Insertion of benzynes into the P=N bond of P-alkenyl(alkynyl)- λ5-phosphazenes

Article abstract of DOI:10.1021/ol202395s

Benzynes, generated from 2-(trimethylsilyl)phenyl triflates, have been found to react with P-Alkenyl-λ⁵-phosphazenes via a formal π-insertion into the P=N bond. A subsequent retro [2 + 2] cycloaddition/6π electrocyclization/protonation cascade

Full text of DOI:10.1021/ol202395s

ORGANIC
LETTERS
2011
Vol. 13, No. 20
5668–5671
Insertion of Benzynes into the PdN Bond
of P-Alkenyl(alkynyl)-λ5-phosphazenes
Mateo Alajarin,*,† Carmen Lopez-Leonardo,*,† Rosalia Raja,† and
Raul-Angel Orenes‡
ꢀ
Departamento de Quꢀımica Organica, Facultad de Quꢀımica, Universidad de Murcia,
ꢀ
Campus de Espinardo, 30100 Murcia, Spain, and Servicio de Apoyo a la Investigacion
(SAI), Universidad de Murcia, Campus de Espinardo, 30100 Murcia, Spain
alajarin@um.es; melill@um.es
Received September 5, 2011
ABSTRACT
Benzynes, generated from 2-(trimethylsilyl)phenyl triflates, have been found to react with P-Alkenyl-λ5-phosphazenes via a formal π-insertion into
the PdN bond. A subsequent retro [2 þ 2] cycloaddition/6π electrocyclization/protonation cascade explains the formation of the resulting 1,
4-benzazaphosphorinium triflates. P-Alkynyl λ5-phosphazenes and phosphane sulfides undergo similar transformations.
In the past decade, aryne chemistry has undergone an
unprecedented revival.1 The introduction of 2-(trimethylsilyl)-
phenyl triflates as mild aryne precursors,2 and a variety of
further reactions applied to these reactive intermediates,
have facilitated access to various ortho-disubstituted are-
nes, which are otherwise difficult to prepare.
Arynes are highly strained and kinetically unstable elec-
trophilic intermediates. Most of their reactions start by the
addition of nucleophiles and are completed by a subsequent
trapping step with electrophiles.3 When a nucleophile and
electrophile belong to the same molecule, these processes
usually lead to benzoannulated systems either by [3 þ 2]
or [4 þ 2] cycloaddition reactions,4,5 by insertion into
σ-bonds,6 or by other tandem processes triggered by the
initial nucleophilic addition.7
Up to now, limited success has been achieved in the
insertion reactions of arynesintoπ-bonds, alsoclassifiedas
(4) For selected recent examples of [3 þ 2] cycloadditions, see: (a)
Spiteri, C.; Sharma, P.; Zhang, F.; Macdonald, S. J. F.; Keeling,
S.; Moses, J. E. Chem. Commun. 2010, 46, 1272–1274. (b) Kivrak,
A.; Larock, R. C. J. Org. Chem. 2010, 75, 7381–7387. (c) Dubrovskiy,
A. V.; Larock, R. C. Org. Lett. 2010, 12, 1180–1183. (d) Wu, C.; Fang,
Y.; Larock, R. C.; Shi, F. Org. Lett. 2010, 12, 2234–2237. (e) Spiteri, C.;
Keeling, S.; Moses, J. E. Org. Lett. 2010, 12, 3368–3371. (f) Wu, K.;
Chen, Y.; Lin, Y.; Cao, W.; Zhang, M.; Chen, J.; Lee, A. W. M.
Tetrahedron 2010, 66, 578–582. (g) Crossley, J. A.; Browne, D. L.
Tetrahedron Lett. 2010, 51, 2271–2273.
(5) For selected examples of [4 þ 2] cycloadditions, see: (a) Caster,
K. C.; Keck, C. G.; Walls, R. D. J. Org. Chem. 2001, 66, 2932–2936. (b)
Schlosser, M.; Catagnetti, E. Eur. J. Org. Chem. 2001, 3991–3997. (c)
Xie, C.; Zhang, Y. Org. Lett. 2007, 9, 781–784. (d) Garr, A. N.; Luo, D.;
Brown, N.; Cramer, C. J.; Buszek, K. R.; VanderVelde, D. Org. Lett.
2010, 12, 96–99.
†
ꢀ
Departamento de Quꢀımica Organica.
‡
ꢀ
Servicio de Apoyo a la Investigacion (SAI).
(1) For reviews, see: (a) Hoffmann, R. W. In Dehydrobenzene and
Cycloalkynes; Academic Press: New York, 1967. (b) Kessar, S. V. In
Comprehensive Organic Synthesis; Trost, B. M., Fleming, I., Eds.; Pergamon:
New York, 1991; Vol. 4, pp 483ꢀ515. (c) Chen, Y.; Wenk, H. H.; Winkler,
M.; Sander, W. Angew. Chem., Int. Ed. 2003, 42, 502–528. (d) Pellissier,
~
ꢀ
H.; Santelli, M. Tetrahedron 2003, 59, 701–730. (e) Pena, D.; Perez, D.;
ꢀ
Guitian, E. Heterocycles 2007, 74, 89–100. (f) Sanz, R. Org. Prep. Proced.
Int. 2008, 40, 215–291. (g) Larock, R. C. Arylation Reactions Involving
the Formation of Arynes. In Modern Arylation Methods; Ackermann, L.,
Ed.; Wiley-VCH: New York, 2009; Chapter 12, pp 401ꢀ473.
(6) For some examples of insertions into σ-bonds, see: (a) Tambar,
K.; Ebner, D. C.; Stoltz, B. M. J. Am. Chem. Soc. 2006, 128, 11752–
11753. (b) Zhang, T.; Huang, X.; Xue, J.; Sun, S. Tetrahedron Lett. 2009,
50, 1290–1294. (c) Tadross, P. M.; Virgil, S. C.; Stoltz, B. M. Org. Lett.
2010, 12, 1612–1614.
(2) (a) Himeshima, Y.; Sonoda, T.; Kobayashi, H. Chem. Lett. 1983,
~
ꢀ
ꢀ
1211–1214. (b) Pena, D.; Cobas, A.; Perez, D.; Guitian, E. Synthesis
2002, 1454–1458. (c) Tadross, P. M.; Gilmore, C D.; Bugga, P.; Virgil,
S. C.; Stoltz, B. M. Org. Lett. 2010, 12, 1224–1227.
(3) For selected recent examples of reactions involving nucleophilic
addition and subsequent protonation, see: (a) Sha, F.; Huang, X. Angew.
Chem., Int. Ed. 2009, 48, 3458–3461. (b) Biju, A. T.; Glorius, F. Angew.
(7) For selected examples, see: (a) Huang, X.; Zhang, T. J. Org.
Chem. 2010, 75, 506–509. (b) Rogness, D. C.; Larock, R. C. J. Org.
Chem. 2010, 75, 2289–2295. (c) Dubrovskiy, A. V.; Larock, R. C. Org.
Lett. 2010, 12, 3117–3119. (d) Hong, D.; Chen, Z.; Wang, Y. Org. Lett.
2010, 12, 4608–4611.
ꢀ
Chem., Int. Ed. 2010, 49, 9761–9464. (c) Remond, E.; Tessier, A.;
ꢀ
Leroux, F. R.; Bayardon, J.; Juge, S. Org. Lett. 2010, 12, 1568–1571.
r
10.1021/ol202395s
Published on Web 09/28/2011
2011 American Chemical Society

[2 þ 2] cycloadditions, although some reports with CdC
bonds have been disclosed leading to stable benzocyclo-
butenes.8 A number of insertions into carbonꢀheteroatom
double bonds are also known,9 but to our knowledge,
similar processes involving heteroatomꢀ-heteroatom double
bonds have not been yet reported.
Some of our recent investigations have been devoted to
the chemistry of λ5-phosphazenes (iminophosphoranes,
R1R2PdN-R3).10 These organophosphorus compounds
exhibit considerable N-nucleophilicity due to their Pþ-Nꢀ
ylidic nature.11 In the particular case of P-alkenyl-λ5-
phosphazenes, we have demonstrated their ability to under-
go a variety of 1,4-additions to its conjugated NdPꢀCdC
heterobutadienyl fragment (Figure 1).12
conceivable. This process is best visualized as a stepwise
mechanism initiated by the nucleophilic attack of the
phosphazene N atom onto the aryne, followed by a sub-
sequent dipolar cyclization step, as represented in Scheme 1.
A priori, the alternative formation of the formal [2 þ 2]
cycloadduct and the concerted nature of both classes of cyclo-
additions should not be ruled out.
Scheme 1. Possible Products of the Reaction of Benzyne and
P-Alkenyl-λ5-phosphazenes
Figure 1. Schematic representation of 1,4-additions to P-alkenyl-
λ5-phosphazenes.
By combining the reactive characteristics of arynes and
P-alkenyl-λ5-phosphazenes 1, we reasoned that a formal
[4 þ 2] cycloaddition between both chemical entities is
The reaction of the N-(4-anisyl)-λ5-phosphazene 1a with
2-(trimethylsilyl)phenyl triflate 2a (3 equiv) and CsF
(4 equiv) in refluxing acetonitrile under a nitrogen atmo-
sphere for 2 h gave a 54% yield of a product, whose
analyticalandspectraldata showedittobeaphosphonium
triflate containing a PꢀCH2ꢀCH2ꢀN fragment instead of
the expected protonated form of the [4 þ 2] cycloadduct
(Scheme 1). In fact, an X-ray crystal structure determina-
tion confirmed that the obtained compound was the 1,
4-benzazaphosphorinium triflate 3a (Scheme 2). The
source of the proton that becomes incorporated into the
ethylene fragment of 3a should be the acetonitrile used as
solvent, a circumstance that is not uncommon in the
reactions of benzynes.3c,9k,13
(8) For some examples of formal insertions into CdC bonds, see: (a)
Hosoya, T.; Hasegawa, T.; Kuriyama, Y.; Matsumoto, T.; Suzuki, K.
Synlett 1995, 177–179. (b) Hosoya, T.; Hasegawa, T.; Kuriyama, Y.;
Suzuki, K. Tetrahedron Lett. 1995, 36, 3377–3380. (c) Gokhale, A.;
Schiess, P. Helv. Chim. Acta 1998, 81, 251–267. (d) Hosoya, T.; Hamura,
T.; Kuriyama, Y.; Miyamoto, M.; Matsumoto, T.; Suzuki, K. Synlett
2000, 520–522. (e) Maurin, P.; Ibrahim-Ouali, M.; Santelli, M. Tetra-
hedron Lett. 2001, 42, 8147–8149. (f) Maurin, P.; Ibrahim-Ouali, M.;
Santelli, M. Tetrahedron Lett. 2002, 43, 5789–5791. (g) Hamura, T.;
Arisawa, T.; Matsumoto, T.; Suzuki, K. Angew. Chem., Int. Ed. 2006, 45,
6842–6844. (h) Hamura, T.; Ibusuki, Y.; Uekusa, H.; Matsumoto, T.;
Suzuki, K. J. Am. Chem. Soc. 2006, 128, 3534–3535. (i) Hamura, T.;
Ibusuki, Y.; Uekusa, H.; Matsumoto, T.; Siegel, J. S.; Baldridge, K. K.;
Suzuki, K. J. Am. Chem. Soc. 2006, 128, 10032–10033. (j) Feltenberger,
J. B.; Hayashi, R.; Tang, Y.; Babiash, E. S. C.; Hsung, R. P. Org. Lett.
2009, 11, 3666–3639. (k) Kraus, G. A.; Wu, T. Tetrahedron 2010, 66,
569–572.
(9) For some examples of formal insertions into the CdO bond of
aldehydes, see: (a) Heaney, H.; Jablonski, J. M. J. Chem. Soc. D, Chem.
Commun. 1968, 1139–1139. (b) Heaney, H.; McCarty, C. T. J. Chem.
Soc. D, Chem. Commun. 1970, 123–123. (c) Nakayama, J.; Yoshida, M.;
Simamura, O. Chem. Lett. 1973, 451–452. (d) Bowne, A. T.; Levin, R. H.
Tetrahedron Lett. 1974, 15, 2043–2046. (e) Yoshida, H; Watanabe, M.;
Fukushima, H; Ohshita, J.; Kunai, A. Org. Lett. 2004, 6, 4049–4051.
Into the CdO bond of ketones, see:(f) Yoshida, H.; Ito, Y.; Yoshikawa,
Y.; Ohshita, J.; Takaki, K. Chem. Commun. 2011, 47, 8664–8666. Into
the CdO bond of amides, see:(g) Yoshioka, E.; Kohtani, S.; Miyabe, H.
Org. Lett. 2010, 12, 1956–1959. (h) Yoshioka, E.; Kohtani, S.; Miyabe,
H. Angew. Chem., Int. Ed. 2011, 50, 6638–6642. Into the CdS bond of
thiones and thioureas, see:(i) Okuma, K.; Shiki, K.; Shioji, K. Chem.
Lett. 1998, 79–80. (j) Okuma, K.; Sonoda, S.; Koga, Y.; Shioji, K. J.
Chem. Soc., Perkin Trans. 1 1999, 2997–3000. (k) Biswas, K.; Greaney,
M. F. Org. Lett. 2011, 13, 4946–4949. Into the CdSe bond of selones,
see:(l) Okuma, K.; Okada, A.; Koga, Y.; Yokomori, Y. J. Am. Chem.
Soc. 2001, 123, 7166–7167. Into the CdN bond of imines and hydra-
zones, see:(m) Nair, V.; Kim, K. H. J. Org. Chem. 1975, 40, 3784–3786.
(n) Aly, A. A.; Mohamed, N. K.; Hassan, A. A.; Mourad, A.-F. E.
Tetrahedron 1999, 55, 1111–1118. (o) Dubrovskiy, A. V.; Larock, R. C.
Org. Lett. 2011, 13, 4136–4139. Into the CdP bond of alkylidenepho-
sphoranes, see:(p) Zbiral, E. Tetrahedron Lett. 1964, 5, 3963–3967.
After some optimization experiments, alternative sol-
vents (1,4-dioxane, benzene) proved to be unsuitable
(10) (a) Alajarin, M.; Lopez-Leonardo, C.; Berna, J. Org. Lett. 2007,
9, 4631–4634. (b) Alajarin, M.; Lopez-Leonardo, C.; Berna, J. In Science
of Synthesis; Ramsden, C. A., Ed.; Thieme: Stuttgart, 2007; Vol. 31b, pp
1539ꢀ1554. (c) Alajarin, M.; Berna, J.; Lopez-Leonardo, C.; Steed,
J. W. Chem. Commun. 2008, 2337–2339. (d) Alajarin, M.; Lopez-
Leonardo, C.; Alvarez-Garcia, A.; Llamas-Lorente, P.; Sanchez-An-
drada, P.; Berna, J.; Pastor, A.; Bautista, D.; Jones, P. G. Chem.;Eur. J.
2010, 16, 3728–3735.
(11) 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; pp 813ꢀ955.
(12) (a) Alajarin, M.; Lopez-Leonardo, C.; Llamas-Lorente, P. Tet-
rahedron Lett. 2001, 42, 605–607. (b) Alajarin, M.; Lopez-Leonardo, C.;
Llamas-Lorente, P.; Bautista, D. Dalton Trans. 2003, 426–434. (c)
Alajarin, M.; Lopez-Leonardo, C.; Llamas-Lorente, P. Lett. Org. Chem.
2004, 1, 145–147.
(13) (a) Jeganmohan, M.; Cheng, C.-H. Chem. Commun. 2006, 2454–
2456. (b) Cant, A. A.; Bertrand, G. H. V.; Henderson, J. L.; Roberts, L.;
Greaney, M. F. Angew. Chem., Int. Ed. 2009, 48, 5199–5202.
Org. Lett., Vol. 13, No. 20, 2011
5669

Table 1. Reaction of P-Alkenyl-λ5-phosphazenes and Aryne
Scheme 2. Reaction of P-Vinyl-λ5-phosphazene 1a with Ben-
zyne Affording 1,4-Benzazaphosphorinium Triflate 3a
Precursors in the Presence of CsFa
entry
Ar
R1
R2
R3 product yield (%)b
1
2
3
4
5
6
7
8
9
4-CH3OC6H4
C6H5
H
H
H
3ac
3b
3c
3d
3e
3f
90
80
85
95
75
70
76
59
81
94
66
57
76
57
whereas the best reaction conditions were established as
those in which the phosphazene/CsF/2a ratio is 1:2:1.2,
and the reaction is run for 4 h in acetonitrile at 25 °C. The
yield of 3a was thus improved up to 90%.
H
H
H
4-CH3C6H4
2-iPrC6H4
H
H
H
H
H
H
4-BrC6H4
H
H
H
2-CH3-5-NO2C6H3
4-CH3C6H4
4-BrC6H4
H
H
H
Next we examined the scope of this reaction under these
optimal reaction conditions by using various N-aryl-
P-vinyl-λ5-phosphazenes bearing both electronreleasing
and electronwithdrawing substituents at the aryl nucleus
(entries 1ꢀ6, Table 1). We extended the substrate
scope to other P-alkenyl counterparts,12,14 such as
the P-(1-phenylvinyl) derivatives (R2 = Ph, R3 = H)
of entries 7 and 8, and the P-(E-1-propenyl) derivatives
(R2 = H, R3 = Me) of entries 9 and 10. In these latter
cases, prolonged reaction times of up to 20 h afforded
the best yields. It is noteworthy that the use as reagent of
the unsymmetrical 3-methoxybenzyne provided a single
reaction product in all the tested cases (entries 11ꢀ14).
Regioselective reactions of 3-methoxybenzyne are well-
known and have been rationalized as involving the more
favorable nucleophilic attack at the meta position for
electronic and steric reasons.4c,7d,15 Interestingly, our
results show that in these reactions electronic factors
dominate over steric ones with isomers 3kꢀn being the
only reaction products (Figure 2). The structure of 3k
was unambiguously confirmed by single-crystal X-ray
analysis (Figure 3).
C6H5
C6H5
H
H
H
3g
3h
3i
H
H
4-CH3C6H4
CH3
CH3
H
H
10 4-CH3OC6H4
H
H
3j
11 4-CH3C6H4
H
OCH3
OCH3
OCH3
OCH3
3kc
3l
12 4-CH3OC6H4
13 4-BrC6H4
H
H
H
H
3m
3n
14 2-CH3-5-NO2C6H3
H
H
a Reactions Conditions: 1 (0.3 mmol), 2 (0.36 mmol), CsF (0.6
mmol), CH3CN (10 mL), 25 °C, nitrogen atmosphere, 4 h for the
synthesis of 3aꢀf, and 20 h for the synthesis of 3gꢀn. b Yield of purified
product. c Structure confirmed by X-ray crystallography.
A reasonable mechanism for explaining the formation of
species 3 is represented in Scheme 3. First, the λ5-phospha-
zene 1 reacts with the in situ generated benzyne 2 to yield
the formal [2 þ 2] cycloadduct, which then undergoes a
retro [2 þ 2] cycloaddition and a further 6π electrocyclic
ring closure to build the 1,4-benzazaphosphorine ring
system in the form of a cyclic alkylidenephosphorane. This
basic intermediate is subsequently protonated by the acet-
onitrile used as solvent to furnish the final cationic part
of triflate 3.
Figure 2. Electronic and steric factors in the reaction of P-vinyl-
λ5-phosphazenes and 3-methoxybenzyne.
We next tested related P-alkynyl derivatives, such as
the N-aryl-P-phenylethynyl-λ5-phosphazenes 416 and the
P-phenylethynylphosphane sulphide 5,17 in their reaction
with the benzyne precursor 2a in the presence of CsF under
similar reaction conditions. As shown in Table 2, triflates 6
resulting from the λ5-phosphazenes 4 (entries 1ꢀ3) were
obtained in moderate yields, whereas compound 7 (entry 4),
derived from the initial [2 þ 2] cycloaddition of benzyne
(14) (a) Kazankova, M. A.; Efimova, I. V.; Kochetkov, A. N.;
Afanas’ev, V. V.; Beletskaya, I. P.; Dixneuf, P. H. Synlett 2001, 497–
500. (b) Alajarin, M.; Lopez-Leonardo, C.; Llamas-Lorente, P. Synlett
2003, 801–804. (c) Baechler, R. D.; Blohm, M.; Rocco, K. Tetrahedron
Lett. 1988, 29, 5353–5354.
(15) Cheong, P. H.-Y; Paton, R. S.; Bronner, S. M.; Im, G.-Y. J.;
Garg, N. K.; Houk, K. N. J. Am. Chem. Soc. 2010, 132, 1267–1269.
(16) Alajarin, M.; Lopez-Leonardo, C.; Llamas-Lorente, P.; Raja, R.
Tetrahedron Lett. 2007, 48, 6987–6991.
(17) (a) Issleib, K.; Harzfeld, G. Chem. Ber. 1962, 95, 268–272. (b)
Alajarin, M.; Lopez-Leonardo, C.; Raja, R. Synlett 2008, 48, 3172–
3176.
5670
Org. Lett., Vol. 13, No. 20, 2011

Table 2. Reaction of P-Alkynyl-λ5-phosphazenes 4 and P-
Alkynylphosphane Sulphide 5 with in-situ Generated Benzynea
entry
X
product
yield (%)b
1
2
3
4
4-CH3C6H4N
4-BrC6H4N
2-CH3-5-NO2C6H3N
S
6a
6b
6cc
7
69
65
59
82
a Reactions Conditions: 1 (0.3 mmol), 2 (0.36 mmol), CsF (0.6
mmol), CH3CN (10 mL), 25 °C, nitrogen atmosphere, 20 h. b Yield of
purified product. c Structure confirmed by X-ray crystallography.
Figure 3. Crystal structure of the 1,4-benzazaphosphorinium
cation of triflate 3k.
reacting benzynes with P-alkenyl and P-alkynyl-λ5-phos-
phazenes. These reactions apparently involve the initial
π-insertion of benzyne into the PdN bond of the organo-
phosphorus reagent, followed by a retro [2 þ 2] cycloaddi-
tion/6π electrocyclization/protonation cascade. Under
this mechanistic scheme, these results show for the first
time the insertion of benzynes into a heteroatom-heteroa-
tom double bond. Further investigations on similar reac-
tions with more simple λ5-phosphazenes and related P(V)
species are currently underway.
Scheme 3. Proposed Mechanism for the Reaction of P-Alkenyl-
λ5-phosphazenes and Arynes
Acknowledgment. We thank the MICINN (Project
ꢀ
ꢀ
CTQ2008.05827/BQU) and Fundacion Seneca-CARM
(Project 08661/PI/08) for the financial support of this
research. R.R. also thanks the University of Murcia for a
fellowship.
Supporting Information Available. Detailed experimen-
tal procedures, characterization data, copies of 1H, 13C, and
31P NMR, and crystallographic information file (CIF) for
compounds 3d, 3k, and 6c. This material is available free of
charge via the Internet at http://pubs.acs.org.
with the PdS double bond of the sulphide 5, was also
conveniently obtained.
In summary, we have successfully developed a method
for the preparation of 1,4-benzazaphosphorinium salts by
Org. Lett., Vol. 13, No. 20, 2011
5671