N-phosphorylated imidazolium salts as precursors to 2- and 5-phosphorylated imidazoles and new imidazol-2-ylidenes featuring the PNCN unit

Article abstract of DOI:10.1021/jo101177h

It has been experimentally proven that the reaction of 1- or 1,2-disubstituted imidazoles with diorganylphosphorus(III) halides proceeds via initial formation of N-phosporylated imidazolium salts. Treatment of these salts with strong bases results in phosphorylation of the parent imidazoles at the 2- or 5-positions, correspondingly. In a previous case, imidazol-2-ylidenes are formed as intermediates. With both N1 and N3 atoms bearing sterically demanding or/and π-donating groups, deprotonation of 1,3-disubstituted imidazolium salts with NaN(SiMe₃)₂ afforded new stable N-phosphorus-substituted Arduengo-type carbenes.

Full text of DOI:10.1021/jo101177h

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N-Phosphorylated Imidazolium Salts as Precursors to 2- and
5-Phosphorylated Imidazoles and New Imidazol-2-ylidenes Featuring the
PNCN Unit
Anatolii P. Marchenko, Heorgii N. Koidan, Anastasiya N. Huryeva,
Evgeniy V. Zarudnitskii, Aleksandr A. Yurchenko, and Aleksandr N. Kostyuk*
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska Str. 5, Kyiv-94,
02094, Ukraine
a.kostyuk@enamine.net
Received June 25, 2010
It has been experimentally proven that the reaction of 1- or 1,2-disubstituted imidazoles with diorga-
nylphosphorus(III) halides proceeds via initial formation of N-phosporylated imidazolium salts.
Treatment of these salts with strong bases results in phosphorylation of the parent imidazoles at the
2- or 5-positions, correspondingly. In a previous case, imidazol-2-ylidenes are formed as intermediates.
With both N1 and N3 atoms bearing sterically demanding or/and π-donating groups, deprotonation of
1,3-disubstituted imidazolium salts with NaN(SiMe3)2 afforded new stable N-phosphorus-substituted
Arduengo-type carbenes.
Introduction
should be highlighted from these experimental studies. (a)
Phosphorus bromides compared to phosphorus chlorides
are much more active phosphorylating agents in these reac-
tions. (b) Lithium halides act as catalysts in the phosphor-
ylation, markedly increasing the rate of the reactions and
their yields. (c) Reaction of 1,2-disubstituted imidazoles both
with phosphorus halides and organolithium compounds
(n-butyllithium, tert-butyllithium) proceeds at the fifth posi-
tion of the imidazole ring probably by the same mechanism.
These data undoubtedly have positive value in a synthetic
planning but are insufficient for understanding the mechan-
ism of these reactions including the nature of intermediates
and their role in the formation of the final products.
Thechemistryofphosphorylatedimidazoleshas undergone
intensive development due to increasing application of such
compounds in metal complex catalysis, biochemistry, phar-
macology, and agriculture. Among literature methods, direct
phosphorylation of azaheterocycles1 with phosphorus(III)
halides is one of the most attractive and synthetically acces-
sible methods.
In our previous work,2,3 we studied in detail phosphoryla-
tion of 1- and 1,2-disubstituted imidazoles with phosphorus-
(III) mono-, di-, and trihalides in pyridine in the presence of
triethylamine affording 2- and 5-phosphorylated imidazoles,
respectively. As a result of exhaustive work, we have deter-
mined the optimum conditions (time, temperature, solvent)
for running these reactions depending on substituents both
at the phosphorus atom and at the imidazole ring. A few facts
It is worth noting that the same is true for 1,3-azoles.
For electrophilic substitution reactions of 1,3-azoles, the so-
called “ylide” mechanism4 is commonly accepted assuming,
initial formation of N-acylazolium salts of type A5 in the case
(1) Van der Jeught, S; Stevens, C. V. Chem. Rev. 2009, 109, 2672.
(2) Yurchenko, A. A.; Huryeva, A. N.; Zarudnitskii, E. V.; Marchenko,
A. P.; Koidan, G. N.; Pinchuk, A. M. Heteroatom Chem. 2009, 10, 289.
(3) Huryeva, A. N.; Marchenko, A. P.; Koidan, G. N.; Yurchenko, A. A.;
Zarudnitskii, E. V.; Pinchuk, A. M.; Kostyuk, A. N. Heteroatom Chem.
2010, 3, 103.
(4) Belenkii, L. I.; Chuvylkin, N. D. Khim. Geterosikl. Soedin. 1996, 11/
12, 1535.
(5) (a) Grimmett, M. R. Adv. Heterocycl. Chem. 1980, 27 (241), 297. (b)
€
Regel, E.; Buchel, K.-H. Justus Lieb. Ann. Chem. 1977, 1, 145. (c) Bastiaansen,
L. A.; Godefroi, E. F. Synthesis 1978, 675.
DOI: 10.1021/jo101177h
r
Published on Web 10/06/2010
J. Org. Chem. 2010, 75, 7141–7145 7141
2010 American Chemical Society

Marchenko et al.
JOCArticle
SCHEME 1
SCHEME 3
SCHEME 2
SCHEME 4
of acylation of 1-substituted imidazoles6 and their condensed
derivatives7 (Scheme 1).
SCHEME 5
Probably, in pyridine electrophilic substitution of imida-
zoles with phosphorus (PIII) halides the reaction also proceeds
via initial formation of N-phosphorylated imidazolium salts
of type A. In this paper, we report on the synthesis of such
intermediates, their reactivity, and their role in the formation
of the 2-and 5-phosphorylated imidazoles.
Results and Discussion
diphenylchlophosphine with N-silylimidazolium salt 3 pre-
pared beforehand by the reaction of imidazole 1a with
trimethylsilyl triflate by the known procedure10 (Scheme 3).
We found that imidazoles 1a,b react readily with bis-
(diisopropylamino)phosphenium triflate 4b9 affording imida-
zolium triflates 5a,b in high yields (Scheme 4). Structures 5a,b
are crystalline, high-melting compounds, insoluble in ether. In
methylene chloride, the 31P NMR signals appear in the range
106-115 ppm. In pyridine immediately after dissolving, com-
pound 5a has a broad signal at 106 ppm that gradually over
48 h shifts downfield to 145 ppm.
Imidazolium salts 2 and 5 feature highly labile P-N bonds
demonstrated in the example of salt 2a. It reacts with selenium
and dimethylamine with cleavage of the P-Nbond(Scheme5).
We have studied the influence of other bases on salts 2 and
5. Thus, the treatment of imidazolium salt 2a with a sterically
hindered base such as sodium hexamethyldisilazanide caused
migration of the diphenylphosphino group from the N(3)
atom to the fifth position affording (1-methyl-2-phenylimida-
zol-5-yl)diphenylphosphine (31P NMR, δ = -33 ppm) as the
major product (75%) and amidophosphine (31P NMR, δ = 29
ppm) as a minor product.2 To separate these compounds, the
reaction mixture was treated with selenium giving selenides 9
and 10 that resulted from hydrolysis on further workup. The
compounds were separated by crystallization (Scheme 6).
In the case of bulky diisopropylamino groups on the
phosphorus atom, formation of amidophosphine of type
10 is completely suppressed. Thus, treatment of compounds
5a,b with sodium hexamethyldisilazanide afforded phosphonite
Determined by 31P NMR spectroscopy, it has been found
that chlorophosphines R2PCl (R = Ph, t-Bu, i-Pr2N) on
mixing with 1,2-disubstituted imidazoles in methylene chlor-
ide, ether, or pyridine at room temperature do not form
stable intermediates so that the starting materials are present
in the reaction mixture. Heating the reaction mixture results
in the final 5-phosphorylated imidazoles. Intermediary pro-
ducts were neither separated nor registered in the reaction
mixture spectroscopically. We assumed that it was due to
high nucleophilicity of a chloride anion. In using phosphorus
bromides we found that diphenylbromophosphine easily
reacts with imidazole 1a in methylene chloride affording
stable salt 2a (Scheme 2) exhibiting the 31P NMR chemical
shift at the range 67-68 ppm as a sharp singlet. In pyridine,
the signal has the same value but appears as a broad singlet.
The salt 2a, a colorless low melting crystalline compound, is
partially soluble in ether and less soluble in pentane.
Bromophosphines such as t-Bu2PBr and (i-Pr2N)2PBr do
not form analogous phosphonium salts probably because of
increased steric hindrance of the substituents at the phos-
phorus atom.
One can expect that imidazolium salts of type 2a bearing a
triflate anion would be stable like triflate poly onio deriva-
tives of pyridine and quinuclidine.8 To this end, we have
developed two approaches to these compounds using diphe-
nylchlorophosphine. Imidazolium triflate 2b can be easily
prepared either by treatment of imidazole 1a with trimethyl-
silyl triflate and diphenylchlophosphine or by the reaction of
(6) Hlasta, D. J. Tetrahedron 1990, 31, 5833.
(7) (a) Anders, E.; Gassner, T. Angew. Chem., Int. Ed. Engl. 1982, 21, 289.
(b) Anders, E.; Boldt, H.-G.; Fuchs, R.; Gassner, T. Tetrahedron Lett. 1984,
25, 1715–1716.
(9) Weiss, R.; Roth, R. J. Chem. Soc., Chem. Commun. 1987, 5, 317.
ꢀ
(10) (a) Roques, C.; Mazieres, M.-R.; Majoral, J.-P.; Sanchez, M. Inorg.
Chem. 1989, 28, 3931. (b) Kim, T. C.; Mazieres, M.-R.; Sanchez, M.
ꢀ
(8) Weiss, R.; Engel, S. Synthesis 1991, 1077.
Tetrahedron Lett. 1990, 31, 4459.
7142 J. Org. Chem. Vol. 75, No. 21, 2010

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SCHEME 6
the catalytic action of LiCl or LiBr on the rate of the reaction
of 1,2-disubstituted imidazoles with phosphorus trihalides2
would be logically explained by formation of highly reactive
N(3)-Li imidazole derivatives. Therefore, it follows that the
reaction of imidazoles with organolithium compounds initi-
ally gives N(3)-Li derivatives, and addition of LiCl would
shift the equilibrium to the right increasing the overall rate of
the reaction (Scheme 10).11
SCHEME 7
This assumption was confirmed by the following experi-
ment. While lithiation of phosphonite 13 in the presence of
1 equiv of LiCl comes to completion in 4 h at -70 °C in
almost quantitative yield (Scheme 11), in the absence of LiCl
after 8 h the reaction mixture consists of ca. 60% of the
unreacted phosphonite 13.3 4,5-Diphosphorylated imida-
zole 14 was further oxidized with selenium to give selenide
15 in 89% yield. Further selenide 15 was reduced with
metallic sodium in toluene to give pure 14.
SCHEME 8
Previously unknown bis(dichlorophosphino)-4,5-imida-
zole 16 was prepared by the reaction of the corresponding
diamide 14 with phosphorus trichloride. Diphosphine 16 is a
distillable light-yellow crystalline compound. In 31P NMR
spectra it appears as a doublet of doublets at 114.4 and 134.6
ppm with coupling constant 3JPP = 324 Hz. It cannot be pre-
pared by direct phosphorylation of imidazol-4-yldichloro-
phosphine with phosphorus trichloride in preparative quan-
tities.3
Comparing our data on phosphorylation and lithiation of
the 1,2-disubstituted imidazoles one can draw a conclusion
that most probably both reactions proceed via the same
mechanism.
11a,b in high yields. These are distillable liquids that solidify on
storage (Scheme 7).
Treatment of salt 2a with tertiary bases led to 5-C-phos-
phorylated imidazoles similar to acylation of 2-unsubstituted
imidazoles.4,5 Thus, heating at 75 °C salt 2a in pyridine in the
presence of such tertiary bases as triethylamine or imidazole
1a results in the phosphine that can be isolated as its selenide 9
in 65-72% yield (Scheme 6).
It is noteworthy that compound 5b does not react with
triethylamine, but the reaction with an excess of imidazole 1b,
3-4 equiv, at 75 °C results in tris(imidazol-5-yl)phosphine (31P
NMR δ = -85.6 ppm)2 instead of the expected phosphonite
11b (Scheme 8).
Thus, summarizing the data obtained, one can conclude
that direct phosphorylation of 1,2-disubstituted imidazoles
proceeds via formation of the N(3)-phosphorylated imida-
zolium salts. This process is reversible and is stipulated by
weakness of the P-N bond and correlates with the above-
mentioned instability of the imidazolium chlorides as well as
weaker phosphorylating ability of chlorophosphines com-
pared to bromophosphines.2
Broadening of the signals of salts 2 and 5 in pyridine shows
that use of donor solvents (ether, THF, pyridine, and triethyl-
amine) also facilitates dissociation of the intermediates on the
starting components so that the rate of formation of 5-phos-
phorylated imidazoles decreases. At the same time, in basic
medium the reaction thermodynamically shifts to formation
of a carbanion at the C5 position of the imidazoles followed
by intermolecular attack by a phosphorus group at N(3) or a
halogenophosphine giving the final product (Scheme 9). Use of
the starting imidazole as a base (instead of pyridine or tri-
ethylamine) as shown previously facilitates the reaction afford-
ing better yields of 5-phosphorylated imidazoles because dis-
sociation of the salts of types 2 and 5 has a degenerate character.
Formation of 5-phosphorylated, not 4-phosphorylated, imi-
dazoles can be rationalized by greater contribution of the reso-
nance structure B in salts 2 and 5 so that removal of a proton
from the C5 position is kinetically controlled (Scheme 9).
This regioselectivity probably does not depend on the
nature of an electrophile at the nitrogen (N3). For example,
As mentioned in the Introduction, imidazol-2-yldiphenyl-
phosphine was prepared by the reaction of 1-methylimida-
zole with Ph2PCl (Br, I) in pyridine at 20 °C.12 In this work,
the 31P NMR signal at δ ∼30 was mistakenly assigned to
intermediate N-phosphorylated imidazolium salts. We now
have found that 2-unsubstituted imidazole 17a, like imida-
zole 1a, reacts readily with Ph2PBr in dichloromethane to
afford imidazolium bromide 18 with the 31P NMR signal at δ
67.8 (CH2Cl2, pyridine) (Scheme 12). In the case of diphenyl-
chlorophosphine, stable imidazolium salts are not formed.
We have developed a method for the synthesis of N-imida-
zolium triflates using a mixture of sodium triflate and a phos-
phinous chloride. By this method, imidazolium triflate 19 bear-
ing a sterically demanding di-tert-butylphosphino group was
prepared (31P NMR δ 116).
Salts 18 and 19 are crystalline compounds that are poorly
soluble in ether and other nonpolar solvents. Treatment of
compound 18 with triethylamine afforded the known com-
pound phosphine 20 described by us previously (Scheme 12).12
This compound has found wide application as a ligand in
coordination chemistry and can also be prepared by the reac-
tion of lithium imidazolide with diphenylchlorophosphine.13
(11) (a) Hill, C.; Bosold, F.; Harms, K.; Lohrenz, J. C. W.; Marsch, M.;
Schmieczek, M.; Boche, G. Chem. Ber. 1997, 130, 1201. (b) Hilf, C.; Bosold,
F.; Harms, K.; Marsch, M.; Boche, G. Chem. Ber. 1997, 130, 1213. (c) Gupta,
L.; Hoepker, A. C.; Singh, K. J.; Collum, D. B. J. Org. Chem. 2009, 74, 2231.
(12) Tolmachev, A. A.; Yurchenko, A. A.; Merkulov, A. S.; Semenova,
M. G.; Zarudnitskii, E. V.; Ivanov, V. V.; Pinchuk, A. M. Heteroatom Chem.
1999, 10, 585.
(13) (a) Jalil, M. A.; Yamada, T.; Fujinami, S.; Honjo, T.; Nishikawa, H.
Polyhedron 2001, 20, 627. (b) Chevykalova, M. N.; Manzhukova, L. F.;
Artemova, N. V.; Luzikov, Yu. N.; Nifantiev, I. E.; Nifantiev, E. E. Izv. Acad.
ꢁ
Nauk. SSSR [Khim.] 2003, 1, 75–80. (c) Dıez, V.; Espino, G.; Jalon, F. A.;
´
ꢁ
Manzano, B. R.; Perez-Manrique, M. J. Organomet. Chem. 2007, 692, 1482.
J. Org. Chem. Vol. 75, No. 21, 2010 7143

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SCHEME 9
SCHEME 10
SCHEME 11
SCHEME 12
Imidazole 17a readily reacts with bis(dimethylamino)-
phosphenium triflate 4a giving imidazolium salt 21, a crystalline
high-melting compound (Scheme 13). Treatment of compound
21 with sodium hexamethyldisilazanide gave an adduct of
2-phosphorylated imidazole 22 with sodium triflate insoluble in
ether. On dissolving in methylene chloride, the adduct 22 decom-
poses, precipitating the sodium triflate and leaving compound 23
in ether. This process is reversible so the adduct can be prepared
by dissolving phosphonite 23 and sodium triflate in THF.
Analogous salts 24a-c were prepared by the reaction of
imidazoles 17a-c with more sterically hindered bis(diiso-
propylamino)phosphenium triflate 4b. Salts 19 and 24 bear-
ing bulky substituents at the phosphorus atom proved to be
inert to bases such as triethylamine. At the same time, the
reaction of salts 24a-c with sodium hexamethyldisilazanide
afforded previously unknown carbenes of new type 25a-c.
Likewise, salt 19 having a di-tert-butylphosphino group gave
carbene 26 upon treatment with the same base (Scheme 14).
Stability of these carbenes varies widely.14 In 31P NMR
spectra, carbene 25a exhibits as a singlet at δ 81.0. In solution
it is stable below 0 °C but completely transforms into
2-substituted imidazole 27a in 24 h at 20 °C (Scheme 15). Like
N,N0-dialkylimidazol-2-ylidenes,15 it readily reacts with tri-
methylchlorosilane affording 2-trimethylsilyl-N-imidazole
2916 and bis(diisopropylamino)chlorophosphine in quanti-
tative yield. Solid carbenes 25b,c and oil 26 were separated as
individual compounds, with carbene 26 being so stable that it
can be distilled. On heating higher than g150 °C, carbenes
25b,c and 26 completely transformed into 2-phosphorylated
imidazoles 27b,c and 28.17
(14) Andreas A. Danopoulos, A. A.; Winston, S.; Gelbrich, T.;
Hursthousea, M. B.; Toose, R. P. Chem. Commun. 2002, 482.
€
(15) Kuhn, N.; Kratz, T.; Blaser, D.; Boese, R. Chem. Ber. 1995, 128, 245.
(16) Jutzi, P.; Sakriss, W. Chem. Ber. 1973, 106, 2815.
(17) Grotjahn, D. B.; Gong, Yi; Zakharov, L.; Golen, J. A.; Rheingold,
A. L. J. Am. Chem. Soc. 2006, 128, 438.
7144 J. Org. Chem. Vol. 75, No. 21, 2010

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SCHEME 13
SCHEME 14
SCHEME 15
ylidenes (δ 223-224).18 The X-ray diffraction study carried
out on 25c allows comparison with numerous known imida-
zolidin-2-ylidenes (Figure 1).
The N-Ccarbene bond distance [1.3770(19) A] and the
carbene bond angle (102.96°) for 25c are in the typical ranges
observed for the imidazolidin-2-ylidenes (1.36-1.38 A) and
(101-103°).
Conclusion
Wehave developed a new methodfor the synthesisof 2-and
5-phosphorylated imidazoles based on 1- and 1,2-disubstitut-
ed imidazoles and diorganylphosphorus(III) halides. We have
shown experimentally that N-phosphorylated imidazolium
salts are intermediates in the reaction. Based on found results,
we can assume that both phosphorylation and lithiation of
imidazoles proceed via the same mechanism. Both reactions
experience marked acceleration upon addition of lithium
halides. N-Phosphorylated imidazolium salts are precursors
to stable imidazol-2-ylidenes that on heating at 20-150 °C
transform into 2-phosphorylated imidazoles. These data
strongly suggested that phosphorylation of azines and azole
bearing a pyridine nitrogen atom will proceed via the same
“carbene mechanism”.
FIGURE 1. Molecular structure of 25c.
The thermal stability of the carbenes depends on steric and
electronic effects of substituents at the nitrogen atoms of imida-
zoles increasing in a row Me < (i-Pr2N)2P<t-Bu. It is note-
worthy that compared to the bis(diisopropylamino)phosphino
group, the di-tert-butylphosphino group has a greater stabilizing
effect on the imidazol-2-ylidenes.
In 13C NMR spectra chemical shift of the divalent carbon
is found in the region typical for singlet imidazolidin-2-
Supporting Information Available: Experiemntal details
and NMR spectra. X-ray data for 25 (CIF). This material
is available free of charge via the Internet at http://
pubs.acs.org.
(18) (a) Bourissou, D.; Guerret, O.; Gabbaı, F. P.; Bertrand, G. Chem.
Rev. 2000, 100, 39–91. (b) Tapu, D; Dixon, D. A.; Roe, C. Chem. Rev. 2009,
109, 3385–3407.
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