OAc)2-
catalyzed C-P coupling reaction of pyridotriazoles
with P(O)H compounds including secondary
phosphine oxides, H-phosphonates and H-
phosphinates to offer a new method for the synthesis
of 2-phosphorylmethyl pyridines. The mechanistic
study indicates that the reaction may proceed via the
interception of the copper pyridyl carbenes by the
phosphorus nucleophiles. Further studies on the
reaction scope and application of this method are
being pursued.
A competition reaction of 1a with electronically
different diarylphosphine oxides 2b and 2c was also
performed (eq. 6). Interestingly, the analysis of the
crude reaction mixture by 31P NMR showed that the
reaction gave a mixture of products in favor of the
formation of 3m (3m/3n = ca. 6/1). This result
Experimental Section
Typical
procedure
C-P
for
the
coupling
copper-catalyzed
reaction of
denitrogenative
suggests that Ar2P(O)H
2
bearing electron-
pyridotriazoles 1 with P(O)H compounds 2: To a flame-
dried Schlenk tube were added Cu(OAc)2 (3.6 mg, 0.02
mmol), pyridotriazole 1a (23.8 mg, 0.2 mmol),
diphenylphosphine oxide 2a (60.6 mg, 0.3 mmol) and 1,4-
dioxane (1 mL) under a dry nitrogen atmosphere. The
withdrawing groups reacts faster to form the product.
It is known that Ar2P(O)H 2 is in equilibrium with its
tautomer 2’ (see Scheme 4), and the introduction of
electron-withdrawing substituents in the phenyl
groups of 2 leads to a shift in equilibrium towards its
tautomer 2’.[17] We thus deduced that the easier
tautomerization of 2 bearing electron-withdrawing
groups than that with electron-donating groups to 2’
may be responsible for the observed result of the
competition experiment.
o
resulting mixture was stirred at 100 C for 6 h, which was
then cooled to room temperature and diluted with saturated
EDTA-4Na solution in water (5 mL). The mixture was
extracted with EtOAc (10 mL×3), and the combined
organic layes was dried with MgSO4, filtrated and
concentrated to dryness. The residue was purified by
column chromatography on silica gel (PE/EtOAc: 1/1-1/3,
with 5 volume% Et3N) to afford 3a (48.1 mg, 82%). This
is a known compound.[6a] 1H NMR (400 MHz, CDCl3):
8.39 (d, J = 4.8 Hz, 1H), 7.78-7.73 (m, 4H), 7.59-7.41 (m,
8H), 7.10-7.07 (m, 1H), 3.94 (d, J = 14.4 Hz, 2H);31P
NMR (CDCl3, 160 MHz): δ 29.9.
Based on the above results and literature reports,[8,
18] a plausible mechanism was proposed in Scheme 4.
The reduction of Cu(OAc)2 by P(O)H compound first
generates the active Cu(I) species, which reacts with
1 to produce the Cu–carbene complex A after the loss
of one molecule of N2. The coordination of P(O)H
compound 2 via its tautomer 2’ with A may form the
Cu–carbene intermediate B. This step may be closely
related to the tautomerization process of the P(V) 2 to
the P(III) species 2’, as indicated by the competition
experiment (eq. 6). The intermediate B subsequently
undergoes 1,2-migration to construct the C-P bond
leading to the formation of the copper intermediate C.
The proto-demetalation process then takes place to
deliver the product 3 and regenerate the catalyst.
Acknowledgements
Financial support from the NSFC (21302095), Jiangsu
Provincial NSF (BK20130924) and Nanjing Tech University is
acknowledged.
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10.1002/adsc.201800909
Advanced Synthesis & Catalysis
UPDATE
Copper(II) Acetate-Catalyzed Synthesis of
Phosphorylated Pyridines via Denitrogenative C-P
Couplings between Pyridotriazoles and P(O)H
Compounds
Adv. Synth. Catal. Year, Volume, Page – Page
Ruwei Shen*, Chao Dong, Jianlin Yang, Li-Biao
Han
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