Cesium Carbonate-Promoted P-Alkylation of Phosphinecarboxamides

Article abstract of DOI:10.1055/s-0037-1611364

An effective method for the P-alkylation of N -arylphosphinecarboxamides was demonstrated. Primary N -arylphosphinecarboxamides without additional protection underwent P-monoalkylation with various alkyl halides in the presence of cesium carbonate as a promoter. The reactivity of phosphinecarboxamides was also explored.

Full text of DOI:10.1055/s-0037-1611364

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© Georg Thieme Verlag Stuttgart · New York
2018, 29, A–D
letter
A
en
X.-G. Chen et al.
Letter
Synlett
Cesium Carbonate-Promoted P-Alkylation of Phosphinecarbox-
amides
Xing-Guo Chena,b
Qiu-Li Wua,b
Fei Houa,b
Xi-Cun Wanga,b
Zheng-Jun Quan*a,b
H
N
H
N
H
P
PH2
Cs2CO3 (1 equiv)
DMSO, r.t., 0.5 h
R2
R2X
R1
R1
+
O
O
17 examples
up to 85% yield
R1 = H, CH3, OCH3, Cl
R2 = Alkyl
• Air- and moisture-stable starting materials
• Mild reaction conditions
X = Cl, Br, I
a College of Chemistry and Chemical Engineering, Northwest
Normal University, Lanzhou, 730070, P. R. of China
b Gansu International Scientific and Technological Cooperation
Base of Water-Retention Chemical Functional Materials,
Lanzhou, 730070, P. R. of China
quanzhengjun@hotmail.com
Received: 09.10.2018
Accepted after revision: 31.10.2018
Published online: 03.12.2018
However, primary phosphines (or phosphanes) are typical-
ly extremely air-sensitive, pyrophoric, noxious, and toxic.8
Furthermore, stoichiometry is important, because overal-
kylation is common in these reactions. To avoid these diffi-
culties, phosphine–borane complexes, which are inert to-
ward moisture and air, have been used.9 Although alkyla-
tion of these compounds can be more easily controlled than
that of the nonadducts, secondary amines needed to be
used to deprotect and release the free phosphine from the
adduct.10 Compared with general primary alkyl- or aryl-
phosphines,11 phosphinecarboxamides are relatively stable
to air and moisture, and they have low toxicity and are safe
and nonflammable. On the basis of the properties of phos-
phinecarboxamides, and the synthesis of N-arylphosphine-
carboxamides by our group,12 it became necessary to ex-
plore the reactivity of N-arylphosphinecarboxamides.
Here, we report a chemoselective method for the direct
P-monoalkylation of N-arylphosphinecarboxamides with a
broad range of alkyl halides by using Cs2CO3 as base. We
also investigated the reaction of N-arylphosphinecarbox-
amides with some nucleophilic reagents, such as morpho-
line or thiophenol.
Initially, N-(4-methoxyphenyl)phosphinecarboxamide
(1a) and iodomethane (2a) were used as model substrates
to explore the optimal reaction conditions (Table 1). In the
absence of a base, no reaction occurred in DMSO at room
temperature after 0.5 hours (Table 1, entry 1). A 23% yield of
the P-monoalkylation product 3a was isolated when K2CO3
(1 equiv) was added as a base (entry 2). A short survey of
bases indicated that Cs2CO3 performed most efficiently in
this transformation (entries 3–6). We then screened vari-
ous solvents, and found that DMSO was the most suitable
solvent for this transformation (entries 7–10). Heating the
reaction led to a decreased yield of product 3a (entry 11),
possibly as a result of the instability of the phosphinecar-
DOI: 10.1055/s-0037-1611364; Art ID: st-2018-w0653-l
Abstract An effective method for the P-alkylation of N-arylphosphine-
carboxamides was demonstrated. Primary N-arylphosphinecarboxam-
ides without additional protection underwent P-monoalkylation with
various alkyl halides in the presence of cesium carbonate as a promoter.
The reactivity of phosphinecarboxamides was also explored.
Key words alkylation, phosphinecarboxamides, arylalkylphosphine-
carboxamides, secondary phosphines, alkyl halides
Organic phosphine compounds are widely used in
flame-retardant materials, photoelectric materials, phar-
maceutical chemistry, and organic synthesis.1 Therefore,
the preparation of organophosphorus compounds is con-
sidered one of the most important research topics in the
field of organic synthesis. Jupp and Goicoechea conducted a
series of studies on the synthesis and properties of urea an-
alogue phosphinecarboxamides,2 including the synthesis of
(phosphino)carbonyl amino acids,3 N-(prop-2-yn-1-
yl)phosphinecarboxamides, and phosphorus-containing
heterocycles. These novel compounds might ultimately be
used for the synthesis of chiral phosphines or as precursors
to polymeric materials.4 The coordination chemistry of
phosphinecarboxamides, which have similar electronic
properties to those of PH3 and of trialkyl phosphites, has
also been investigated.5 In the chemical vapor deposition
synthesis of zinc phosphide thin films, phosphinecarbox-
amide is a safer and more efficient precursor than highly
toxic, corrosive, and flammable phosphine, which was pre-
viously used.6
Generally, primary phosphines can be used as starting
materials for the synthesis of secondary phosphines by P-
alkylation; for example, BuLi has been used to achieve
deprotonation in the alkylation of primary phosphines.7
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

B
X.-G. Chen et al.
Letter
Synlett
boxamide at the higher temperature. Prolonging reaction
times led to a slight lowering of the yield of the reaction
(entry 12).
Having determined the optimal conditions (Table 1, en-
try 4), we examined the scope and limitations of this meth-
od (Scheme 1).13 First, the reactions of a series of N-aryl-
phosphinecarboxamides were evaluated with iodomethane
as a methylating reagent. N-Arylphosphinecarboxamide
bearing an electron-rich methyl or methoxy group afforded
the desired products 3a–e smoothly in yields of 76–85%.
The slightly lower yield of the ortho-methyl-substituted N-
arylphosphinecarboxamide 3c indicated that the reaction
was slightly sensitive to a steric effect in the N-arylphos-
phinecarboxamide. In the same way, this reaction was also
applicable to N-arylphosphinecarboxamides bearing elec-
tron-withdrawing substituents, and the products 3f and 3g
were obtained in high yields of 80 and 75%, respectively.
Next, the reactions of a series of alkyl halides 2 were evalu-
ated. Under the standard conditions, several primary alkyl
bromides or iodides (1-bromoethane, 1-iodoethane, 1-bro-
mobutane, 1-iodobutane, 1-bromohexane, and 1-bromo-
heptane) reacted with 1 (R1 = 4-MeO) to afford the desired
secondary phosphines 3h–m in yields of 63–76%. Activated
alkyl halides (benzyl chloride, benzyl bromide, or propargyl
bromide) afforded the desired products 3n–p in yields of
56–73%. The yield was affected by the activity of the benzyl
halide (3o versus 3p). Disappointingly, cyclohexyl bromide
gave only a 20% isolated yield of the P-monoalkylated prod-
uct 3q, and the introduction of a sterically hindered substit-
uent, for example in 2-bromo-2-methylpropane, resulted in
failure to obtain the corresponding product, possibly due to
a detrimental steric effect.
Table 1 Optimization of Reaction Conditionsa
H
N
H
H
PH2
base
N
P
+
CH3I
solvent, T/°C
O
O
MeO
MeO
1a
2a
3a
Entry
Base
–
Solvent
Yieldb (%)
c
1
2
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMF
–
K2CO3
23
43
85
15
64
53
60
34
70
50
66
3
K3PO4
Cs2CO3
Et3N
4
5
6
DBU
7
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
8
acetone
i-PrOH
MeCN
DMSO
DMSO
9
10
11d
12e
a Reaction conditions: 1a (0.2 mmol), 2a (0.24 mmol, 1.2 equiv), base (0.2
mmol), solvent (4.0 mL), r.t., 0.5 h.
b Yields of isolated product
c NR = no reaction.
d This reaction was conducted at 60 °C.
e This reaction was conducted for 12 h.
H
H
N
H
N
PH2
P
Cs2CO3 (1 equiv)
DMSO, r.t.., 0.5 h
R2
R1
R1
+
R2X
O
O
X = Cl, Br, I
3
1
2
H
H
H
H
H
H
P
H
H
H
H
H
H
N
P
N
P
N
N
P
N
P
N
P
O
O
O
O
O
O
MeO
Cl
3a, X = I, 85%
3b, X = I, 82%
3c, X = I, 76%
3d, X = I, 81%
3e, X = I, 83%
3f, X = I, 80%
H
H
H
N
H
H
N
H
H
N
H
H
N
H
P
H
H
N
P
P
P
P
N
P
3
5
6
O
O
O
O
O
O
MeO
MeO
MeO
MeO
MeO
Cl
3g, X = I, 75%
3l, X = Br, 74%
3m, X = Br, 70%
3n, X = Br, 64%
3h, X = Br, 71%
3i, X = I, 76%
3j, X = Br, 63%
3k, X = I, 69%
H
H
H
H
P
H
H
N
P
N
N
P
O
O
O
MeO
MeO
MeO
3o, X = Cl, 56%
3p, X = Br, 73%
3q, X = Br, 20%
3r, X = Br, 0%
Scheme 1 Substrate scope for the reaction of N-arylphosphinecarboxamides with alkyl halides
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

C
X.-G. Chen et al.
Letter
Synlett
H
H
H
N
N
PH2
K2CO3 (2 equiv)
N
P
a)
b)
+
CH3I
CH3CN, 80 °C, 6 h
O
O
O
O
MeO
MeO
MeO
MeO
OMe
OMe
2a
(3 equiv)
1a
4, 67% yield
H
N
H
H
H
N
Cs2CO3 (1 equiv)
DMSO, r.t., 6 h
PH2
N
P
O
O
1a
5, 23% yield
Scheme 2 Control experiments
When we used an excess of iodomethane in an attempt
to obtain the dimethylated product under the standard con-
ditions (2.0 equiv Cs2CO3 as a base and DMSO as the solvent
at room temperature), the expected dimethylated product
was not formed, but a small amount of product 4 (12%
yield) together with the major product 3a (61% yield) were
obtained. We explored various reaction conditions in an at-
tempt to improve the yield of product 4 and, finally, we
found that product 4 could be obtained in 67% yield by us-
ing 2.0 equivalents of K2CO3 as a base and MeCN as the sol-
vent at 80 °C [Scheme 2(a)]. We found that when no methyl
iodide was added, 2a reacted with itself in the presence of
Cs2CO3 (1 equiv) as base and DMSO as solvent to form the
biuret [NH(CONH2)2] analogue 5 [Scheme 2(b)].14 This re-
sult was similar to one previously reported,15 and other re-
lated anionic species, such as [P(CO2Me)2]–, generated by
using a different synthetic protocol, have previously been
reported.16
Because no thorough study has been made of the chem-
ical properties of N-arylphosphinecarboxamides, it is nec-
essary to report some of the properties we found in the fol-
lowing experiments, which should be helpful in further re-
searches on N-arylphosphinecarboxamides. The I2-
promoted substituted reaction of 1a with morpholine (1
equiv) resulted in the formation of N-(4-methoxyphe-
nyl)morpholine-4-carboxamide (6) [Scheme 3(a)]. Similar-
ly, the reaction of 1a with thiophenol or diphenyl disulfide
gave the P-substituted product S-phenyl (4-methoxyphe-
nyl)thiocarbamate (7) [Schemes 3(b) and 3(c)]. We there-
fore believe that an addition–elimination process occurred
in which the carbonyl site of the phosphoramide was easily
attacked by the nucleophiles, with removal of phosphorus
in the form of PH3.
In summary, we have established an efficient and che-
moselective Cs2CO3-promoted method for the direct P-
monoalkylation of primary phosphinecarboxamides with
alkyl halides in the absence of additives or catalysts, per-
mitting the preparation of a range of secondary phosphines
in good yields. The reaction has the advantages of mild re-
action conditions, starting materials that are stable to air
and moisture, and short reaction times. Meanwhile, we
found that nucleophilic reagents, such as morpholine, thio-
phenol, and diphenyl disulfide, readily attack the carbonyl
group of N-arylphosphinecarboxamides, resulting in an ad-
dition–elimination reaction to form ureas or thiocarba-
mates. These studies have implications in relation to the ex-
ploration of the reactivity of phosphinecarboxamides.
Funding Information
We are thankful for the financial support from the National Nature
Science Foundation of China (No 21562036), and the Scientific and
Technological Innovation Engineering program of Northwest Normal
University (NWNU-LKQN-15-1).
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n
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C
h
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6
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6)
O
H
O
HN
N
N
(a)
(b)
Supporting Information
O
I2, r.t., 1 min
MeO
MeO
MeO
6, 81% yield
Supporting information for this article is available online at
https://doi.org/10.1055/s-0037-1611364.
H
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n
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S
SH
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1a
O
t-BuOH, Cs2CO3, r.t., 0.5 h
References and Notes
7, 86% yield
H
(1) (a) De Clercq, E. Med. Res. Rev. 2011, 31, 118. (b) Katti, K. V.; Gali,
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S
S
Ph
Ph
S
(c)
O
t-BuOH, Cs2CO3, r.t., 0.5 h
7, 84% yield
Scheme 3 The reaction of phosphinecarboxamide 1a with the nucleo-
philic reagents morpholine, thiophenol, and diphenyl disulfide
© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D

D
X.-G. Chen et al.
Letter
Synlett
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(13) Phosphinecarboxamides 3a–q; General Procedure
The appropriate N-arylphosphinecarboxamide 1 (0.2 mmol)
and haloalkane 2 (0.24 mmol, 1.2 equiv) were added to a sealed
tube charged with a mixture of Cs2CO3 (0.2 mmol, 1 equiv) in
DMSO (4 mL), and the resulting mixture was stirred at r.t. for 0.5
h. When the reaction was complete (TLC), H2O (30 mL) was
added and the mixture was extracted with EtOAc. The organic
phase was separated, dried (MgSO4), filtered, and concentrated.
The crude product was purified by column chromatography
[silica gel, PE–EtOAc (4:1)].
N-(4-Methoxyphenyl)-1-methylphosphinecarboxamide (3a)
White solid; yield: 33 mg (85%); mp 75–76 °C. 1H NMR (600
MHz, CDCl3): δ = 7.69 (s, 1 H), 7.39 (d, J = 8.4 Hz, 2 H), 6.81 (d, J =
8.4 Hz, 2 H), 4.02 (dq, J = 206.4, 7.8 Hz, 1 H), 3.76 (s, 3 H), 1.36
(dd, J = 7.2, 3.0 Hz, 3 H). 13C NMR (150 MHz, CDCl3): δ = 176.67
(d, J = 14.6 Hz), 156.48, 131.01 (d, J = 4.1 Hz), 121.80, 114.09,
55.44, 1.10 (d, JC–P = 8.1 Hz, PCH3). 31P NMR (162 MHz, CDCl3):
δ = –74.42. HRMS(ESI): m/z [M + H]+ Calcd for C9H13NO2P:
198.0678; Found: 198.0679.
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© Georg Thieme Verlag Stuttgart · New York — Synlett 2018, 29, A–D