Facile synthesis of C-phosphanylformamidines via a carbene pathway

Article abstract of DOI:10.1016/j.tetlet.2013.07.160

A direct synthetic approach to C-phosphanyl-N,N-dialkyl-N′- aryl(alkyl)-formamidines was developed. It was shown that phosphorylation of the formamidines proceeds at the nitrogen atom affording N-phosphanylformamidinium salts. Upon deprotonation, these salts gave C-phosphanylformamidines via formation of carbenes followed by a 1,2-phosphorus shift.

Full text of DOI:10.1016/j.tetlet.2013.07.160

Tetrahedron Letters 54 (2013) 5671–5673
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Facile synthesis of C-phosphanylformamidines via a carbene
pathway
⇑
Anatoliy Marchenko, Georgyi Koidan, Anastasiya Hurieva, Aleksandr Savateev, Aleksandr Kostyuk
Institute of Organic Chemistry, National Academy of Sciences of Ukraine, Murmanska 5, Kyiv-94 02660, Ukraine
a r t i c l e i n f o
a b s t r a c t
A direct synthetic approach to C-phosphanyl-N,N-dialkyl-N0-aryl(alkyl)-formamidines was developed. It
was shown that phosphorylation of the formamidines proceeds at the nitrogen atom affording N-phos-
phanylformamidinium salts. Upon deprotonation, these salts gave C-phosphanylformamidines via forma-
tion of carbenes followed by a 1,2-phosphorus shift.
Article history:
Received 20 March 2013
Revised 12 July 2013
Accepted 31 July 2013
Available online 11 August 2013
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
C-Phosphanylformamidines
N-Phosphanylformamidinium triflates
Phosphanylation
Deprotonation
Formamidines are important organic compounds as starting
materials for other syntheses, as well as being valuable in their
own right.1 C-Phosphanylformamidines are potential P,N-biden-
tate ligands because compounds of this class are actively utilized
in various catalytic processes.2 At the same time, C-phosphanyl-
formamidines are only accessible with difficulty. The main method
for their synthesis is via addition of either P(III)H or P(V)H com-
pounds to carbodiimides, usually under basic catalysis. Thus, the
method is limited by the availability of carbodiimides and affords
only symmetrical C-phosphanylformamidines (Scheme 1).3
There are a few examples of the nucleophilic substitution with
amines on C-phosphanylimidoyl chlorides and thioformimidic acid
derivatives, but they are themselves not easily accessible com-
pounds.4 We have previously described a convenient approach to
C-phosphanyl P(V) arylformamidines by the reaction of N-arylam-
idotrichloromethyl phosphoroyl derivatives with secondary
amines. On reduction of N-arylformamidino-phosphonoselenides,
the corresponding C-phosphanyl P(III) arylformamidines were ob-
tained (Scheme 2). This method was successfully applied to the
synthesis of C-phosphanylformamidines bearing ferrocenyl
substituents.5
the presence of sodium triflate, or with a phosphenium cation
(i-Pr2N)2P+TfOꢀ affording N-phosphanylazolium salts, followed by
treatment with a strong base. The second occurs via deprotonation
of N-substituted imidazoles (benzimidazoles) having bulky
X
P
RNH
RN
R
RN
NR
NAlk2
Scheme 1. Synthesis of C-phosphanylformamidines based on addition of PH
compounds to carbodiimides.
X
P
X
P
Alk2N
ArN
Alk2N
ArN
P
R
CCl3
R
R
NAlk2
NHAr
NAlk2
X = O, S, Se
Scheme 2. Synthesis of C-phosphanylformamidines via N-arylamidotrichlorom-
ethyl phosphoroyl derivatives.
In our investigations directed at the synthesis of C-phosphanyl
nitrogen-containing heterocycles we developed two convenient
approaches via N-phosphanyl-substituted N-heterocyclic carbenes
(NHCP ligands) (Scheme 3). The first involves a direct phosphany-
lation of the heterocycles (benzimidazoles, imidazoles, triazoles)
with either di-tert-butylbromophosphane in tetrahydrofuran in
P
N
P
N
N
N
X
X
X
P
+
N
N
Imidazole; ref. 6a and 6d; benzimidazole; ref. 6b and 6d; triazole; ref. 6c;
formamidines; this work
⇑
Corresponding author. Tel.: +380 67 209 9273.
E-mail address: a.kostyuk@yahoo.com (A. Kostyuk).
Scheme 3. Available approaches to C-phosphanylheterocycles via N-
phosphanylcarbenes.
0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tetlet.2013.07.160

5672
A. Marchenko et al. / Tetrahedron Letters 54 (2013) 5671–5673
-
+
i
NPr2-
p-MeC6H4
p
N
C6H4Me-
R'2P
TfO
(Me3Si)2NNa
Se
N
P
R
R
N
-
+
4c
2c
N
N
N+
N
NPr2-i
P
TfO
N
NPr -
2 i
Se
(Me3Si)2NNa
for 2a
Ph2PBr, CF3SO3Na
PR'2
8
9
i
NPr2-
1a,b
2a,b,c; 3b,c
δp
= 88
R
R'
1a
C6H4Me-p --
Scheme 5. The trapping reaction of carbene 8.
R'
Se
N
2a,4a,6a C6H4Me-p Ph
2b,4b C6H4Me-p Me2N
2c,4c,6c C6H4Me-p i-Pr2N
PR'2
P
R'
R
Se
R
N
N
N
We have also demonstrated that various 1,3-azoles react readily
with bis-(dialkylamino)phosphenium triflate giving analogous N-
phosphanylimidazolium triflates.6a–c This procedure was found to
fit well for the formamidines.
1b
i-Pr
--
3b,5b,7b
i-Pr
Me2N
6a,c; 7b,c
4a,b,c; 5b,c
3c,5c,7c
i-Pr
i-Pr2N
Scheme 4. Synthesis of C-phosphanylformamidines.
It is also worth noting that azomethines react with bis-(dial-
kylamino)phosphenium triflate in a totally different way giving
cyclic products.12
N-substituents with n-BuLi, followed by the reaction of the result-
ing Li-imidazolides with di-tert-butylchlorophosphane. Many of
these NHCP ligands are quite stable and can be separated as indi-
vidual compounds; some of them can be distilled under high vac-
uum. Nevertheless all these carbenes can be readily transformed
into their corresponding C-phosphanylheterocycles.6
All these heterocycles (imidazole, benzimidazole, and 1,2,4-tri-
azole) possess the formamidine moiety (N@CH–N–), on which
phosphorylation proceeds. Based on this structural analogy, it
might be expected that these approaches could be applied to
N,N-dialkyl-N0-aryl(alkyl)formamidines as well.
It should be noted that the direct phosphanylation of formami-
dines has been described using phosphorus tribromide.7 We have
found that the phosphanylation of N,N-dimethyl-N0-arylformami-
dines by PBr3 in dichloromethane yields instead of the claimed
C-phosphanylformamidines, cyclic zwitterionic phosphoranides
as intermediate products, which were isolated.8 It is worth men-
tioning that no other phosphinohalides take part in this reaction.
In contrast to 1,3-azoles, which can be deprotonated with
strong bases and then enter into reactions with electrophiles,
N,N-dialkyl-N0-aryl(alkyl)formamidines bearing the same moiety
(–N@CH–N–) cannot be deprotonated as proton removal proceeds
Formamidines 1 reacted readily with (dialkylamino)-phospho-
nium triflates at ꢀ90 °C to afford triflates 2b, 2c, 3b, and 3c in high
yields. These compounds are white solids, and were not very soluble
in ether or hydrocarbons, and were highly sensitive to air. The range
of 31P NMR chemical shifts for the iminium salts extends from 124.1
to 143.0 ppm. The 1H NMR chemical shift for the formamidine pro-
ton ranges between 7.51 and 8.03 ppm, a downfield shift compared
to the starting formamidines 1a (7.51 ppm) and 1b (7.28 ppm). The
13C NMR chemical shift for the formamidine carbon was observed at
153–157 ppm with small or no splitting to phosphorus (Scheme 4).
Treatment of salts 2 and 3 with sodium hexamethyldisilazide
gave C-phosphanylformamidines 4 and 5 in high yields. These
compounds were separated and characterized. They are crystalline
compounds, sensitive to moisture and oxygen, and readily soluble
in many organic solvents such as diethyl ether, benzene, and hex-
ane. These reactions are characterized by the disappearance of the
signal due to the formamidine proton in the 1H NMR spectrum and,
in the 13C NMR spectrum, the appearance of a signal due to the
formamidine carbon, the most downfield (ꢁ160 ppm) coupled to
phosphorus. Compounds 4 and 5 reacted readily with selenium
to give stable pentavalent phosphorus derivatives 6 and 7. The
molecular structures of 6 and 7 were confirmed unambiguously
by full sets of solution NMR spectroscopic data. In the 31P NMR
spectra the phosphorus signals coupled to selenium (JPSe = 744–
756 Hz) were indicative of these compounds.13
Phosphanylformamidines 4 and 5 are thought to form via a 1,2-
phosphorus shift in the intermediate carbenes of type 8. In our
study on N-phosphanylheterocyclic carbenes, it was shown that
the (i-Pr2N)2P group stabilizes the carbenes much better compared
to Ph2P. Hence, we proposed to either isolate or detect carbene 8.
Indeed, at ꢀ95 °C, on treatment of salt 2c with sodium hexameth-
yldisilazide (Scheme 5), the 31P NMR spectrum exhibited a signal
(dP 88 ppm) which could be attributed to carbene 8. The 31P NMR
chemical shift for N-phosphanylimidazol-2-ylidenes ranges be-
tween 78 and 98 ppm.6a
In order to confirm the formation of carbenes, deprotonation of
salt 2c was carried out in the presence of an equimolar amount of
selenium. The reaction of carbenes with group 16 elements affords
stable adducts, formation of which can serve as a proof for tran-
sient and persistent carbenes.14 Besides compound 4c, we have
separated compound 9 (Scheme 5). Its formation confirmed our
hypothesis that deprotonation led to carbenes that reacted with
selenium followed by a phosphorus shift from nitrogen to sele-
nium. Although there are no previous examples of the nitrogen-
selenium phosphorus shift, a similar nitrogen to sulfur shift is de-
scribed in the literature, both for trivalent and pentavalent phos-
phorus groups.15 Compound 9 is a stable, distillable compound.
Its structure was confirmed by single crystal X-ray crystallogra-
phy16 (Fig. 1) and multinuclear NMR spectroscopy (1H, 13C, 31P).
The 31P NMR signal occurred at 107.9 ppm (JPSe = 240 Hz) with
splitting to selenium typical for a P–Se single bond.
either at the a-position of the N,N-dialkylamino group, or at the a-
position of the N0-alkyl group.9,10 This property was successfully
utilized for the synthesis of substituted amino acids10 and
flumazenil.11
Thus, the structural similarity of N,N-dialkyl-N0-aryl(alkyl)form-
amidines with N-alkylimidazoles, N-alkylbenzimidazoles, and N-
alkyltriazoles allows us to assume that the approaches developed
for the synthesis of N-phosphanylhetero-cyclic carbenes and the
corresponding C-phosphanylheterocycles might be applied to
formamidines. This Letter describes the exploration of these
methods.
Indeed, we found that the previously developed method for the
preparation of N-phosphanylazolium salts could be applied to N,N-
dialkyl-N0-arylformamidines. Thus, diphenylbromophosphine re-
acts easily with N,N-dimethyl-N0-arylformamidine 1a in THF in
the presence of sodium triflate, affording N-phosphanylformamid-
inium triflate 2a (Scheme 4). It is a crystalline powder, unstable in
air, and insoluble in THF, petroleum ether, and diethyl ether, but
soluble in methylene chloride and acetonitrile. The 31P NMR signal
for 2a appears at 102.7 ppm, almost 40 ppm downfield compared
to analogous imidazolium salts (61.6 ppm). The 1H NMR signals
of the NMe2 group are not equivalent occurring as broad singlets
at 2.56 and 3.43 ppm. The N@CH–N proton resonates at 8.2 ppm
(JPH 5.5 Hz), being downfield compared to the same proton in the
starting formamidine 1a (7.51 ppm). The same trend was observed
for the 13C signals for the N@CH–N carbon, which appears at
159 ppm as a doublet (1JPC 53 Hz), downfield from the same carbon
of the starting formamidine 1a at 153.1 ppm.
Unfortunately, we failed to extend this approach to other phos-
phinohalides [tBu2PBr, (Me2N)2PBr], as they did not react with
formamidines 1.

A. Marchenko et al. / Tetrahedron Letters 54 (2013) 5671–5673
5673
Figure 1. ORTEP plot of 9.
Marchenko, A. P.; Hurieva, A. N.; Koidan, G. N.; Kostyuk, A. N.; Rampazzi, V.;
Cattey, H.; Pirio, N.; Hierso, J.-C. Organometallics 2012, 31, 5986–5989.
6. (a) Marchenko, A. P.; Koidan, H. N.; Huryeva, A. N.; Zarudnitskii, E. V.;
Yurchenko, A. A.; Kostyuk, A. N. J. Org. Chem. 2010, 75, 7141–7145; (b)
Marchenko, A. P.; Koidan, H. N.; Hurieva, A. N.; Pervak, I. I.; Shishkina, S. V.;
Shishkin, O. V.; Kostyuk, A. N. Eur. J. Org. Chem. 2012, 21, 4018–4033; (c)
Marchenko, A. P.; Koidan, H. N.; Zarudnitskii, E. V.; Hurieva, A. N.; Kirilchuk, A.
A.; Yurchenko, A. A.; Biffis, A.; Kostyuk, A. N. Organometallics 2012, 31, 8257–
8264; (d) Marchenko, A. P.; Koidan, H. N.; Pervak, I. I.; Huryeva, A. N.;
Zarudnitskii, E. V.; Tolmachev, A. A.; Kostyuk, A. N. Tetrahedron Lett. 2012, 53,
494–496.
In summary, our new synthetic route to C-phosphanyl-N,N-dial-
kyl-N0-aryl(alkyl)formamidines greatly expands the availability of
compounds of this class. The accessibility of these compounds is
limited only by the availability of the starting formamidines, mak-
ing possible fine-tuning of the steric and electronic characteristics.
Deprotonation of formamidinium triflates proceeds via the forma-
tion of carbenes followed by a 1,2-phosphorus shift.
Supplementary data
7. (a) Tolmachev, A. A.; Merkulov, A. S. Khim. Geterotsikl. Soedin. 1997, 7, 1000–
1001; (b) Tolmachev, A. A.; Merkulov, A. S.; Oshovskii, G. V. Chem. Heterocycl.
Compd. 1997, 33, 877–878.
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.07.
160.
8. Marchenko A. Unpublished results.
9. Meyers, A. I.; Hoeve, W. T. J. Am. Chem. Soc. 1980, 102, 7125–7126.
10. Fitt, J. J.; Gschwend, H. W. J. Org. Chem. 1977, 42, 2639–2641.
11. Rogers-Evans, M.; Spurr, P.; Hennig, M. l. Tetrahedron Lett. 2003, 44, 2425–
2428.
12. (a) Mazieres, M. R.; Roques, C.; Khim, T.; Majoral, J. P.; Wolf, R. Sanchez.
Phosphorus, Sulfur Silicon Relat. Elem. 1990, 49–50, 309–312; (b) Kim, T. C.;
Maziéres, M. R.; Wolf, R.; Sanchez, M. Tetrahedron Lett. 1990, 31, 4459–4462.
13. (a) McFarlane, W.; Rycroft, D. S. J. Chem. Soc., Dalton Trans. 1973, 2162–2166;
(b) Allen, D. W.; Taylor, B. F. J. Chem. Soc., Dalton Trans. 1982, 51–54.
14. Bourissou, D.; Guerret, O.; Gabbaı, F. P.; Bertrand, G. Chem. Rev. 2000, 100, 39–
91.
15. (a) Blonski, C.; Gasc, M. B.; Hegarty, A. F.; Klaebe, A.; Perie, J. J. J. Am. Chem. Soc.
1984, 106, 7523; (b) Malenko, D. M.; Sinitsa, A. D. J. Gen. Chem. USSR (Engl.
Transl.) 1986, 56, 1654–1655; (c) Malenko, D. M.; Sinitsa, A. D. J. Gen. Chem.
USSR (Engl. Transl.) 1986, 56, 1467–1468.
16. Crystallographic data (excluding structure factors) for the structure of 9 have
been deposited with the Cambridge Crystallographic Data Centre as
supplementary publication CCDC 927183. Copies of the data can be obtained,
free of charge, on application to CCDC, 12 Union Road, Cambridge CB2 1EZ, UK,
(fax: +44 (0)1223 336033 or e-mail: deposit@ccdc.cam.ac.uk).
References and notes
1. (a) Krygowski, T. M.; Wozniak, K. In The Chemistry of Amidines and Imidates;
Patai, S., Rappoport, Z., Eds.; John Wiley & Sons: Chichester, 1991; (b) Enthaler,
S.; Schröder, K.; Inoue, S.; Eckhardt, B.; Junge, K.; Beller, M.; Drieß, M. Eur. J. Org.
Chem. 2010, 75, 4893–4901.
2. McManus, H. A.; Cusack, D.; Guiry, P. J. In Phosphorus Ligands in Asymmetric
Catalysis; Borner, A., Ed.; WILEY-VCH GmbH & KGaA: Weinheim, 2008.
3. (a) Afarinkia, K.; Rees, C. W. Tetrahedron 1990, 46, 7175–7196; (b) Kamalov, R.
M.; Makarov, G. M. Zh. Obshch. Khim. 1990, 60, 778; (c) Issleib, K.; Franze, K.-D.
J. Prakt. Chem. 1973, 315, 471–482; (d) Pudovik, A. N.; Romanov, G. V.;
Stepanova, T. Y. Izv. Akad. Nauk SSSR, Ser. Khim. 1982, 1416; (e) Nifant’ev, E. E.;
Shilov, I. V. Zh. Obshch. Khim. 1973, 43, 2654.
4. (a) Regel, E.; Hammann, I.; Stendel, W.; DE Patent 2547512, 1977; Chem. Abstr.
1977, 87; 135913.; (b) Tashma, Z. J. Org. Chem. 1983, 48, 3966.
5. (a) Marchenko, A. P.; Koidan, G. N.; Hurieva, A. N.; Merkulov, A. S.; Pinchuk, A.
M.; Yurchenko, A. A.; Kostyuk, A. N. Tetrahedron 2010, 66, 3668–3677; (b)