Pd-catalyzed P-C cross-coupling reactions for versatile triarylphosphine synthesis

Article abstract of DOI:10.1021/ol303448j

Practical and versatile syntheses of tertiary phosphine derivatives have been achieved by palladium-catalyzed deformylative P-C cross-coupling reactions of hydroxymethylphosphine derivatives. Sequential couplings of orthogonally protected precursors provide a simple and practical route toward a variety of tertiary phosphine derivatives having aryl substituents in any combination.

Full text of DOI:10.1021/ol303448j

ORGANIC
LETTERS
2013
Vol. 15, No. 3
628–631
Pd-Catalyzed PꢀC Cross-Coupling
Reactions for Versatile
Triarylphosphine Synthesis
Minoru Hayashi,* Takashi Matsuura, Ippei Tanaka, Hidetoshi Ohta, and Yutaka Watanabe
Department of Materials Science and Biotechnology, Graduate School of Science and
Engineering, Ehime University, 3 Bunkyo-cho, Matsuyama 790-8577, Japan
mhayashi@ehime-u.ac.jp
Received December 17, 2012
ABSTRACT
Practical and versatile syntheses of tertiary phosphine derivatives have been achieved by palladium-catalyzed deformylative PꢀC cross-coupling
reactions of hydroxymethylphosphine derivatives. Sequential couplings of orthogonally protected precursors provide a simple and practical
route toward a variety of tertiary phosphine derivatives having aryl substituents in any combination.
Organophosphorus compounds play important roles in
organic synthesis, especially as synthetic reagents and li-
gands for transition metal catalysis.1 Much attention has
been paid toward the development of functionalized and
sophisticated organophosphines for selective transition-
metal catalysis because of the high impact of their structure
on the reactivity, selectivity, and even the reaction pathway,
i.e. products formed, of the catalytic reactions being studied.2
In addition to classical nucleophilic PꢀC bond forming
methods,3 a number of catalytic reactions for the synthesis
of organophosphines have also been developed that use
various phosphine precursors in nucleophilic addition,4
hydrophosphination,5 and PꢀC cross-coupling reactions.6,7
In contrast to the classical stoichiometric organometallic
reactions for phosphine syntheses, metal-catalyzed PꢀC
bond formations have many advantages due to high func-
tional group tolerance, which is often problematic in the
classic methods. However, most of the reported catalytic
reactions can construct only one PꢀC bond, through
(5) (a) Alonso, F.; Beletskaya, I. P.; Yus, M. Chem. Rev. 2004, 104,
3079. (b) Wicht, D. K.; Glueck, D. S. In Catalytic Heterofunctionaliza-
tion; Togni, A., Gr€utzmacher, H., Eds.; Wiley-VCH: Weinheim, 2001; p 143.
(6) For reviews: (a) Tappe, F. M. J.; Trepohl, V. T.; Oestreich, M.
Synthesis 2010, 3037. (b) Glueck, D. S. Top. Organomet. Chem. 2010,
31, 65.
(1) (a) Clarke, M. L.; Williams, M. J. In Organophosphorus Reagents;
Murphy, P. J., Ed.; Oxford University Press: New York, 2004; Chapter 2.
(b) Gilheany, D. G.; Mitchell, C. M. In The Chemistry of Organophosphorus
Compounds; Hartley, F. R., Ed.; John Wiley & Sons: Chichester, 1990;
Vol. 1, p 151.
(2) For examples: (a) Wong, S. M.; So, C. M.; Kwong, F. Y. Synlett
2012, 23, 1132. (b) Birkholz, M.-N.; Freixa, Z.; van Leeuwen, P. W. N.
M. Chem. Soc. Rev. 2009, 38, 1099. (c) Borner, A., Ed. Phosphorus
(7) Recent examples of catalytic PꢀC bond formation: (a) Cieslikie-
ꢀ
wicz, M.; Bouet, A.; Juge, S.; Toffano, M.; Bayardon, J.; West, C.;
€
Lewinski, K.; Gillaizeau, I. Eur. J. Org. Chem. 2012, 1101. (b) Zhao,
Y.-L.; Wu, G.-J.; Han, F.-S. Chem. Commun. 2012, 48, 5868. (c) Sun, M.;
Zhang, H.-Y.; Han, Q.; Yang, K.; Yang, S.-D. Chem.;Eur. J. 2011,
9566. (d) Zhao, Y.-L.; Wu, G.-J.; Li, Y.; Gao, L.-X.; Han, F.-S. Chem.;
Eur. J. 2012, 9622. (e) Li, J.; Luts, M.; Spek, A. L.; van Klink, G. P. M.;
van Koten, G.; Gebbink, R. J. M. K. J. Organomet. Chem. 2010, 695,
2618. (f) Julienne, D.; Delacroix, O.; Gaumont, A. -C. Compt. Rend.
Chim. 2010, 1099. (g) Damian, K.; Clarke, M. L.; Cobley, C. J. Appl.
Organomet. Chem. 2009, 23, 272.
Ligands in Asymmetric Catalysis; Wiley-VCH: Weinheim, 2008; Vol. 3.
€
(d) Jakel, C.; Paciello, R. Chem. Rev. 2006, 106, 2912.
(3) (a) Quin, L. D. In A Guide to Organophosphorus Chemistry; John
Wiley & Sons: New York, 2000; p 68. (b) Hey-Hawkins, E., Karasik, A. A.
In Science of Synthesis, Houben-Weyl Methods of Molecular Transfor-
mations; Georg Thieme Verlag: Stuttgart, 2008; Vol. 42, p 71.
(4) Enders, D.; Saint-Dizier, A.; Lannou, M. -I.; Lenzen, A. Eur. J.
Org. Chem. 2006, 29.
r
10.1021/ol303448j
Published on Web 01/18/2013
2013 American Chemical Society

activation of one precursor bond. Moreover, these reactions
cannot simply be extended to consecutive multiple coupling
sequences in a selective manner because of the unavailability
of suitable precursors having more than one functionality
on the phosphorus atom being activated, although some
nonselective multiple couplings are known.8 Successful se-
quential construction of three PꢀC bonds by using nucleo-
philic organometallic reagents can be found in the literature,
but the problem of functional group tolerance can arise, like
in the classical reactions.9 The sequential synthesis of organo-
phosphines with wide functional group tolerance has yet to
be achieved.
(entry 7), whereas the other bidentate phosphine ligands or
a sterically hindered ligand gave unsatisfactory results
(entries 2ꢀ6). Although both the precursor and the pro-
duct can coordinate to the Pd, and some of phosphine
sulfides reported to work as a ligand,13 the reaction did not
proceed in the absence of an additional phosphine ligand
(entry 8). DBU was found to be suitable for this reaction.
The reactions conducted below 40 °C did not proceed at
all, probably becausethe initial oxidativeaddition does not
occur at that temperature.
Herein we report a novel, practical, and versatile method
for organophosphine synthesis based on newly developed
palladium-catalyzed deformylative PꢀC cross-coupling re-
actions. Successful extension of the strategy provides simple
and easy procedures for organophosphine syntheses, which
can connect up to three different substituents onto the
phosphorus atom, in a selective, actually sequential manner.
A key to success in multiple selective PꢀC couplings is to
develop suitable phosphine precursors for exclusive gen-
eration of a reactive site under selective conditions during
each step. We have focused on hydroxymethylphosphine
derivatives as precursors for PꢀC cross-coupling reactions,
because these compounds generate the parent phosphides
through deformylation under mild basic conditions.10,11 In
addition, various kinds of protective groups are available for
the hydroxyl group, which can be selectively activated.
Selective and stepwise transformation sequences can be
realized when bis- and tris-hydroxymethyl derivatives with
orthogonal protection are applied in a selective manner.
Prior to attempting multiple couplings, we tried to
develop catalytic PꢀC cross-coupling processes suitable
for multiple sequential couplings through deformylation
of protected and nonprotected hydroxymethylphosphine
precursors, even though a number of catalytic monosub-
stitutions of phosphine derivatives are known.6,7 As a
model, monohydroxymethylphosphine sulfide 1 was cho-
sen for an initial investigation of our strategy.12 The
reaction of 1 with p-iodotoluene 2b was carried out in
toluene at 40 °C in the presence of the Pd catalyst prepared
Table 1. Ligand/Base Screening for the PꢀC Coupling of 1
entry
solventa
base
ligandb
Ph3P
yield (%)c
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
THF
DBU
DBU
DBU
DBU
DBU
DBU
DBU
DBU
Et3N
K2CO3
K2CO3
90
2
tBu3P
dppe
dppp
dppb
(S)-BINAP
dppf
3
3
9
4
49
5
40
6
33
7
99 (99)
8
ꢀ
0
7
3
1
9
dppf
10
11
dppf
dppf
a Conditions: 1 (0.5 mmol), 2b (1.05 equiv), solvent (5 mL), Pd2(dba)3
(1 mol %). b P/Pd = 2.0. c Yield calculated from 31P NMR signal ratio.
Isolated yield is shown in parentheses.
Under the optimized conditions, several iodoarenes,
2aꢀo, with various steric and electronic features, were
smoothly coupled with 1 to give the corresponding aryl-
phosphine sulfides 3aꢀo in excellent yield (Table 2).
Although iodoarenes with an electron-donating substitu-
ent require a longer reaction time to complete the reaction,
the coupling products can be obtained almost quantita-
tively. Iodobenzenes with other halogens also react with-
out trouble, with the other halogens remaining untouched
under the reaction conditions. A sterically hindered sub-
stituent engaged in the coupling reaction, but a longer
reaction time and/or more severe conditions were required
(entries 4, 15ꢀ16). Even under elevated temperatures, the
reaction of 2,6-disubstituted iodoarene 2p proceeded
slowly to give the coupled product 3p in a moderate yield
(entry 16). Otherwise, the reactions could be readily ap-
plied to a wide variety of substrates as shown in the table.
As shown above, 1 acts as a potential masked-phosphine
equivalent for the present palladium-catalyzed PꢀC cross-
coupling reaction under basic conditions.
from Pd2(dba)3 CHCl3 and Ph3P. By using diazabicyclo-
3
[5.4.0]-7-undecene (DBU) as a base to trigger the reaction,
1 actually gave the expected coupling product 3b in good
yield (Table 1, entry 1). A survey of the phosphine ligands
revealed that 1,10-bis(diphenylphosphino)ferrocene (dppf)
is particularly suitable for the present coupling reaction
(8) (a) Stark, G. A.; Riermeier, T. H.; Beller, M. Synth. Commun.
2000, 30, 1703. (b) Allen, D. W.; Hibbs, D. E.; Hursthouse, M. B.; Malik,
K. M. A. J. Organomet. Chem. 1999, 572, 259.
(9) (a) Baccolini, G.; Boga, C.; Mazzacurati, M. J. Org. Chem. 2005,
4774. (b) Singh, S.; Nicholas, K. M. Chem. Commun. 1998, 149.
(10) (a) Moiseev, D. V.; Patrick, B. O.; James, B. R. Inorg. Chem.
2007, 46, 11467. (b) Nagata, K.; Matsukawa, S.; Imamoto, T. J. Org.
Chem. 2000, 65, 4185. See also, ref 3b.
(11) Some catalytic PꢀC cross-couplings of hydroxymethylpho-
sphine derivatives are reported, see ref 8.
(12) (a) Kilah, N. L.; Wild, S. B. In Science of Synthesis, Houben-
Weyl Methods of Molecular Transformations; Georg Thieme Verlag:
Stuttgart, 2008; Vol. 42, p 618. (b) Romeo, R.; Wozniak, L. A.; Chatgi-
lialoglu, C. Tetrahedron Lett. 2000, 41, 9899. (c) Yamamura, M.; Kano,
N.; Kawashima, T. J. Am. Chem. Soc. 2005, 127, 11954.
(13) (a) Hayashi, M.; Hashimoto, Y.; Yamamoto, Y.; Usuki, J.;
Saigo, K. Angew. Chem., Int. Ed. 2000, 39, 631. (b) Hayashi, M.;
Takezaki, H.; Hashimoto, Y.; Takaoki, K.; Saigo, K. Tetrahedron Lett.
1998, 39, 7529.
Org. Lett., Vol. 15, No. 3, 2013
629

deprotection were investigated (Table 3). The reaction of
TBDMS-protected substrate 8 with iodoarenes was car-
ried out in the presence of fluoride, instead of a base, to
trigger the reaction through desilylation. By using CsF in
THF at 70 °C, the desired direct cross-coupling reaction
proceeded smoothly to give the coupling product in quan-
titative yields, even though an extended reaction time was
required for completion. Benzoyl-protected 9 also reacted
with iodoarenes through alcoholysis by using sodium
ethoxide in THF at 70 °C, to give the same products.
Iodoarenes with an electron-withdrawing substituent re-
acted slowly under the alcoholytic conditions, and the
yields considerably decreased, even though the reactions
were extended. Otherwise, coupling through alcoholysis
gave the products in excellent yields within 2 h. The results
of these direct deprotectionꢀcoupling sequences of the
protected precursors 8 and 9 are summarized in Table 3.
Selective transformations of unsymmetrically protected
diol 10 revealed that each group reacted exclusively to give
thecorrespondingmonocoupled product withoutaffecting
the other protective group (Scheme 2).
Table 2. Pd-Catalyzed PꢀC Cross-Coupling of 1 with Various
Substrates
entry
Ar-
time (h)
product
yield (%)a
1
Ph- (2a)
3
3a
3b
3c
3d
3e
3f
99
99
99
86
93
95
99
99
99
99
99
96
95
97
97
32b
2
p-CH3-C6H4- (2b)
m-CH3-C6H4- (2c)
o-CH3-C6H4- (2d)
p-CH3O-C6H4- (2e)
p-CH3O2C-C6H4- (2f)
p-F-C6H4- (2g)
3
3
3
4
12
12
3
5
6
7
3
3g
3h
3i
8
p-Cl-C6H4- (2h)
3
9
p-Br-C6H4- (2i)
3
10
11
12
13
14
15
16
p-NC-C6H4- (2j)
3
3j
p-CF3-C6H4- (2k)
p-NO2-C6H4- (2l)
p-OHC-C6H4- (2m)
p-HOCH2-C6H4- (2n)
1-naphthyl- (2o)
2,6-(CH3)2C6H3- (2p)
3
3k
3l
3
3
3m
3n
3o
3p
3
18
6
Table 3. Direct PꢀC Bond Formation by Using Protected
Substrates 8 and 9
a Isolated yield. Unless otherwise noted, the reaction was conducted
at 40 °C for 3 h in the presence of 2 mol % of Pd catalyst and DBU
(2 equiv, basic condition). The Pd catalyst was prepared in situ from Pd2-
(dba)3 CHCl3 (1 mol %) and dppf (2 mol %). b The reaction was conducted
3
under reflux. The reaction at temperatures lower than 100 °C did not proceed.
Selective reactions of the hydroxymethyl substrate in the
presence of another hydroxy-protected group were checked
next for selective multiple couplings. A tert-butyldimethylsilyl
group and a benzoyl group were chosen for orthogonal
protection. Transformations of monoprotected substrates 4
and 5 were examined under basic conditions (Scheme 1).
Under the optimized conditions for 1, silyl ether 4 smoothly
reacted with 2b to give the coupled product 6 in excellent
yield. Benzoate 5 also gave the product 7 in good yield,
although some byproducts derived from disproportionation
of the esters were observed under these conditions. In both
cases, only the unprotected part was selectively converted to
the aryl group.
entry
ArꢀX
2a (H)
results for 8a
results for 9a
1
2
3
4
5
6
7
8
99%
99%
2b (p-Me)
2c (m-Me)
2d (o-Me)
2e (p-OMe)
2f (p-CO2Me)
2j (p-CN)
99%
99%
99%
96%
98%
57% (12 h)
99%
87%
b
91%
ꢀ
97% (24 h)
99% (24 h)
32% (24 h)
38% (6 h)
2l (p-NO2)
a Isolated yield. Reaction conditions unless otherwise noted; for 8
(fluoride condition): CsF (2 equiv), THF, 70 °C, 12 h; for 9 (alkoxide
condition): NaOEt (2 equiv), THF, 70 °C, 2 h. Pd-dppf was prepared
same as described in Table 2. b Not examined.
An extension of the present strategy to sequential triple
couplings would yield phosphines having a variety of
structures. For selective triple couplings, we have prepared
precursor 13 by selective protections of the two hydroxyl
groups of tris(hydroxymethyl)phosphine14 sulfide which
can be easily synthesized from commercially available
tetrakis(hydroxymethyl) phosphonium chloride.15
Scheme 1. Selective Coupling of 4 and 5 (Basic Condition)
Direct triple couplings of 13 were then demonstrated;
iterative couplings under the basic, the alkoxide-mediated,
Although two unique aromatics can be incorporated
by using 4 or 5 through repetitive PꢀC couplings after
deprotection, it would be a more straightforward process if
the protected side chain could be directly and selectively
applied to further PꢀC cross-couplings. Thus, direct cou-
plings of protected substrates 8 and 9 through in situ
(14) Tris(hydroxymethyl)phosphine is known as an equivalent of the
parent phosphine; see ref 8. Alkylphosphines can be also prepared by
alkylationꢀdeformylation processes of this precursor; see ref 3b.
(15) (a) Woodward, G.; Padda, R. S.; Regius, C. T. WO 00 24 752
(2000); Chem. Abstr. 2000, 132, 308507. (b) Higham, L. J.; Whittlesey,
M. K.; Wood, P. T. Dalton Trans. 2004, 4202–4208.
630
Org. Lett., Vol. 15, No. 3, 2013

Scheme 2. Selective Coupling of Unsymmetrically Protected 10
Scheme 3. Triarylphosphine Synthesis by Sequential Triple
Couplings
results of mono- and bis-protected substrates shown
above, a variety of aromatic groups can be introduced
onto the phosphorus atom via sequential repetitive cou-
plings. Some representative results are summarized in
Table 4. In all cases, the triple-coupled triarylphosphine
sulfide 14 was isolated in quite good yield in each step,
totally over 80%. As shown in Scheme 2, swapping the
order of the applied conditions in the second and third
steps did not disturb the coupling (entry 5). Some of the
products, including a sensitive functional group such as a
formyl group and a cyano group, which could not be
accessed by other classical organometallic methods, could
also be synthesized by the present coupling, without any
problem (entries 3 and 4).16
Table 4. Pd-Catalyzed Sequential Multiple PꢀC Couplings
of 13
In conclusion, we have developed effective PꢀC cross-
coupling reactions of hydroxymethylphosphine deriva-
tives, which can be applied in a true sequential synthesis
of tertiary phosphine derivatives. The application of this
methodology to access synthetically valuable triarylpho-
sphine derivatives in a combinatorial fashion including
stereoselectively, using other aryl halides and pseudoha-
lides which are not reactive under the conditions described
here, is currently under investigation.
a Substrates in each step were shown. Conditions applied in each step
were noted in parentheses: (A) Basic condition same as Table 2; (B)
Alkoxide condition same as Table 3; (C) Fluoride condition same as
Table 3. Reactions were conducted using 13 (0.5 mmol), ArI (1.05 equiv),
solvent (5 mL), Pd2(dba)3 (1 mol %), dppf (2 mol %). Intermediates in
each step were isolated and used in the next step. b Suffixes of the
compound number represent the substituents including in the corre-
sponding ArI; see Table 2. c Isolated yield for three steps.
Acknowledgment. This work was partly supported by a
Grant-in-Aid for Scientific Research (C) (23550055).
and the fluoride-mediated conditions gave the correspond-
ing triarylphosphine sulfide 14abe in fairly good overall
yield in quite a selective manner (Scheme 3). Based on the
Supporting Information Available. Reaction proce-
dures and spectra. This material is available free of charge
via the Internet at http://pubs.acs.org.
(16) The products, triarylphosphine sulfides, are known as fine
equivalents of the parent trivalent phosphines; they can be easily
transformed back to the parent trivalent phosphines, can be handled
without care under the air, and can be easily purified due to their low
polarity and high tendency to crystallize. See ref 12.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
631