The alkylation of aminophosphanes: A new synthesis of iminophosphoranes

Article abstract of DOI:10.1055/s-2003-38730

Iminophosphoranes are prepared by P-alkylation of easily available N,P,P-trisubstituted aminophosphanes with reactive alkyl halides and further deprotonation.

Full text of DOI:10.1055/s-2003-38730

LETTER
801
The Alkylation of Aminophosphanes: A New Synthesis of Iminophosphoranes
I
minophosphoranes by
a
Alkylation
t
of
A
m
e
inophospha
o
nes Alajarín,* Carmen López-Leonardo, Pilar Llamas-Lorente
Departamento de Química Orgánica, Facultad de Química, Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain
Fax +34(968)364149; E-mail: alajarin@um.es
Received 11 February 2003
this general approach to iminophosphanes has not been
Abstract: Iminophosphoranes are prepared by P-alkylation of eas-
systematically explored.
ily available N,P,P-trisubstituted aminophosphanes with reactive
alkyl halides and further deprotonation.
In our hands, easily accessible 4-tolylamino-
diphenylphosphane7 reacted with a variety of activated
alkyl bromides yielding aminophosphonium bromides
1a–m (Scheme 1, Table 1).8 In most of the cases the alky-
lation reaction was carried out in diethyl ether as solvent
(entries 1–10) in order to facilitate the precipitation of the
resulting salts. In this way aminophosphonium bromides
1a–j were obtained in good yields (70–86%) and high de-
gree of purity (>98% by 1H and 31P NMR analysis). When
the same solvent was used in reactions involving di or tri-
halides (entries 11–13) the isolated bis(aminophosphoni-
um) dibromides 1k,l and the tris(aminophosphonium)
tribromide 1m were contaminated with the salts resulting
from partial substitution of the bromine atoms. In these
cases better results in 1k–m were obtained when the reac-
tions were run in dichloromethane as solvent, followed by
a simple precipitation work-up.
Key words: alkyl halides, alkylation, phosphorus, ylides, imino-
phosphoranes
During the last few decades the use of iminophosphoranes
(λ5-phosphazenes or phosphine imines) has emerged as a
powerful tool in organic synthetic strategies directed to-
wards the construction of C=N double bonds, due to the
wide applicability of the inter- and intramolecular aza-
Wittig reactions.1 Two methods are most commonly used
for the preparation of iminophosphoranes: the Staudinger
reaction,2 the effective imination of a tertiary phosphane
with an organic azide, and the Horner–Oediger method,3
basically the reaction of amines with tertiary phosphane
dihalides in the presence of base.
Herein we disclose a new method for preparing these
compounds which, instead of joining the P and N moieties
of the final iminophosphorane (as in the two methods cit-
ed above), starts with compounds bearing P-N single
bonds, aminophosphanes. Most importantly, this new
procedure will be shown to be a valuable and easy way of
introducing a versatile organophosphorus functionality
into a carbon chain.
b)
a)
R22P N-R3
R1
R22P-NH-R3
R22P NH-R3
R1-Br +
R1
Br
1
2
Scheme 1 Reagents and conditions: a) see Table 1; b) Et3N (1.2
equiv), C6H6, 25 ºC, 2 h.
In our ongoing research program devoted to the discovery
of new reactions in organophosphorus chemistry,4 our at-
tention was attracted by an isolated 1961 report on the re-
action of t-butylaminodiphenylphosphane with benzyl
halides leading to the corresponding P-benzyl amino-
phosphonium salts in good yields.5 We reasoned that the
observed regioselective P-alkylation (vs N-alkylation) of
the ambident nucleophile t-butylaminodiphenylphos-
phane is probably not a consequence of the bulky t-butyl
group placed on the nitrogen atom thus preventing its
alkylation, but instead may be explained on electronic
grounds.6 If these reactions were generally applicable to
Attempts to alkylate the same aminophosphane by less
reactive alkyl halides (e.g. 1-bromobutane and 1,4-dibro-
mobutane) failed, even under stronger reaction conditions
(C6H6 or THF, reflux, 24 h).
Aminophosphanes other than the more common P,P,N-
triaryl were also successfully alkylated under the standard
conditions (entries 14 and 15).
The deprotonation of aminophosphonium salts 1 was car-
ried out under exceedingly mild conditions (C6H6, 25 ºC,
2 h) by using triethylamine (1.2 equiv for each halide unit)
as base to give the new iminophosphoranes 2 in very good
yields (Scheme 1 and Table 1).9 The only exception was
the deprotonation of the less acidic N-alkyl aminophos-
phonium salt 1o which, as anticipated, required the use of
a stronger base, DBU.
other aminophosphanes of general formula R1 P-NH-R2
2
(λ3-phosphanamines, phosphinous amides), then a new
route to iminophosphoranes would be open, as it is well
known that NH-aminophosphonium salts are easily
deprotonated by a variety of bases.1d To our knowledge,
Although the conversion of the aminophosphanes into 2
was also carried out in a one-pot operation, better yields
and purities of compounds 2 were obtained in the two-step
process.
Synlett 2003, No. 6, Print: 05 05 2003.
Art Id.1437-2096,E;2003,0,06,0801,0804,ftx,en;D03203ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

802
M. Alajarín et al.
LETTER
After several attempts, the P-allyl iminophosphorane 2a Pure iminophosphorane 3a was obtained by heating either
(entry 1) was always found to be contaminated with vari- the impure iminophosphorane 2a or the salt 1a in benzene
able amounts of the corresponding P-(E)-1-propenyl for 2 hours in the presence of an excess of triethylamine.
iminophosphorane 3a, the product resulting from the ther- The isomerization of P-allyl to P-1-propenyl iminophos-
modynamically driven isomerization of the double bond. phoranes has been previously observed in the study of the
Table 1 Aminophosphonium Salts 1 and their Deprotonation to Iminophosphoranes 2
Entry
1
R1-Br
R2
Ph
R3
Alkylation conditions
Et2O, 25 ºC, 24 h
Yield 1 (%) Yield 2 (%)
a
a
4-CH3C6H4
76
74
-
Br
Br
2
b
Ph
4-CH3C6H4
Et2O, 25 ºC, 12 h
92
3
4
5
c
d
e
Ph
Ph
Ph
4-CH3C6H4
4-CH3C6H4
4-CH3C6H4
Et2O, 25 ºC, 12 h
Et2O, 25 ºC, 6 h
Et2O, 25 ºC, 12 h
70
70
73
93
97
94
Br
Br
Br
Ph
6
7
f
Ph
Ph
4-CH3C6H4
4-CH3C6H4
Et2O, 25 ºC, 6 h
Et2O, 25 ºC, 6 h
78
76
94b
91b
O
Br
Ph
g
O
Br
4-CH3C6H4
8
9
h
i
Ph
Ph
4-CH3C6H4
4-CH3C6H4
Et2O, 25 ºC, 6 h
Et2O, 25 ºC, 6 h
86
81
92b
89
O
Br
4-ClC6H4
O
Br
MeO
10
11
j
Ph
Ph
4-CH3C6H4
4-CH3C6H4
Et2O, 25 ºC, 6 h
77
96
Ph
Br
k
CH2Cl2, 40 ºC, 12 h
79c
90d
Br
Br
12
13
l
Ph
Ph
4-CH3C6H4
4-CH3C6H4
CH2Cl2, 40 ºC, 12 h
CH2Cl2, 40 ºC, 36 h
83c
81e
91d
Br
Br
Br
m
88f
Br
Br
Ph
14
15
n
o
iPr
Ph
4-CH3C6H4
PhCH2
Et2O, 25 ºC, 6 h
Et2O, 25 ºC, 6 h
81
83
92
Br
90g
Br
a Not isolated, see text.
b See ref.10
c Yield of bis(aminophosphonium) dibromide.
d Yield of bis(iminophosphorane).
e Yield of tris(aminophosphonium) tribromide.
f Yield of tris(iminophosphorane).
g Obtained by using DBU instead Et3N.
Synlett 2003, No. 6, 801–804 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Iminophosphoranes by Alkylation of Aminophosphanes
803
Staudinger reaction between allyldiphenylphosphane and lide units, which is reminiscent of the Michaelis–Arbuzov
phenylazide.11 Compound 2b could also be efficiently reaction of halides with O-alkyl phosphinites, e.g. Ph2P-
transformed into the P-vinyl isomer 3b by treatment with OMe, for preparing phosphane oxides.13 In this sense, our
DBU (Scheme 2). By contrast, P-allyl iminophospho- methodology is a useful alternative to the Michaelis–Ar-
ranes 2c–e and 2o did not convert into their P-vinyl iso- buzov reaction, as the resulting phosphazene functions are
mers under the action of triethylamine or DBU, most easily converted into other organophosphorus functional
probably because their respective equilibria should lie on groups due to their high reactivity.1d To illustrate this
the side of the 2-propenyl isomers.
point we have prepared the tris(phosphane oxide) 714 and
the tris(phosphane sulfide) 815 by triple aza-Wittig reac-
tion of tris(iminophosphorane) 2m with phenylisocyanate
and phenylisothiocyanate, respectively (Scheme 4). Both
reactions are rapidly completed and the products were iso-
lated by a simple workup and obtained in good yields.
X
Ar-N
PPh2
PPh2
Scheme 2 Reagents and conditions: Et3N, C6H6, ∆, 2 h (for 2a) and
DBU, C6H6, ∆, 24 h (for 2b).
P
X
P
N-Ar
Ph2
Ph2
+ PhNCNAr
The monoalkylations of 4-tolylaminodiphenylphosphane
with α,α′-dibromo-o-xylene and its meta isomer were
achieved by using a fourfold excess of alkylating agent.
These reactions were carried out in diethyl ether at 25 ºC
for 12 hours and the products were purified by column
chromatography. Whereas with α,α′-dibromo-m-xylene
the expected aminophosphonium bromide 4 was isolated
in 60% yield, in the case of α,α′-dibromo-o-xylene the
alkylation provided the cyclic aminophosphonium bro-
mide 5 (62% yield) as a result of double, P and N, alkyla-
tion of the starting aminophosphane. Most probably both
alkylations occur sequentially, first on phosphorus and
second, in an intramolecular fashion on nitrogen. Com-
pound 5 underwent basic hydrolysis in diluted aqueous
NaOH to give the amino functionalised phosphane oxide
612 in 58% yield (Scheme 3).
Ph2P
X
Ph2P
N-Ar
2m
7
8
X = O 74%
X = S 78%
Ar = 4-CH3C6H4
Scheme 4 Reagents and conditions: Ph-N=C=X/C6H6, 25 ºC, 1 h.
In summary, we have explored the P-alkylation reaction
of mono-N-substituted aminophosphanes with a variety
of activated alkyl halides. The reaction products, NH-
aminophosphonium salts, are easily deprotonated to the
corresponding iminophosphoranes. In the overall trans-
formation of R1X into R1R2 P=NR3 the starting amino-
2
phosphane is a synthetic equivalent of an imino-
phosphide16 anion [R2 P=NR3]–. Efforts to extend this
2
methodology to solid phase synthesis, by the utilization of
polymer-supported aminophosphanes, is currently under-
way in our laboratories.
NH-Ar
P
Ph2
Acknowledgment
Br
Br
This work was supported by MCYT and FEDER (Project
BQU2001-0010) and Fundación Séneca-CARM (Project PI-1/
00749/FS/01). P. L.-L. also thanks Fundación Séneca-CARM for a
fellowship.
4 60%
PPh2
PPh2
O
N
Br
Ar
References
NH-Ar
5 62%
Ar = 4-CH3C6H4
6 58%
(1) (a) Gusar, N. I. Russ. Chem. Rev. (Engl. Transl.) 1991, 60,
146. (b) Barluenga, J.; Palacios, F. Org. Prep. Proced. Int.
1991, 23, 1. (c) Eguchi, S.; Matsushita, Y.; Yamashita, K.
Org. Prep. Proced. Int. 1992, 24, 209. (d) Johnson, A. W.;
Kaska, W. C.; Ostoja-Starzewski, K. A.; Dixon, D. A. In
Ylides and Imines of Phosphorus; Johnson, A. W., Ed.;
Wiley: New York, 1993, 403. (e) Molina, P.; Vilaplana, M.
J. Synthesis 1994, 1197.
(2) (a) Staudinger, H.; Meyer, J. Helv. Chim. Acta 1919, 2, 635.
(b) Gololobov, Y. G.; Zhmurova, I. N.; Kasukhin, L. F.
Tetrahedron 1981, 37, 437. (c) Gololobov, Y.; Kasukhin, L.
F. Tetrahedron 1992, 48, 1353.
Scheme 3 Reagents and conditions: NaOH (2%), ∆, 16 h.
The method described herein for preparing iminophos-
phoranes is versatile, occurs under mild conditions and
can be considered a suitable complement to the proce-
dures previously disclosed. At the same time, the alkyla-
tion of aminophosphanes is a simple way to introduce a
P(V) functionality onto carbon chains bearing reactive ha-
(3) Horner, L.; Oediger, H. Liebigs Ann. Chem. 1959, 627, 142.
Synlett 2003, No. 6, 801–804 ISSN 0936-5214 © Thieme Stuttgart · New York

804
M. Alajarín et al.
LETTER
(4) (a) Alajarín, M.; López-Leonardo, C.; Llamas-Lorente, P.;
Bautista, D. Synthesis 2000, 2085. (b) Alajarín, M.; López-
Leonardo, C.; Llamas-Lorente, P. Tetrahedron Lett. 2001,
42, 605. (c) Alajarín, M.; López-Leonardo, C.; Llamas-
Lorente, P. Tetrahedron Lett. 2001, 42, 1041. (d) Alajarín,
M.; López-Leonardo, C.; Llamas-Lorente, P.; Bautista, D.;
Jones, P. G. Dalton Trans. 2003, 426.
(5) Sisler, H. H.; Smith, N. L. J. Org. Chem. 1961, 26, 4733.
(6) The more polarizable, heavier element P should show
greater nucleophilicity, see: Quin, L. D. A Guide to
Organophosphorus Chemistry; John Wiley and Sons: New
York, 2000, 129.
C
arom). 31P {1H} NMR (161 MHz, CDCl3): δ = 7.08. MS (EI):
m/z (rel. intensity) = 382 (24) [M+ + 1], 381 (79) [M+], 380
(25) [M+ – 1), 290 (100). Anal. Calcd for C26H24NP: C,
81.87; H, 6.34; N, 3.67. Found: C, 81.75; H, 6.50; N, 3.75.
(10) In solution, iminophosphoranes 2f–h exist in the enol
tautomeric form, forming intramolecular hydrogen-bonded
six membered ring (Scheme 5). This is clearly apparent from
their NMR spectra, where the characteristic signals of the P-
CH=C(Ar)-OH fragment are observed, and also by the
absence of the carbonyl absorption in their IR spectra. The
enol OH structure is believed to be favoured over the C-H
form as result of the favourable intramolecular N···H-O
hydrogen bond, see: Steiner, T. Angew. Chem. Int. Ed. 2002,
41, 48.
(7) Kato, S.; Goto, M.; Hattori, R.; Nishiwaki, K.; Mizuta, M.;
Ishida, M. Chem. Ber. 1985, 118, 1668.
(8) Typical Procedure for the Synthesis of Bromides 1: To a
solution of 4-tolylaminodiphenylphosphane (0.3 g, 1.03
mmol) in dry Et2O (15 mL) was added benzyl bromide (0.25
g, 1.5 mmol). The mixture was stirred for 6 h under N2
atmosphere. The appearance of a white precipitate of 1j was
observed, which was filtered, washed with Et2O (5 mL) and
dried under reduced pressure. An analytically pure sample
was obtained by recrystallization from CH2Cl2–Et2O (white
prisms). Yield (0.37 g, 77%); mp 176–178 ºC. IR (nujol):
2758, 1515, 1437, 1386, 1116, 750, 698 cm–1. 1H NMR (400
MHz, CDCl3): δ = 2.15 (s, 3 H, CH3), 4.72 (d, 2 H,
2JHP = 16.2 Hz, CH2P), 6.84 (d, 2 H, 3JHH = 8.2 Hz, Harom),
6.91–6.93 (m, 4 H, Harom), 7.11 (t, 2 H, 2JHH = 7.4 Hz, Harom),
7.22 (m, 1 H, Harom), 7.51–7.56 (m, 4 H, Harom), 7.63–7.74
(m, 6 H, Harom), 10.07 (d, 1 H, 2JHH = 8.6 Hz, NH). 13C {1H}
NMR (75 MHz, CDCl3): δ = 20.60 (CH3), 34.45 (d,
1JCP = 61.6 Hz, CH2P), 118.87 (d, 1JCP = 95.7 Hz, q, Ci),
120.17 (d, 3JCP = 7.1 Hz, Carom), 127.00 (d, 2JCP = 7.4 Hz, q,
Ar1
Ar1
Ph2P
N
Ph2P
N
O
O
Ar2
H
Ar2
2f-h
Scheme 5
(11) Baechler, R. D.; Blohm, M.; Rocco, K. Tetrahedron Lett.
1988, 29, 5353.
(12) Compound 6: Colorless prisms (from CH2Cl2–Et2O), mp
181–183 ºC. IR (nujol): 3390, 1515, 1439, 1182, 1121, 778,
721 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.24 (s, 3 H,
CH3), 3.76 (d, 2 H, 2JHP = 13.2 Hz, CH2P), 4.18 (s, 2 H,
CH2N), 6.60 (d, 2 H, 3JHH = 8.5 Hz, Harom), 6.80 (dt, 1 H,
4JHH = 1.7 Hz, 3JHH = 7.7 Hz, Harom), 6.98 (d, 2 H, 3JHH = 8.5
Hz, Harom), 7.05 (dd, 1 H, 4JHH = 1.1 Hz, 3JHH = 7.5 Hz,
C
arom), 128.37 (d, 5JCP = 4.2 Hz, Carom), 128.78 (d, 4JCP = 3.5
H
arom), 7.16 (dt, 1 H, 4JHH = 1.7 Hz, 3JHH = 7.5 Hz, Harom),
Hz, Carom), 129.71 (d, 3JCP = 12.9 Hz, Cm), 129.73 (Carom),
131.01 (d, 3JCP = 5.7 Hz, Carom), 132.96 (q, Carom), 133.57 (d,
2JCP = 10.1 Hz, Co), 134.93 (d, 4JCP = 3.0 Hz, Cp), 135.63 (d,
2JCP = 3.8 Hz, q, Carom). 31P {1H} NMR (121 MHz, CDCl3):
δ = 35.36. MS (EI): m/z (rel. intensity) = 383 (4) [M+ + 1 –
Br], 382 (29) [M+ – Br], 381 (100) [M+ – HBr], 183 (46).
Anal. Calcd for C26H25BrNP: C, 67.54; H, 5.45; N, 3.03.
Found: C, 67.62; H, 5.62; N, 3.21.
7.32 (m, 1 H, Harom), 7.38–7.57 (m, 6 H, Harom), 7.62–7.74
(m, 4 H, Harom), NH proton obscured. 13C {1H} NMR (100
MHz, CDCl3): δ = 20.49 (CH3), 34.70 (d, 1JCP = 65.8 Hz,
CH2P), 47.47 (CH2N), 113.16 (Carom), 126.49 (q, Carom),
127.41 (d, JCP = 6.6 Hz, Carom), 127.42 (Carom), 128.65 (d,
3JCP = 11.7 Hz, Cm), 129.71 (Carom), 130.15 (d, 3JCP = 8.4 Hz,
q, Carom), 130.34 (d, JCP = 2.6 Hz, Carom), 131.06 (d, JCP = 4.5
Hz, Carom), 131.37 (d, 2JCP = 9.2 Hz, Co), 132.02 (d,
4JCP = 2.8 Hz, Cp), 132.24 (d, 1JCP = 97.3 Hz, q, Ci), 138.46
(d, 2JCP = 5.2 Hz, q, Carom), 146.22 (q, Carom). 31P {1H} NMR
(161 MHz, CDCl3): δ = 30.74. Anal. Calcd for C27H26NOP:
C, 78.81; H, 6.37; N, 3.40. Found: C, 78.62; H, 6.32; N, 3.23.
(13) Hudson, H. R. In The Chemistry of Functional Groups. The
Chemistry of Organophosphorus Compounds, Vol. 1;
Hartley, F. R.; Patai, S., Eds.; John Wiley and Sons:
Chichester, 1990, 387.
(9) Typical Procedure for the Synthesis of Iminophos-
phoranes 2: To a suspension of 1j (0.3 g, 0.65 mmol) in dry
C6H6 (20 mL) was added Et3N (0.08 g, 0.8 mmol). The
mixture was stirred for 1 h under N2 atmosphere and the
precipitate of Et3N·HBr was filtered. The solvent from the
filtrate was removed under vacuum and the residue was
triturated with dry Et2O (10 mL). White crystalline 2j was
isolated by filtration and dried under reduced pressure. An
analytically pure sample was obtained by recrystallization
from CH2Cl2–Et2O (white prisms). Yield (0.24 g, 97%); mp
138–140 ºC. IR(nujol): 1506, 1438, 1329, 1109, 1026, 910,
822 cm–1. 1H NMR (400 MHz, CDCl3): δ = 2.20 (s, 3 H,
CH3), 3.91 (d, 2 H, 2JHP = 14.2 Hz, CH2P), 6.67 (d, 2 H,
3JHH = 8.1 Hz, Harom), 6.84–6.86 (m, 4 H, Harom), 7.08–7.15
(m, 3 H, Harom), 7.37–7.44 (m, 4H, Harom), 7.49-7.53 (m, 2H,
(14) Lindner, E.; Khanfar, M.; Steimann, M. Eur. J. Inorg. Chem.
2001, 2411.
(15) Compound 8: Colorless prisms (from CHCl3–Et2O), mp
227–229 ºC. IR (nujol): 1437, 1182, 1099, 1029, 751, 693
cm–1. 1H NMR (400 MHz, CDCl3): δ = 1.49 (s, 3 H, CH3),
3.95 (d, 2 H, 2JHP = 13.8 Hz, CH2P), 7.37–7.42 (m, 4 H,
Harom), 7.44–7.48 (m, 2 H, Harom), 7.50–7.80 (m, 4 H, Harom).
13C {1H} NMR (100 MHz, CDCl3): δ = 19.89 (CH3), 38.30
(d, 1JCP = 50.4 Hz, CH2P), 128.52 (d, 3JCP = 12.4 Hz, Cm),
129.18 (m, q, Carom), 131.45 (Cp), 131.68 (d, 2JCP = 9.9 Hz,
Co), 133.34 (d, 1JCP = 76.6 Hz, q, Ci), 137.17 (m, q, Carom).
31P {1H} NMR (161 MHz, CDCl3): δ = 38.84. MS (FAB+):
m/z (rel. intensity) = 812 (45) [M+ + 1].
H
arom), 7.62-7.67 (m, 4H, Harom). 13C {1H} NMR (CDCl3,
100 MHz): δ 20.61 (CH3), 35.71 (d, 1JCP = 64.7 Hz, CH2P),
122.81 (d, 3JCP = 18.0 Hz, Carom), 126.84 (d, 5JCP = 2.1 Hz,
C
arom), 128.13 (d, 4JCP = 2.6 Hz, Carom), 128.40 (q, Carom),
128.66 (d, 3JCP = 11.5 Hz, Cm), 129.43 (Carom), 130.57 (d,
3JCP = 5.0 Hz, Carom), 130.67 (d, 1JCP = 90.7 Hz, q, Ci),
131.91 (br s, Cp), 132.26 (d, 2JCP = 8.9 Hz, Co), 134.88 (d,
2JCP = 10.27.4 Hz, q, Carom), 148.63 (d, 2JCP = 2.9 Hz, q,
(16) Wetzel, T. G.; Dehnen, S.; Roesky, P. W. Angew. Chem. Int.
Ed. 1999, 38, 1086.
Synlett 2003, No. 6, 801–804 ISSN 0936-5214 © Thieme Stuttgart · New York