Tetraarylphosphonium halides as arylating reagents in Pd-catalyzed heck and cross-coupling reactions

Article abstract of DOI:10.1002/anie.200501582

(Chemical Equation Presented) Highly efficient: Tetraarylphosphonium halides, Ar₄P⁺X^-, as arylating reagents efficiently deliver an aryl group in Pd-catalyzed reactions with olefins, organoboron compounds, and terminal alkynes (see scheme).

Full text of DOI:10.1002/anie.200501582

Communications
Synthetic Methods
is activated catalytically in agreement with the previous
report.[10] We envisioned that the employment of electrospray
ionization mass spectrometry (ESI-MS) could lead us to trace
the activation process because it allows facile detection of
DOI: 10.1002/anie.200501582
Tetraarylphosphonium Halides as Arylating
Reagents in Pd-Catalyzed Heck and Cross-
Coupling Reactions**
highly
unstable
and/or
sensitive
metal-containing
intermediates.[15]
Lee Kyoung Hwang, Youngim Na, Junseong Lee,
Youngkyu Do, and Sukbok Chang*
Transition-metal-catalyzed olefination and cross-coupling
reactions have become one of the most powerful tools in
organic synthesis.[1] While aryl, alkenyl, alkynyl, and, more
recently, alkyl halides are typically employed as coupling
reagents, a variety of different types of pseudohalide species
have been also investigated as useful electrophiles. Among
these, representative recent examples are carboxylic acids,[2]
acid anhydrides,[3] aryl esters,[4] sulfonates,[5] phosphonic
acids,[6] sulfonium ions,[7] and ammonium salts.[8] Although
When 1 was treated with 0.5 equivalents of [Pd2(dba)3]
(dba = trans,trans-dibenzylideneacetone) at 1008C, a set of
ion peaks were detected in the ESI-mass spectra which were
attributed to transient metal species resulting from the
À
activation of the P phenyl bond of 1 (Figure 1). It was
observed that a dba ligand in the complex was gradually
displaced by acetonitrile to give a series of peaks for
[(PPh3)2PhPd(CH3CN)m] (m = 1–3) at the expense of phos-
phonium ion (Figure 1, all m/z values are reported on the
basis of the 106Pd isotope).[16] When Pd(OAc)2 was employed
instead of [Pd2(dba)3], the activation process occurred more
slowly and the corresponding peaks started to appear only
after a few hours under the same conditions. The fact that a
complex of Pd0 is more active than a PdII species for the
activation is in a good agreement with the generally accepted
assumption that PdII precursors are reduced initially into Pd0
complexes, which are catalytically active in most cross-
coupling reactions.[17]
À
metal-mediated C P bond cleavage of organophosphorus
species was previously investigated,[9] the use of such com-
pounds in cross-coupling reactions has been relatively under-
developed. Yamamoto and co-workers suggested that quater-
nary phosphonium iodide (Ph4P+IÀ) oxidatively adds to Pd0
complexes through P-aryl bond cleavage and they showed
briefly that one phenyl group was transferred to react with
activated olefins, although in low yields (32–36%).[10] Reetz
et al. reported that the efficiency of the Heck reaction with
normally unreactive aryl halides was significantly improved
by the presence of phosphonium halides.[11] Additionally,
several research groups described mechanistic details for the
observed aryl–aryl interchange process between phosphinyl-
and Pd-bound aryl groups in cross-coupling reactions that
relied on the composition of the products[12] and theoretical
considerations.[13] Herein, we describe our recent studies on
the utility of tetraarylphosphonium halides as arylating
reagents in Heck and cross-coupling reactions, as well as
providing spectroscopic details on the activation process.[14]
At the outset of our studies, we attempted to optimize the
reaction conditions for the Pd-catalyzed olefination reaction
using tetraarylphosphonium ions. When tetraphenylphospho-
nium chloride (1) was treated with n-butyl acrylate (3.0 equiv)
in the presence of Pd(OAc)2 (10 mol%) and sodium acetate
(3.0 equiv), n-butyl trans-cinnamate was isolated in 85% yield
À
Pd-mediated cleavage of the P C bond of tetraarylphos-
phonium ions was further supported by the isolation and
characterization of an oxidatively inserted palladium species.
When Ph4P+ClÀ (1) was treated with 0.5 equivalents of
[Pd2(dba)3] in the presence of PPh3, a transparent solid 2
was isolated (54%) that revealed a square-planar geometry
with two triphenylphosphine groups positioned trans to each
other (Figure 2). The bond lengths and angles of 2 are within
comparable range of those previously reported, although the
same palladium species was prepared starting from a different
precursor by a ligand-exchange method.[18] When the isolated
Pd complex 2 was treated with n-butyl acrylate,[19] reaction
occurred readily in the presence of sodium acetate at
temperatures over 808C to afford butyl cinnamate in
55%.[20] This result led us to postulate that phosphonium
species play a dual role, as a source of the arylating group and
as a stabilizing ligand on palladium complexes, upon release
of phosphine from the phosphonium ions.
À
[Eq. (1)], which thus clearly suggested that the C P bond of 1
[*] L. K. Hwang, Y. Na, J. Lee, Prof. Y. Do, Prof. S. Chang
Center for Molecular Design and Synthesis (CMDS)
Department of Chemistry and School of Molecular Science (BK 21)
Korea Advanced Institute of Science and Technology (KAIST)
Daejeon 305-701 (Korea)
During the course of optimization of the conditions for
olefination with phosphonium halides, it was found that
higher yields (ca. 20%) were obtained when the reaction was
carried out under atmospheric oxygen relative to those
performed under N2.[21] It is thought that oxygen oxidizes
liberated triphenylphosphine into its oxide, thus driving the
reaction to completion more readily. Indeed, a side product of
triphenylphosphine oxide was seen to be generated (> 80%)
during the olefination reaction under an O2 atmosphere
Fax: (+82)42-869-2810
E-mail: sbchang@kaist.ac.kr
[**] This research was supported by the Center for Molecular Design and
Synthesis at KAIST.
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
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Chemie
Figure 1. ESI mass spectra obtained from the treatment of tetraphenylphosphonium chloride (1) with [Pd2(dba)3] (0.5 equiv) at 1008C.
Table 1: Heck olefinations with 1.[a]
Figure 2. Preparation and X-ray crystal structure of 2.
Entry
Alkene
Yield [%][b]
1
72
85
98
74
76
70[d]
71
59
[Eq. (1)]. Whereas sodium acetate turned out to be most
effective of the various bases examined, it was interesting to
observe that olefination proceeds even in the absence of an
external base, albeit with moderate yields (53% from the
reaction of Equation (1) under such conditions).[22] Addition-
ally, the efficiency of the reaction was dependent on the
nature of the counteranions of the phosphonium salts
[Eq. (2)]. Whereas reactions with phosphonium species that
bear chloride ions gave the highest yield, other halide salts
such as bromide and iodide resulted in reduced yields.
However, upon addition of LiCl (2.0 equiv) in a reaction
with Ph4P+BrÀ, the efficiency was recovered to the same level
as with Ph4P+ClÀ.
2
3
4
5[c]
6
7
8
9
70
[a] Reaction conditions: alkenes (3.0 equiv), catalyst (10 mol%), NaOAc
(3.0 equiv), 1308C, 12 h under O2 (1 atm). [b] Yield of isolated product.
[c] 3.0 equivalents of Cs2CO3 was used instead of NaOAc. [d] E/Z=4:1.
Under the optimized conditions, the olefination of 1 was
examined with a range of alkenes (Table 1).[23] Whereas
reactions with acrylic esters, amides, vinyl sulfone, and vinyl
phosphonate proceeded efficiently to afford the correspond-
ing olefinated products exclusively in the E form, olefination
with acrylonitrile produced cinnamonitrile with modest
selectivity (E/Z = 4:1). Notably, acrylic acid was also readily
coupled with 1 to afford (E)-cinnamic acid in good yield.[24]
The use of phosphonium species in the Suzuki–Miyaura
reaction was next investigated (Table 2). While electronic and
steric variations on organoboron compounds have negligible
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Table 2: Suzuki coupling reactions with 1.[a]
not observed [Eq. (3)]. Independent of the electronic nature
of the aryl substituents, a mixture of unsubstituted (major)
and substituted cinnamates (minor) were produced with a
ratio of 3–4:1. The rather statistical aryl transfer in the Heck
olefination was also observed in Suzuki and Sonogashira
reactions. These results can be presumably attributed to fast
aryl–aryl interchange processes between phosphinyl- and Pd-
Entry
Organoborane
Yield [%][b]
1
2
3
4
5
6
7
C6H5-B(OH)2
77
80
95
83
70
75
91
4-Ac-C6H4-B(OH)2
4-MeO-C6H4-B(OH)2
2-Me-C6H4-B(OH)2
4-Br-C6H4-B(OH)2
4-CHO-C6H4-B(OH)2
À
bound aryl groups that are generated upon cleavage of the C
aryl bond of the heterogeneously substituted phosphonium
species.
8
63
9
70
[a] Reaction conditions: organoboranes (1.5 equiv), catalyst (10 mol%),
NaOAc (3.0 equiv), 1008C, 12 h under N2. [b] Yield of isolated product.
In summary, conditions have been optimized for the Pd-
catalyzed reactions of tetraarylphosphonium halides with
olefins, organoborons, and alkynes that demonstrate the
utility of the phosphonium species as facile arylating reagents.
Characterization of reaction intermediates by ESI mass
spectrometry and X-ray crystallography add important
effects on efficiency, several functional groups were tolerated
under the reaction conditions. As demonstrated in entry 9, a
boronic ester derived from catechol was also employed as an
efficient coupling partner with 1. Although the exact reason is
not clear at present, the effect of oxygen observed in the Heck
olefination was not observed in case of Suzuki and Sonoga-
shira reactions (see below).[25]
In the Sonogashira-type reaction, tetraarylphosphonium
halides were also readily employed as efficient arylating
reagents with a wide range of alkynes (Table 3). In a similar
À
knowledge to the Pd-mediated activation pathway of the C
P bond of phosphonium precursors.
Received: May 10, 2005
Revised: June 13, 2005
Table 3: Sonogashira coupling reactions with 1.[a]
À
Keywords: C P activation · cross-coupling · mass spectrometry ·
olefination · phosphorus
.
Entry
Alkyne
Yield [%][b]
[1] a) R. F. Heck in Comprehensive Organic Synthesis, Vol. 4 (Eds.:
B. M. Trost, I. Fleming), Pergamon, Oxford, 1991; b) N.
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1
2
3
4
C6H5
99
86
62
99
4-F-C6H4
4-Me-C6H4
4-PhO-C6H4
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5
6
62
77
7
8
HO(CH2)3
CH3CH(OH)CH2
64
63
9
77
[7] J. Srogl, G. D. Allred, L. S. Liebeskind, J. Am. Chem. Soc. 1997,
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(iPr)3S
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alkynylation was not significantly affected by aryl substitu-
ents. Note that coupling of 1 with 1-phenyl-2-(trimethylsilyl)-
acetylene, an internal alkyne, was also carried out efficiently
(98% yield) when 1,3-bis(2,4,6-trimethylphenyl)imidazolium
chloride was employed as an additive (10 mol%).
When differently substituted tetraarylphosphonium hal-
ides[26] were used in olefinations, a selective aryl transfer was
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Chemie
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2001, 42, 4833; b) S. Chang, M. Lee, S. Kim, Synlett 2001, 1557;
c) Y. Na, S. Park, S. B. Han, H. Han, S. Ko, S. Chang, J. Am.
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[16] See Supporting Information for a comparison of the distribution
of isotopic ratios between the calculated and obtained spectra.
[17] a) F. Ozawa, A. Kubo, T. Hayashi, Chem. Lett. 1992, 2177; b) C.
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[19] It was reported that some [ArPdCl(PPh3)2] complexes react with
olefins in the presence of Et3N as base; see: a) H. A. Dieck, R. F.
Heck, J. Am. Chem. Soc. 1974, 96, 1133; b) C.-M. Andersson, A.
Hallberg, G. D. Daves, J. Org. Chem. 1987, 52, 3529.
[20] Amatore et al. established that acetate ions substitute the iodide
ion from [PhPdI(PPh3)2] to afford [PhPd(OAc)(PPh3)2], which is
determined to be an essential intermediate in the Heck reaction;
see: C. Amatore, E. Carrꢃ, A. Jutand, M. A. MꢂBarki, G. Meyer,
Organometallics 1995, 14, 5605.
[21] Although the intermediate [Pd0(PPh3)2] species that is generated
at the end of the catalytic cycle is known to be very sensitive to
oxygen,[1] the present results suggest that its oxidative addition
with the phosphonium salts might be faster than its reaction with
oxygen. We thank one reviewer for indicating this.
[22] One reviewer suggested that triphenylphosphine, which is
liberated during the reaction, may serve as a base, although
the same role by chloride ion cannot be ruled out at present.
[23] Although the reported yields were obtained from reactions with
Pd(OAc)2 catalyst (10 mol%), use of [Pd2(dba)3] (5 mol%)
resulted in almost comparable results.
[24] When tetra-p-tolylphosphonium chloride was employed, n-butyl
trans-3-(4-methylphenyl)acrylate was obtained in 99% yield.
[25] Suzuki and Sonogashira reactions under oxygen atmosphere
afforded significantly lower yields relative to those obtained
under N2; see the Supporting Information for details.
[26] T. Migita, T. Nagai, K. Kiuchi, M. Kosugi, Bull. Chem. Soc. Jpn.
1983, 56, 2869.
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