1,2-Bis(diphenylphosphino)carborane as a dual mode ligand for both the Sonogashira coupling and hydride-transfer steps in palladium-catalyzed one-pot synthesis of allenes from aryl iodides

Article abstract of DOI:10.1021/ol060538v

One-pot allene synthesis from aryl iodides 1 and propargyldicyclohexylamine 2 proceeded in the presence of Pd₂(dba)₃·CHCl ₃ catalyst (2.5 mol %), 1,2-bis(diphenylphosphino)carborane 5 (10 mol %), Cul (15 mol %), and Et₃N (150 mol %) to give the corresponding allenes 4 in good to high yields. Electron-deficient bidentate phosphines, such as 1,2-bis(diphenylphosphino)carborane 5 and (C₆F₅) ₂PC₂H₄P(C₆F₅) ₂, play the role of a dual mode ligand for both the Sonogashira coupling and hydride-transfer reactions.

Full text of DOI:10.1021/ol060538v

ORGANIC
LETTERS
2006
Vol. 8, No. 10
2095-2098
1,2-Bis(diphenylphosphino)carborane As
a Dual Mode Ligand for Both the
Sonogashira Coupling and
Hydride-Transfer Steps in
Palladium-Catalyzed One-Pot Synthesis
of Allenes from Aryl Iodides
Hiroyuki Nakamura,* Takaya Kamakura, and Shinya Onagi
Department of Chemistry, Faculty of Science, Gakushuin UniVersity, Mejiro,
Toshima-ku, Tokyo 171-8588, Japan
hiroyuki.nakamura@gakushuin.ac.jp
Received March 4, 2006
ABSTRACT
One-pot allene synthesis from aryl iodides 1 and propargyldicyclohexylamine 2 proceeded in the presence of Pd2(dba)3‚CHCl3 catalyst (2.5
mol %), 1,2-bis(diphenylphosphino)carborane 5 (10 mol %), CuI (15 mol %), and Et3N (150 mol %) to give the corresponding allenes 4 in good
to high yields. Electron-deficient bidentate phosphines, such as 1,2-bis(diphenylphosphino)carborane 5 and (C6F5)2PC2H4P(C6F5)2, play the role
of a dual mode ligand for both the Sonogashira coupling and hydride-transfer reactions.
The proper choice of ligands for transition-metal-catalyzed
reactions is crucial for expanding the scope of reactions in
organic synthesis.1 We recently found the allene transforma-
tion from propargylic amines via palladium-catalyzed hy-
dride-transfer reaction.2 In this transformation, propargylic
amines can be handled as an allenyl anion equivalent,
which reacts with various aryl halides and heterocyclic
halides through the Sonogashira coupling reaction to be
transformed into allenes. Although trispentafluorophenyl-
phosphine [(C6F5)3P] was found to be a potent ligand for
the palladium-catalyzed hydride-transfer reaction, it was not
effective for the Sonogashira coupling step.2a Therefore, two
separate steps were needed for the synthesis of allenes from
organic halides (1 f 3 f 4 pathway in Scheme 1). A
carborane framework involves three-center two-electron
(1) Littke, A. F.; Fu, G. C. Angew. Chem., Int. Ed. 2002, 41, 4176.
(2) (a) Nakamura, H.; Kamakura, T.; Ishikura, M.; Biellmann, J.-F. J.
Am. Chem. Soc. 2004, 126, 5958. (b) Nakamura, H.; Onagi, S.; Kamakura,
T. J. Org. Chem. 2005, 70, 2357. (c) Nakamura, H.; Tashiro, S.; Kamakura,
T. Tetrahedron Lett. 2005, 46, 8333. (d) Nakamura, H.; Onagi, S.
Tetrahedron Lett. 2006, 47, 2539.
10.1021/ol060538v CCC: $33.50
© 2006 American Chemical Society
Published on Web 04/14/2006

allenes from organic iodides without using a stoichiometric
amount of metals.
Scheme 1
We first examined the one-pot allene synthesis from
4-iodoacetanilide 1a and propargyldicyclohexylamine 22c
using various phosphine ligands as shown in Table 1. The
Table 1. Optimization of Reaction Conditionsa
bonding3,4 and is thus known as an electron-deficient cluster.
We utilized this framework for a skeleton of ligands (5 and
6) on palladium catalysts and found that 1,2-bis(diphenyl-
yieldsb,c of
3a/4a [%]
entry
ligand
solvent
1
2
3
4
5
6
7
8
PPh3
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
dioxane
CHCl3
70/23
53/40
-/- (99)
-/87
-/87
-/50
-/57 (37)
-/33 (67)
P(OPh)3
P(C6F5)3
(C6F5)2PC2H4P(C6F5)2
5
6
5
5
a All reactions were carried out in the presence of Pd2(dba)3‚CHCl3
catalyst (2.5 mol %), ligand (20 mol % of monodentate ligands (entries
1-3) or 10 mol % of bidentate ligands (entries 4-8)), CuI (15 mol %),
and Et3N (150 mol %) at 80 °C for 3 h, and then the temperature was
increased to 100 °C for 20 h. b Isolated yield based on 1a. c Recovery of
1a is indicated in parentheses.
phosphino)carborane 55 plays the role of a dual mode ligand
for both the Sonogashira coupling and hydride-transfer
reactions (1 f 4 pathway in Scheme 1). Herein we report
the palladium-catalyzed one-pot synthesis of allenes6 from
organic iodides. Palladium-catalyzed direct coupling reactions
of allenylic metals, such as allenylstannanes,7 allenylindi-
ums,8 and allenylzincs,9 with organic halides have been
reported. The current transformation enables us to synthesize
reaction was carried out at 80 °C for 3 h and monitored by
TLC to confirm the generation of 3a, then the reaction
temperature was raised to 100 °C. The reaction proceeded
in the presence of Pd2(dba)3‚CHCl3 catalyst (2.5 mol %),
PPh3 (20 mol %), CuI (15 mol %), and Et3N (150 mol %)
to give the allene 4a in 23% yield along with the Sonogashira
coupling product 3a in 70% yield (entry 1). The use of
P(OPh)3 as a ligand increased the yield of 4a (40%, entry
2). However, the reaction did not proceed in the presence of
P(C6F5)3 ligand, which is effective for the palladium-
catalyzed hydride-transfer step (entry 3).2a Although the
reactions failed with various bidentate phosphine ligands,
such as bis(diphenylphosphino)methane (dppm), 1,2-bis-
(diphenylphosphino)ethane (dppe), and 1,1′-bis(diphenylphos-
phino)ferrocene (dppf), (C6F5)2PC2H4P(C6F5)2 was found to
be effective for both the Sonogashira coupling and hydride-
transfer steps and 4a was obtained in 87% yield, exclusively
(entry 4). This result indicates that an electron deficient
bidentate phosphine may be suitable for the one-pot synthesis
of allenes. It occurred to us that use of a carborane cluster
as a skeleton of ligands would be more effective for the
current reaction. We synthesized the diphosphinocarborane
ligands 5 and 6 from 1,2-dilithiocarborane3,10 with ClPPh2
(3) Carboranes; Grimes, R. N., Ed.; Academic: New York, 1970.
(4) (a) Nakamura, H.; Aoyagi, K.; Yamamoto, Y. J. Am. Chem. Soc.
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Chem. 1997, 62, 780.
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Crespo, O.; Gimeno, M. C.; Jones, P. G.; Laguna, A. Inorg. Chem. 1994,
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Luzuriaga, J. M.; Perez, J. L.; Ramon, M. A.; Veiros, L. F. Inorg. Chem.
2000, 39, 4280.
(6) Other synthetic methods for allenes: (a) Allenes in Organic Synthesis;
Coppola, G. M., Schuster, H. F., Eds.; Wiley: New York, 1984. (b)
Hoffmann-Roder, A.; Krause, N. Angew. Chem., Int. Ed. 2002, 41, 2933.
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Soc. 1990, 112, 8042. (d) Searles, S.; Li, Y.; Nassim, B.; Robert Lopes,
M.-T.; Tran, P. T.; Crabbe´, P. J. Chem. Soc., Perkin Trans. 1 1984, 747.
(e) Myers, A. G.; Zheng, B. J. Am. Chem. Soc. 1996, 118, 4492. (f)
Ogasawara, M.; Ikeda, H.; Nagano, T.; Hayashi, T. J. Am. Chem. Soc. 2001,
123, 2089. (g) Zimmermann, M.; Wibbeling, B.; Hoppe, D. Synthesis 2004,
765. (h) Fukuhara, K.; Okamoto, S.; Sato, F. Org. Lett. 2003, 5, 2145. (i)
Tanaka, K.; Otsubo, K.; Fuji, K. Synlett 1995, 993. (j) Brummond, K. M.;
Dingess, E. A.; Kent, J. L. J. Org. Chem. 1996, 61, 6096. (k) Delouvrie,
B.; Lacote, E.; Fensterbank, L.; Malacria, M. Tetrahedron Lett. 1996, 40,
3565. (l) Tsuji, J.; Sugiura, T.; Yuhara, M.; Minami, I. Chem. Commun.
1986, 922. (m) Tsuji, J.; Sugiura, T.; Minami, I. Synthesis 1987, 603.
(7) (a) Badone, D.; Cardamone, R.; Guzzi, U. Tetrahedron Lett. 1994,
35, 5477. (b) Huang, C.-W.; Shanmugasundaram, M.; Chang, H.-M.; Cheng,
C.-H. Tetrahedron 2003, 59, 3635.
(8) (a) Lee, K.; Seomon, D.; Lee, P. H. Angew. Chem., Int. Ed. 2002,
41, 3901. (b) Lin, M.-J.; Loh, T.-P. J. Am. Chem. Soc. 2003, 125, 13042.
(9) (a) Ma, S.; He, Q. Angew. Chem., Int. Ed. 2004, 43, 988. (b) Ma, S.;
Zhang, A. J. Org. Chem. 1998, 63, 9601.
(10) (a) Nakamura, H.; Sadayori, N.; Sekido, M.; Yamamoto, Y. Chem.
Commun. 1994, 2581. (b) Nakamura, H.; Aoyagi, K.; Singaram, B.; Cai,
J.; Nemoto, H.; Yamamoto, Y. Angew. Chem., Int. Ed. 1997, 36, 367. (c)
Nakamura, H.; Sekido, M.; Yamamoto, Y. J. Med. Chem. 1997, 40, 2825.
2096
Org. Lett., Vol. 8, No. 10, 2006

and ClP(OEt)2, respectively. The reaction proceeded with
1,2-bis(diphenylphosphino)-o-carborane 5 to give only 4a
in 87% yield, although the yield of 4a was lower in the case
of 1,2-bis(diethoxyphosphino)-o-carborane 6 (entries 5 and
6). We also examined the reactions using 5 as a ligand in
various solvents, such as dioxane (entry 7), CHCl3 (entry
8), dimethoxyethane, THF, toluene, and dimethylformamide;
however, 4a was obtained in low yields (22-57%).
Table 2. One-Pot Synthesis of Various Allenes 4 from Aryl
Iodides 1 with Propargyldicyclohexylamine 2a
With optimized conditions established, we next investi-
gated the one-pot synthesis of various allenes from the
corresponding aryl iodides using 1,2-bis(diphenylphosphino)-
o-carborane 5. The results are summarized in Table 2. The
aryl iodides, which have an electron-donating group such
as AcNH- (1a and 1b), MeO- (1c), and dimethyl (1d),
underwent the one-pot allene transformation to give the
corresponding allenes 4a-d in high yields (entries 1-4).
Although allenylbenzene 4e was produced from iodobenzene
1e quantitatively (entry 5), 2-iodonaphthalene 1f gave 4f in
60% yield (entry 6). The use of (C6F5)2PC2H4P(C6F5)2 as a
ligand for the reactions gave the allenes in lower yields (i.e.,
4b 44%, 4d 67%, and 4e 59%). In the case of 4-bromoiodo-
benzene 1g, the reaction took place at the iodo-substituted
position, selectively, to afford 4-bromoalleneylbenzene 4g
in 68% yield, whereas 1,4-diiodobenzene 1h gave 1,4-
diallenylbenzene 4h in 65% yield (entries 7 and 8). It is noted
that the current transformation takes place selectively at an
iodide group. The aryl iodides, which have an electron-
withdrawing group such as acetyl (1i) and esters (1j-l), gave
the corresponding allenes 4i-l in 74-99% yields (entries
9-12). It is noted that (C6F5)2PC2H4P(C6F5)2 is a suitable
ligand for the reactions of 1i and 1j. We also demonstrated
the one-pot allene transformation from iodoheterocycles
(1m-o). The reactions of 5-iodo-2,4-dimethoxypyrimidine
1m, 2-chloro-5-iodopyridine 1n, and 3-iodoquinoline 1o
proceeded in the presence of Pd2(dba)3‚CHCl3 catalyst (2.5
mol %), (C6F5)2PC2H4P(C6F5)2 (10 mol %), CuI (15 mol %),
and Et3N (150 mol %) in chloroform to give the correspond-
ing allenes 4m-o in 67-99% yields (entries 13-15). The
combination of (C6F5)2PC2H4P(C6F5)2 with chloroform as a
solvent was effective for the synthesis of heterocyclic
allenes.2b
To clarify the reaction rate and mechanism of this one-
pot allene transformation, we monitored the concentration
of 1b, 3b, and 4b during the reaction for 11 h by HPLC
analysis (Figure 1). Within 20 min after addition of 2 at 80
°C, 1b was consumed and the Sonogashira coupling product
3b was produced in 25% yield along with the allene 4b in
3% yield. The consumption of 1b and generation of 3b and
4b plateaued after 3 h. When the reaction temperature was
raised to 100 °C, the yield of 4a increased along with
consumption of 1b and 3b. We do not know why the reaction
stopped after 3 h; however, it was essential to heat the
reaction to 100 °C to achieve allene transformation with high
yields. The reaction carried out at 100 °C after addition of
2 did not complete the Sonogashira coupling step due to the
decomposition of catalysts. According to our proposed
mechanism reported previously, the anionic palladium hy-
dride species generated by a hydride transfer from the
a All reactions were carried out in the presence of Pd2(dba)3‚CHCl3
catalyst (2.5 mol %), 5 (10 mol %), CuI (15 mol %), and Et3N (150 mol
%) at 80 °C for 3 h, and then the temperature was increased to 100 °C.
b Isolated yield based on 1. c The diallene product was obtained exclusively.
d (C6F5)2PC2H4P(C6F5)2 was used instead of 5. e The reaction was carried
out in CHCl3.
cyclohexyl carbon of 3 would be a key intermediate.2b
Therefore, a certain extent of reactivity at the oxidative
addition step in addition to an ability to stabilize the
palladium hydride intermediate was required of a potent
ligand for one-pot allene transformation. In this regard, the
electron-deficient bidentate ligands such as the diphosphino-
Org. Lett., Vol. 8, No. 10, 2006
2097

coupling followed by the hydride-transfer reaction in one
pot. In the current transformation, the use of 1,2-bis-
(diphenylphosphino)carborane 5 as well as (C6F5)2PC2H4P-
(C6F5)2 was found to be effective as dual mode phosphine
ligands for both the Sonogashira coupling and hydride-
transfer steps. It is a first example to utilize carboranylphos-
phine ligands for transition-metal-catalyzed coupling reac-
tions, although hydrogenation has been studied with use of
rhodium-nido-carborane complexes.5c,11 Since many attempts
have been made to introduce an allenic moiety into the
backbone of certain pharmacologically active molecules to
develop new biological and pharmacological properties,2d,12
we believe that the current finding would be influential not
only in development of new transition-metal-catalyzed
synthetic methods but also in development of pharmacologi-
cally active allenes in organic synthesis.
Figure 1. Concentrations of 3b and 4b with time during the
reaction of 1b and 2 for 0-11 h. The reaction was carried out in
the presence of Pd2(dba)3‚CHCl3 catalyst (2.5 mol %), 5 (10 mol
%), CuI (15 mol %), and Et3N (150 mol %) at 80 °C and the
reaction temperature was raised to 100 °C after 3 h. The amounts
(yields) of 1b, 3b, and 4b were determined by HPLC analysis.
Supporting Information Available: Detailed experi-
mental procedures and characterization data for compounds
4b, 4d, 4f-i, 4k,l, 4n, and 6. This material is available free
of charge via the Internet at http://pubs.acs.org.
OL060538V
carborane ligands 5 and (C6F5)2PC2H4P(C6F5)2 were suitable
for both catalytic cycles of the Sonogashira coupling and
hydride-transfer steps.
In conclusion, we succeeded in the synthesis of allenes
from the corresponding organic iodides via the Sonogashira
(11) (a) Paxon, T. E.; Hawthorne, M. F. J. Am. Chem. Soc. 1974, 96,
4674. (b) Belmont, J. A.; Soto, J.; King, R. E., III; Donaldson, A. J.; Hewes,
J. D.; Hawthorne, M. F. J. Am. Chem. Soc. 1989, 111, 7475.
(12) Krause, N.; Hoffmann-Ro¨der, A. In Modern Allene Chemistry;
Krause, N., Hashmi, S., Eds.; Wiley-VCH: Weinheim, Germany, 2004;
Vol. 2, pp 997-1039.
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Org. Lett., Vol. 8, No. 10, 2006