provide new phosphines that are difficult to synthesize by
other methods but also offers a conceptually new approach
to heteroarylphosphines.
Scheme 1
Treatment of diphenyl(phenylethynyl)phosphine sulfide
(1a) with 2 equiv of N-methyl-2-iodoaniline (2a) in the
presence of a catalytic amount of bis(acetylacetonato)palla-
dium and 2 equiv of potassium carbonate in DMSO at 90
°C for 11 h afforded 2-diphenylthiophosphinyl-1-methyl-3-
phenylindole (3aa) in 76% NMR yield and in 74% isolated
yield as a major product (Table 1, entry 1).11,12 Regioisomer
4aa was also observed as a minor product (6% NMR yield),
which was easily separable from 3aa by column chromato-
graphic purification. The choice of palladium source was
important.13 Other palladium(II) complexes such as Pd(OAc)2
and PdCl2, as well as palladium(0) complexes such as
Pd2(dba)3, led to lower yields.14 Aprotic polar solvents were
suitable solvents and DMSO gave the best result. Choice of
base also affected the yield. Cesium carbonate and sodium
carbonate were less effective, while potassium phosphate
gave a similar result to potassium carbonate. Addition of
phosphine ligands such as triphenylphosphine led to lower
yield. Under the reaction conditions, sulfur transfer from
1-alkynylphosphine sulfide to phosphine ligands occurred,
which would deactivate the palladium catalyst.15
With the optimized reaction conditions in hand, the scope
of 1-alkynylphosphine sulfides was investigated (Table 1,
entries 1-9). Not only phenylacetylene derivative 1a but also
alkyl-substituted substrates 1b-d underwent the annulation
reactions (entries 1-4). The reactions of primary and
secondary alkyl-substituted 1b and 1c proceeded smoothly,
while tert-butyl-substituted 1d provided product 3da in low
yield probably due to its bulkiness. It is worth noting that
none of the regioisomers 4 were detected in the reactions of
1b-d. A variety of functional groups, such as keto, ester,
methoxy, and 2-thienyl groups, were compatible under the
reaction conditions (entries 5-9).
phine sulfides participated in the construction of benzene
rings.6
By using 1-alkynylphosphine derivatives as key starting
materials, we have developed a new strategy aiming at the
synthesis of bulky heteroarylphosphines (Scheme 1). We
report herein palladium-catalyzed annulation7 of 1-alky-
nylphosphine sulfides with 2-iodoanilines to afford 2-in-
dolylphosphine sulfides. The newly formed indole rings
naturally have a substituent derived from 1-alkynylphosphine
sulfides adjacent to the thiophosphinyl group, which creates
a sterically congested environment around the phosphorus
in cooperation with a substituent on the nitrogen atom. The
product, phosphine sulfides, can be easily reduced to the
corresponding trivalent phosphines.
Although a variety of heteroarylphosphines,8 including
indole-based phosphines,9,10 have been designed and syn-
thesized so far, most of the syntheses involve metalation of
heteroaromatic compounds followed by treating with chlo-
rophosphines. This conventional approach requires prepara-
tion of proper heteroaromatic compounds prior to introduc-
tion of a phosphorus moiety, which sometimes necessitates
a multistep synthesis. In the present reaction, incorporation
of a phosphorus moiety and a substituent at the proper
positions occurs at the same time as construction of a
heteroaromatic ring. Hence, this protocol does not only
(9) (a) Lee, H. W.; Lam, F. L.; So, C. M.; Lau, S. P.; Chan, A. S. C.;
Kwong, F. Y. Angew. Chem., Int. Ed. 2009, 48, 7436–7439. (b) Wassenaar,
J.; van Zutphen, S.; Mora, G.; Le Floch, P.; Siegler, M. A.; Spek, A. L.;
Reek, J. N. H. Organometallics 2009, 28, 2724–2734. (c) So, C. M.; Yeung,
C. C.; Lau, C. P.; Kwong, F. Y. J. Org. Chem. 2008, 73, 7803–7806. (d)
Wassenaar, J.; Kuil, M.; Reek, J. N. H. AdV. Synth. Catal. 2008, 350, 1610–
1614. (e) Wassenaar, J.; Reek, J. N. H. Dalton Trans. 2007, 3750–3753.
(f) Yu, J. O.; Lam, E.; Sereda, J. L.; Rampersad, N. C.; Lough, A. J.;
Browning, C. S.; Farrar, D. H. Organometallics 2005, 24, 37–47. (g)
Artemova, N. V.; Chevykolava, M. N.; Luzikov, Y. N.; Nifant’ev, I. E.;
Nifant’ev, E. E. Tetrahedron 2004, 60, 10365–10370. (h) Rataboul, F.; Zapf,
A.; Jackstell, R.; Harkal, S.; Riermeier, T.; Monsees, A.; Dingerdissen, U.;
Beller, M. Chem.sEur. J. 2004, 10, 2983–2990. (i) Brnincori, T.; Piccolo,
O.; Rizzo, S.; Sannicolo`, F. J. Org. Chem. 2000, 65, 8340–8347. (j) Claridge,
T. D. W.; Long, J. M.; Brown, J. M.; Hibbs, D.; Hursthouse, M. B.
Tetrahedron 1997, 53, 4035–4050. (k) Berens, U.; Brown, J. M.; Long, J.;
Selke, R. Tetrahedron: Asymmetry 1996, 7, 285–292.
(6) Syntheses of arylphosphines by Diels-Alder reactions of 1-alky-
nylphosphine oxides were reported: (a) Ashburn, B. O.; Carter, R. G.;
Zakharov, L. N. J. Am. Chem. Soc. 2007, 129, 9109–9116. (b) Ashburn,
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(7) The palladium-catalyzed annulation of alkynes with 2-iodoanilines
was reported by Larock and others: (a) Larock, R. C.; Yum, E. K. J. Am.
Chem. Soc. 1991, 113, 6689–6690. (b) Larock, R. C.; Yum, E. K.; Refvic,
M. D. J. Org. Chem. 1998, 63, 7652–7662. (c) Larock, R. C.; Yum, E. K.;
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(8) For selected references, see: (a) Sergev, A. G.; Schulz, T.; Torborg,
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(11) The structure of 3aa was confirmed by X-ray crystallographic
analysis. See the Supporting Information.
(12) The reaction of 1.2 equiv of 2a gave 3aa in 61% NMR yield. The
concentration of 2a would affect the efficiency of the reaction.
(13) See the Supporting Information.
(14) The reason why Pd(acac)2 gave the best result is not clear at this
stage. The ligand on palladium precursors would affect the catalytic activity.
Pd(II) precursors would be reduced to Pd(0) complexes under the reaction
conditions, which would participate in the catalytic cycle.
(15) A significant amount of phosphine sulfide derived from an additional
phosphine ligand was observed after the reaction.
Org. Lett., Vol. 12, No. 7, 2010
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