With DBU-activated N-bromophthalimide as potential N-sources to achieve P-N cross-coupling of P(O)-H compounds

Article abstract of DOI:10.1016/j.tetlet.2016.05.076

We have demonstrated that N-haloimides can be utilized as an aminating reagent, in addition to the traditional brominating reagent. Herein, the P-N cross-coupling of P(O)-H compounds and N-bromophthalimide has been developed with the DBU activation strate

Full text of DOI:10.1016/j.tetlet.2016.05.076

Accepted Manuscript
With DBU-activated N-bromophthalimide as potential N-sources to achieve
P–N cross-coupling of P(O)–H compounds
Yueju Li, Fushun Liang
PII:
S0040-4039(16)30610-4
DOI:
http://dx.doi.org/10.1016/j.tetlet.2016.05.076
TETL 47695
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
18 April 2016
19 May 2016
20 May 2016
Please cite this article as: Li, Y., Liang, F., With DBU-activated N-bromophthalimide as potential N-sources to
achieve P–N cross-coupling of P(O)–H compounds, Tetrahedron Letters (2016), doi: http://dx.doi.org/10.1016/
j.tetlet.2016.05.076
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With DBU-activated N-bromophthalimide as potential N-sources to achieve P―N
cross-coupling of P(O)―H compounds
Yueju Li,a Fushun Liang*,a,b
a Department of Chemistry, Northeast Normal University, Changchun 130024, China.
bCollege of Chemistry, Liaoning University, Shenyang 110036, China
*Corresponding authors. Tel. +86 431 8509 9759; Fax. +86 431 8509 9759.
E-mail addresses: liangfs112@nenu.edu.cn.
ABSTRACT
We have demonstrated that N-haloimides can be utilized as an aminating reagent, in addition
to traditional brominating reagent. Herein, the P―N cross-coupling of P(O)―H compounds
and
source may arise from internal
external phthalimide derivatives (with NBS-DBU activation system). The reaction features
broad phosphorous compounds scope, including -phosphinates, -phosphonates and
-phosphine oxides, and short reaction time (less than 10 min). This method provides a
N-bromophthalimide has been developed with the DBU activation strategy. The nitrogen
N-bromophthalimide itself (a self-immolating reagent) or
H
H
H
simple, convenient, efficient and green route towards phosphoramidates which are of
biological importance under mild conditions.
Keywords: P―N cross-coupling; P(O)―H compounds; N-bromophthalimide; aminating reagent;
DBU
Phosphoramidates are key structural units in a number of biologically active natural products, which
not only show antibacterial, antifungal, antitumor (such as Agrocin 841a, Phosmidosin1b, Microcin C71c)
and anti-HIV biological activities,1 but also are important chiral auxiliaries for asymmetric synthesis.2
Phosphoramidates are also used as flame retardants.3 One of the synthetic methods for
phosphoramidates involves the utilization of phosphoryl halides or phosphoryl azide species, which
need to prepare in advance and are potentially hazardous.4 The development of novel and green
synthetic procedures for phosphoramidates directly from P(O)―H substrates is highly desirable,
because they are more readily available, easy-to-handle and no prefunctionalization step is required.
Thus the overall synthetic efficiency is greatly improved. To date, there has been made significant
progress in the development of P N bond forming reactions via direct activation of the P―H bond, for
example, well-known Atherton–Todd reaction.5 However, the reaction is limited by the use of toxic
CCl4, excess base and long reaction time. Metal-catalyzed P N cross-coupling reaction of P(O)―H
compounds has been recently reported.6 Mizuno and co-workers communicated a cross-coupling of
phosphites and amides to form phosphoramidates by using Cu(II) acetate and a stoichiometric amount
of base.6a Hayes et al. presented a Cu(I) iodide-catalyzed aerobic oxidative cross-coupling reaction of
H-phosphonates and amines.6b Metal-free phosphorylation of amines is accomplished using molecular
iodine as a catalyst and H2O2 or molecular oxygen in air as the sole oxidant under mild reaction
conditions.7a,b
Our research group has demonstrated the N-haloimides like N-bromosuccinimide (NBS) and
N-bromophthalimide (NBP) can be utilized as an aminating reagent, in addition to traditional
brominating reagent. By DBU activation strategy, a variety of amination reaction of -dicarbonyl

compounds, aryl alkyl ketones, , -unsaturated enones, specific alkenes and indole derivatives, by
employing N-haloimides as potential N-sources has been developed.8 We hoped to expand the general
utility of the N-haloimides-DBU combination system to a variety of fundamental substrates. In this
work, we set out to explore the imidation reaction of trivalent phosphorus compounds to achieve
phosphoramidate derivatives which are of great importance.9 As a result, a metal-free P N
cross-coupling of P(O) H compounds with N-bromophthalimides was developed, which provides a
simple, convenient and efficient protocol towards phosphoramidates, directly from P(O)―H substrates.
Beginning with our previously reported reaction conditions, we tested the DBU (1.5 equiv) mediated
coupling reaction between ethyl phenylphosphinate 1a and N-bromophthalimide (NBP, 1.5 equiv)
(Table 1). The reaction conducted either at room temperature or upon heating was messy. Thus, we
decided to try the reaction by lowering the temperature. To our delight, the reaction conducted in DMF
o
at 0 C gave the desired ethyl (1,3-dioxoisoindolin-2-yl)(phenyl)phosphinate (2a) in 42% yield (entry
1). Other solvents like THF, toluene and DCM afforded improved yields (entries 2-4) and MeCN
proved to be the most efficient, furnishing 2a in 85% yield within 10 min (entry 5). Other than DBU,
Lewis bases including MTBD, DBN, DABCO, Et3N and PPh3 were selected as the activator. The
results indicate that all of them were much less efficient than DBU (entries 6-10). Furthermore,
inorganic bases like NaOH, t-BuOK and K2CO3 were proved to be inefficient, indicating that DBU
works not only as a base, but also an effective activator. Catalytic amount of DBU (e.g. 0.5 equiv) was
not enough to drive the reaction to completion (entry 11).10
Table 1. Optimization of the reaction conditionsa-c
Entry Activator (equiv)
Solvent
DMF
Time (min)
Yield (%)d
1
2
DBU (1.5)
DBU (1.5)
DBU (1.5)
DBU (1.5)
DBU (1.5)
MTBD (1.5)
DBN (1.5)
DABCO (1.5)
Et3N (1.5)
PPh3 (1.5)
DBU (0.5)
10
10
90
10
10
10
30
90
90
90
90
42
58
78
82
85
trace
48
40
0
THF
3
toluene
DCM
4
5
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
6
7
8
9
10
11
0
32
a Reactions were carried out with 1a (1 mmol), NBP (1.5 equiv) and activator (1.5 equiv) in solvent (2.0 mL) at 0 oC.
b Reactions were carried out in the open air. c In all cases, NBP mixed with DBU firstly, followed by the addition of
d
the P(O)―H substrates. Isolated yield. DBU = 2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepine; MTBD =
7-methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene; DBN = 3,4,6,7,8,9-hexahydro-2H-pyrido[1,2-a]pyrimidine; DABCO =
1,4-diazabicyclo[2.2.2]octane.
Table 2. P―N cross-coupling: Scope of P(O)―H substratesa-c

O
O
O
P
O
P
DBU
+
N
Br
N
R
H
R
MeCN, 0
open air
C
R'
R'
O
O
1
2
a
Reactions were carried out with 1 (1 mmol), NBP (1.5 equiv) and DBU (1.5 equiv) in MeCN (2.0 mL) at 0 oC. b In
all the cases, NBP mixed with DBU firstly, followed by the addition of the P(O)―H substrates. c Isolated yield.
Figure 1. The X-ray structure of 2j.
In the following work, we investigated the generality of the protocol for various trivalent phosphrous
substrates (Table 2).11 H-phosphinates (both cyclic and acyclic) afforded the corresponding
phosphoramidates 2b-e in 78-81% yields. A series of H-phosphonates were tested under otherwise
identical conditions. The substituents on the P center include alkyloxy, CF3-containing alkyloxy and
aryloxy. The phosphoramidate products 2f-m were obtained in moderate yields (52-75%). The
structure of 2j was confirmed by X-ray single-crystal diffraction (Fig. 1).12 Diarylphosphine oxides can

also engage in the cross-coupling with NBP to produce the corresponding phosphoramidate derivatives
2n and 2o in moderate yields. From above one can see that the scope of the P(O)―H components in
the P―N coupling reaction is broad and the reaction time is quite short (less than 10 min). It was
noteworthy that all the reactions listed in Table 2 need to be carried out in the open air. No reaction
took place under a N2 atmosphere. This indicated that dioxygen in air might facilitate the reaction,
however, the reason was still unclear.
The scope of N-Haloimide components were investigated, but appears to be narrow. For
N-halophthalimides (halogen = Br and Cl), although NBP is efficient (85% yield), NCP was less
efficient (45%). N-halosuccinimides (halogen
= Cl, Br and I), N-bromosaccharin and
1,3-dibromo-5,5-dimethyl hydantoin were inefficient for the coupling reaction.13
In view that the reaction of NBS/DBU with 1a gave no phosphoramidate product, we decided to
introduce external nitrogen nucleophiles to the reaction (Scheme 1). In this case, DBU-activated NBS
is supposed to transform the P(O)―H substrates into phosphoryl bromides. With NBS/DBU system,
the reaction of 1a and phthalimide (1.5 equiv) may take place, giving compound 2a in 75% yield. In
the P N coupling reactions of ethyl phenylphosphinate and diethyl phosphonate with
4-nitrophthalimide (1.5 equiv) in the presence of NBS (1.2 equiv) and DBU (1.2 equiv), the imidated
products 2p and 2q were achieved in 87% and 80% yields, respectively. Diethyl phosphonate reacts
with 4-bromophthalimide to give diethyl (5-bromo-1,3-dioxoisoindolin-2-yl)phosphonate 2r in 74%
yield. We did not get a success for other type of external N-components presently.
Scheme 1. P N cross-coupling between P(O) H compounds and phthalimide derivatives.
In a control experiment, TEMPO (1.5 equiv) was added immediately to a mixture of ethyl
o
phenylphosphinate (1.0 mmol), NBP (1.5 equiv) and DBU (1.5 equiv) in MeCN at 0 C (Scheme 2).
Compared to the reaction without TEMPO, the yield has almost no change. The result may help one to
exclude the possible radical pathway.
Scheme 2. Control experiment.
A possible mechanism for the coupling reaction was proposed in Scheme 3. NBP reacts with DBU
to form 1-bromo-2,3,4,6,7,8,9,10-octahydropyrimido[1,2-a]azepin-1-ium 1,3-dioxoisoindolin-2-ide
(I)8,14 followed by in situ electrophilic bromination of P(O)―H compounds to give phosphoryl bromide

II.7a Further addition/elimination affords the corresponding cross-coupled product 2. The function of
DBU is to deprotonate the phosphorus substrates (as base) and to activate NBP (as a promoter) to be
more electrophilic bromine cation and potentially nucleophilic phthalimide anion.15
Scheme 3. Possible mechanism.
In summary, we have developed a DBU-mediated cross-coupling reaction of a variety of
phosphorous compounds including H-phosphinates, H-phosphonates and H-phosphine oxides and
N-bromophthalimide for the formation of phosphoramidate products under mild conditions. This
process uses N-bromophthalimide as cationic halogen and anionic N-nucleophile sources. In situ
formation of phosphoryl bromide and subsequent addition/elimination make the reaction to be
environmentally benign and synthetically efficient. Further research on the utilization of N-haloimide
as potential nitrogen source in organic transformations is ongoing in our laboratory.
Acknowledgements
We gratefully acknowledge the National Science Foundation of China (No. 21372039) for financial
support.
Supplementary data
Supplementary data associated with this article can be found, in the online version, at
http://dx.doi .org/10.1016/j.tetlet.2016.??????.
References and notes
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10 HBr side-product would consume 1.0 equiv of DBU.
11 General procedure for the preparation of 2 (2a as an example): To a solution of NBP (1.5 mmol, 0.339 g) and
DBU (1.5 mmol, 0.218 mL) in MeCN (2.0 mL), ethyl phenylphosphinate 1a (1.0 mmol, 0.154 mL) was added.
o
The reaction mixture was stirred at 0 C for 10 min. After the starting material 1a was consumed as indicated by
TLC, the reaction mixture was poured into water and then extracted with CH2Cl2 (3 × 10 mL). The combined
organic phase was washed with water (3 × 10 mL), dried over anhydrous MgSO4, filtered and concentrated under
reduced pressure. The crude product was purified by flash chromatography (silica gel, petroleum ether : ethyl
acetate = 3 : 1) to give 2a (268 mg, 85%) as a white solid.
11 CCDC number 1407192 contains the supplementary crystallographic data for this paper. The data can be
obtained
www.ccdc.cam.ac.uk/data_request/cif.
12 The reason for this is unclear at the moment.
free
of
charge
from
The
Cambridge
Crystallographic
Data
Centre
via
13 The existence of strong interaction between NBP and DBU has been demonstrated by i) DFT calculation; ii) 1H
NMR study; and iii) the ionic conductivity measurement. See ref. 8e.
14 Only in the case of NBP mixed with DBU firstly, followed by the addition of P(O)―H compounds, can the
target compound be observed. That P-atom acting as a nucleophile to directly react with NBP in the first step was
tentatively excluded. Please refer to: Mitova, V.; Koseva N.; Troev, K. RSC Adv., 2014, 4, 64733.

Graphical abstract

ꢀ
ꢀ
ꢀ
ꢀ
A metal-free P―N cross-coupling is developed.
Halogen bonding activation by DBU is the driving force for the P―N cross-coupling.
An ionic rather than a radical mechanism is proposed.
N-haloimides can be utilized as an aminating reagent.