Arenediazonium tetrafluoroborates in palladium-catalyzed C-P bond-forming reactions. Synthesis of arylphosphonates, -phosphine oxides, and -phosphines

Article abstract of DOI:10.1039/c0ob00243g

A novel palladium-catalyzed synthesis of arylphosphonates from arenediazonium tetrafluoroborates and triethylphosphite or diethylphosphite is presented. The reaction tolerates useful substituents including bromo, chloro, nitro, ether, cyano, keto, and ester groups, can be performed as a one-pot process from anilines omitting the isolation of arenediazonium salts, and can be extended to the preparation of arylphosphine oxides and arylphosphines.

Full text of DOI:10.1039/c0ob00243g

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Arenediazonium tetrafluoroborates in palladium-catalyzed C–P bond-forming
reactions. Synthesis of arylphosphonates, -phosphine oxides, and -phosphines†
Roberta Berrino,a Sandro Cacchi,*a Giancarlo Fabrizi,a Antonella Goggiamania and Paolo Stabileb
Received 10th June 2010, Accepted 28th July 2010
DOI: 10.1039/c0ob00243g
Table 1 Optimization studiesa
A novel palladium-catalyzed synthesis of arylphosphonates
from arenediazonium tetrafluoroborates and triethylphos-
phite or diethylphosphite is presented. The reaction tolerates
useful substituents including bromo, chloro, nitro, ether,
cyano, keto, and ester groups, can be performed as a one-
pot process from anilines omitting the isolation of arenedi-
azonium salts, and can be extended to the preparation of
Entry
[Pd]
Additive
Base
Time/h
Yield% of 2ab
arylphosphine oxides and arylphosphines.
1
2
3
4
5
6
7
8
—
—
—
—
—
—
—
—
Et3N
Cs2CO3
Et3N
Et3N
Et3N
Et3N
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Et3N
K2CO3
Cs2CO3
Cs2CO3
Cs2CO3
Cs2CO3
15
15
16
24
24
24
24
15
18
18
24
30
24
18
20
24
24
8
26c
12d
18e
19f
Arylphosphonates and their derivatives have found a wide range
of applications in medicinal1 and polymer2 chemistry. They have
also been used as ligands3 and synthetic intermediates.4 Classical
syntheses5 usually involve their preparation from aryl halides
and trialkylphosphites via photoinduced reactions5a–c or under
thermal AIBN/n-Bu3SnH conditions.5d After the first palladium-
catalyzed reaction of aryl halides with hydrogen phosphonates
reported by Hirao et al.,6 a large number of transition metal-
catalyzed procedures for the conversion of aryl halides into
arylphosphonates have been developed based on palladium,7
copper,8 and nickel3c,9 catalysis. Aryl triflates have also been used.10
Surprisingly, despite their potential as aryl partners in this type
of chemistry, there are no examples of arenediazonium salts.
Therefore, as part of a program devoted to the development of
arenediazonium salt based palladium-catalyzed syntheses,11 we
decided to investigate the feasibility of a palladium-catalyzed
approach to aryl phosphonates from arenediazonium tetrafluo-
roborates.
We started our study by examining the reaction of 4-
methoxydiazobenzene tetrafluoroborate 1a with P(OEt)3 at 80 ◦C
in MeCN. An initial screen showed that 2a could be isolated in
low yield omitting palladium, with (Et3N or Cs2CO3) or without
bases12 (Table 1, entries 1–3). The addition of Pd(PPh3)4 did
not change the reaction course significantly. A complex reaction
mixture was obtained from which 2a was isolated in 18% yield
along with 3a and 4, isolated in 11 and 17% yield, respectively
(Table 1, entry 4). Most probably, compound 4 is formed via
an exchange reaction between the phenyl groups bound to
coordinated phosphine and that bound to the palladium center.13
The addition of NaI gave a similar result (Table 1, entry 5) and
the use of H(O)P(OEt)2 revealed unsuccessful as well, leading
to the isolation of significant amounts of 5a in the absence of
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(PPh3)4
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
NaI
—
NaI
—
NaI
KI
NaI
NaI
NaI
KI
KI
KI
KI
g,h
—
32g,i
52
9
83
82
40
68
10
11
12
13
14
15
16
17
65
84j
58k
81g
7l
a Unless otherwise stated, reactions were carried out on a 0.5 mmol scale
at 80 ◦C using 1 equiv. of 1a, 2 equiv. of P(OEt)3, 2 equiv. of base (when
added), 3 equiv. of NaI or KI (when added) 0.05 equiv. of [Pd] in 3 mL of
anhydrous MeCN. b Yields are given for isolated products. c 3a was isolated
in 17% yield. d 3a was isolated in 7% yield. e 3a and 4 were isolated in 11
and 17% yield, respectively. f 3a and 4 were isolated in 3 and 17% yield.
g Carried out with H(O)P(OEt)2. h 5a was isolated in 24% yield.14 i 4 was
isolated in 23% yield. j 1.5 equiv. of P(OEt)3. k 2 equiv. of KI and 1.5 equiv.
of P(OEt)3. l At 50 ◦C. 4-Iodoanisole was isolated in 58% yield.
NaI (Table 1, entries 6) and of 4 when NaI was added (Table 1,
entry 7).
Subsequently, we found that the reaction of 1a with P(OEt)3
in the presence of 5 mol% of Pd(OAc)2 and 2 equiv. of Cs2CO3
produced 2a after 18 h in 52% yield (Table 1, entry 8). No evidence
of homocoupling product15 was obtained. However, formation of
arylphosphonates under these conditions resulted to be strongly
dependent on the nature of the substituents. For example, the
reaction of an electron-poor arenediazonium salt such as 4-
acetyldiazobenzene tetrafluoroborate with triethylphosphite gave
the corresponding phosphonate derivative only in 6% yield after
24 h.
aDipartimento di Chimica e Tecnologie del Farmaco, Sapienza, Universita`
di Roma, P.le A. Moro 5, 00185 Rome, Italy. E-mail: sandro.cacchi@
uniroma1.it; Fax: +39-06-4991-2780; Tel: +39-06-4991-2795
bChemical Development Department, GlaxoSmithKline, Via Fleming 4, I-
37135 Verona, Italy
† Electronic supplementary information (ESI) available: A complete
description of experimental details and product characterization. See DOI:
10.1039/c0ob00243g
Searching for an appropriate set of conditions that would
provide higher yields as well as conversions of a wide variety
4518 | Org. Biomol. Chem., 2010, 8, 4518–4520
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Table 3 Synthesis of arylphosphine oxides 6 and arylphosphines 7a
Table 2 Synthesis of arylphosphonates from arenediazonium tetrafluo-
roborate and triethylphosphitea
Entry
Arenediazonium salt 1
Time/h
Yield% of 2b
1
2
3
4
5
6
7
8
4-MeOC6H4N2BF4
4-MeC6H4N2BF4
3,5-Me2C6H3N2BF4
3,4,5-(MeO)3C6H2N2BF4
2-Me,4-MeOC6H3N2BF4
PhN2BF4
4-MeCOC6H4N2BF4
4-EtO2CC6H4N2BF4
4-NO2C6H4N2BF4
4-CNC6H4N2BF4
3-CF3C6H4N2BF4
4-FC6H4N2BF4
18
4
6
84
84
65
75
55
81
80
89
95
88
82
81
88
80
98
54
2a
2b
2c
2d
2e
2f
2g
2h
2i
2j
2k
2l
2m
2n
2o
2p
4
Entry Arenediazonium salt 1
P-donor
Time/h Yield%b
26
22
4
5
10
8
6
8
6
1
2
3
4
5
6
7
8
9
4-MeOC6H4N2BF4
PhN2BF4
4-EtO2CC6H4N2BF4
4-ClC6H4N2BF4
2-Me,4-MeOC6H3N2BF4 HP(O)Ph2
2-ClC6H4N2BF4
3,4,5-MeO3C6H2N2BF4
3,5-Me2C6H3N2BF4
4-EtO2CC6H4N2BF4
HP(O)Ph2
HP(O)Ph2
HP(O)Ph2
HP(O)Ph2
4
6
6
24
24
26
28
24
2
90
90
60
50
—
12
82
75
70c
6a
6b
6c
6d
6e
6f
6g
6h
7a
9
10
11
12
13
14
15
16
HP(O)Ph2
HP(O)Ph2
HP(O)Ph2
HPCy2
4-ClC6H4N2BF4
2-ClC6H4N2BF4
4-BrC6H4N2BF4
2-BrC6H4N2BF4
24
2.5
26
a Reactions were carried out on a 0.5 mol scale using 1 equiv. of 1, 1.5 equiv.
of P-donor, 2 equiv. of Cs2CO3, 3 equiv. of KI, 0.05 equiv. of Pd(OAc)2
in 3 mL of anhydrous MeCN at 80 ◦C. b Yields are given for isolated
products. c (4-methoxyphenyl)dicyclohexylphosphine oxide was isolated
in 10% yield.
a Reactions were carried out on a 0.5 mol scale using 1 equiv. of 1, 1.5 equiv.
of triethylphosphite, 2 equiv. of Cs2CO3, 3 equiv. of KI, 0.05 equiv. of
Pd(OAc)2 in 3 mL of anhydrous MeCN at 80 ◦C. b Yields are given for
isolated products.
of substrates, we found that adding 3 equiv. of KI and us-
ing 1.5 equiv. of P(OEt)3 led to the isolation of 2g in 80%
yield after 4 h. These conditions proved satisfactory with 4-
methoxydiazobenzene tetrafluoroborate as well. The phosphonate
2a was isolated in 84% yield (Table 1, entry 14). H(O)P(OEt)2
can also be employed. The reaction of 4-methoxydiazobenzene
tetrafluoroborate with H(O)P(OEt)2 gave 2a in 81% yield (Table 1,
entry 16). The use of Pd2(dba)3 (Table 1, entry 11) or Et3N or
K2CO3 (Table 1, entries 12 and 13), decreasing the excess of the
additive (Table 1, entry 15) or the reaction temperature (Table 1,
entry 17) provided lower yields.
Scheme 1 One-pot synthesis of arylphosphonates from anilines.
Using the optimized conditions and triethylphosphite as the P-
donor, we next explored the scope and generality of the process.
As shown in Table 2, a variety of electron-rich and electron-poor
arenediazonium tetrafluoroborates give the desired products in
good to excellent yields. Ortho substituents are also tolerated
(Table 2, entries 5, 14, 16).
The synthesis of arylphosphine oxides and arylphosphines was
also briefly investigated. The results obtained are summarized in
Table 3. With ortho substituted arenediazonium salts, H(O)PPh2
displayed lower reactivity than P(OEt)3 (compare Table 2, entries
5 and 14 with Table 3, entries 5 and 6).
The entire diazonium salt synthesis/iododediazoniation/C–P
bond forming sequence can be performed as a one-pot process,
without the isolation of the arenediazonium salt intermediate16
(Scheme 1). The best result was obtained by adding the reagents
required for the iododediazoniation/C–P bond forming reaction
to the crude mixture resulting from the first step concentrated
under reduced pressure. Neglecting the evaporation of the volatile
material produced lower yields. For example, 4-anisidine gave the
corresponding phosphonate only in 16% yield.
In analogy to related palladium-catalyzed reactions of arene-
diazonium salts in the presence of iodide anions,11e we believe
that the reaction proceeds through the mechanism that starts
with a iododediazoniation step and that has been depicted for
the synthesis of arylphosphonates (Scheme 2, path a).
Scheme 2 Proposed mechanism for the palladium-catalyzed synthesis of
arylphosphonates from arenediazonium tetrafluoroborates and P(OEt)3.
Most probably, the alternative catalytic cycle involving the
capture of a s-arylpalladium cation by P(OEt)3 (Scheme 2, path
b) is operative when KI is not used (Table 1, entry 4). It appears
less likely in the presence of iodide anions. Control experiments
revealed that arenediazonium salts are quickly converted into the
corresponding aryl iodides in the presence of iodide salts. For
example, 4-methoxy- and 4-acetyldiazobenzene tetrafluoroborate
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are converted into the corresponding iodides in 58 and 89% yield
after 5 min at room temperature.
5 (a) R. Obrycki and C. E. Griffin, J. Org. Chem., 1968, 33, 632; (b)
J.-J. L. Fu and W. G. Bentrude, J. Am. Chem. Soc., 1973, 95, 7710;
(c) J. F. Bunnett and X. Creary, J. Org. Chem., 1974, 39, 3612; (d) X.-Y.
Jiao and W. G. Bentrude, J. Org. Chem., 2003, 68, 3303; (e) For a review
on the direct phosphonylation of azaheterocycles, see: S. Van der Jeught
and C. V. Stevens, Chem. Rev., 2009, 109, 2672.
6 (a) T. Hirao, T. Masunaga, Y. Ohshiro and T. Agawa, Synthesis, 1981,
56; (b) T. Hirao, T. Masunaga, N. Yamada, Y. Ohshiro and T. Agawa,
Bull. Chem. Soc. Jpn., 1982, 55, 909.
7 (a) P.-A. Jaffre`s, N. Bar and D. J. Villemin, J. Chem. Soc., Perkin
Trans. 1, 1998, 2083; (b) K. Haaf, Comb. Chem. High T. Scr., 2005,
8, 637; (c) Y. Belabassi, S. Alzghari and J. Montchamp, J. Organomet.
Chem., 2008, 693, 3171; (d) M. C. Kohler, J. G. Sokol and R. A.
Stockland Jr, Tetrahedron Lett., 2009, 50, 457; (e) For a review
on the palladium-catalyzed reactions of aryl halides with soft, non-
organometallic nucleophiles, see: D. Prim, J.-M. Campagne, D. Joseph
and B. Andrioletti, Tetrahedron, 2002, 58, 2041.
8 (a) T. Ogawa, N. Usuki and N. Ono, J. Chem. Soc., Perkin Trans. 1,
1998, 2953; (b) D. Gelman, L. Jiang and S. L. Buchwald, Org. Lett.,
2003, 5, 2315; (c) C. Huang, X. Tang, H. Fu, Y. Jiang and Y. Zhao,
J. Org. Chem., 2006, 71, 5020; (d) H. Rao, Y. Jin, H. Fu, Y. Jiang and
Y. Z h a o , Chem.–Eur. J., 2006, 12, 3636.
9 (a) J. Heinicke, N. Gupta, A. Surana, N. Peulecke, B. Witt, K.
Steinhauser, R. K. Bansal and P. J. Jones, Tetrahedron, 2001, 57, 9963;
(b) D. Villemin, A. Elbilali, F. Simeon, P.-A. Jaffre`s, G. Maheut, M.
Mosaddak and A. Hakiki, J. Chem. Res. (S), 2003, 2003, 436; (c) von
G. Ma¨rkl, K. Gschwendner, I. Ro¨tzer and P. Kreitmeier, Helv. Chim.
Acta, 2004, 87, 825; (d) Q. Yao and S. Levchik, Tetrahedron Lett., 2006,
47, 277; (e) E. Montoneri, G. Viscardi, S. Bottigliengo, R. Gobetto,
M. R. Chierotti, R. Buscaino and P. Quagliotto, Chem. Mater.,
2007, 19, 2671; (f) M. V. Reddington, Bioconjugate Chem., 2007, 18,
2178.
In conclusion, we have developed a novel palladium-catalyzed
synthesis of arylphosphonates from arenediazonium tetrafluorob-
orates and triethylphosphite or diethylphosphite. The reaction
tolerates a variety of useful substituents including bromo, chloro,
nitro, ether, cyano, keto, and ester groups. Ortho substituents such
as methyl, bromo, and chloro are also tolerated. The presence of KI
pays a key role for the success of the reaction that proceeds through
a domino iododediazoniation/C–P bond forming process. Fur-
ther, the entire diazonium salt synthesis/iododediazoniation/C–P
bond forming sequence can be performed as a one-pot process
from anilines. The method has been extended to the preparation
of arylphosphine oxides and arylphosphines.
Acknowledgements
We gratefully acknowledge Dr Alcide Perboni of GlaxoSmithK-
line for valuable discussions. We are also indebted to MURST and
to the University “La Sapienza” for financial support.
Notes and references
1 (a) For selected references, see: Y. C. Kim, S. G. Brown, T. K. Harden,
J. L. Boyer, G. Dubyak, B. F. King, G. Burnstock and K. A. Jacobson,
J. Med. Chem., 2001, 44, 340; (b) M. Sawa, T. Kiyoi, K. Kurokawa,
H. Kumihara, M. Yamamoto, T. Miyasaka, Y. Ito, R. Hirayama, T.
Inoue, Y. Kirii, E. Nishiwaki, H. Ohmoto, Y. Maeda, E. Ishibushi, Y.
Inoue, K. Yoshino and H. Kondo, J. Med. Chem., 2002, 45, 919; (c) G.
Scapin, S. B. Patel, J. W. Becker, Q. Wang, C. Desponts, D. Waddleton,
K. Skorey, W. Cromlish, C. Bayly, M. Therien, J. Y. Gauthier, C. S. Li,
C. K. Lau, C. Ramachandran, B. P. Kennedy and E. Asante-Appiah,
Biochemistry, 2003, 42, 11451; (d) D. Ma and W. Zhu, J. Org. Chem.,
2001, 66, 348; (e) R. Nagarajan and R. F. Pratt, Biochemistry, 2004,
43, 9664; (f) N. P. Dolman, J. C. A. More, A. Alt, J. L. Knauss, H. M.
Troop, D. Bleakman, G. L. Collingridge and D. E. Jane, J. Med. Chem.,
2006, 49, 2579; (g) A. Nordqvist, M. T. Nilsson, S. Ro¨ttger, L. R. Odell,
W. W. Krajewski, C. E. Andersson, M. Larhed, S. L. Mowbray and A.
Anders Karle´n, Bioorg. Med. Chem., 2008, 16, 5501.
2 (a) H. Onouchi, K. Maeda and E. Yashima, J. Am. Chem. Soc., 2001,
123, 7441; (b) H. R. Allcock, M. A. Hofmann, C. M. Ambler and
R. V. Morford, Macromolecules, 2002, 35, 3484; (c) H. Onouchi, T.
Miyagawa, A. Furuko, K. Maeda and E. Yashima, J. Am. Chem. Soc.,
2005, 127, 2960.
3 (a) For some reviews, see: M. McCarthy and P. J. Guiry, Tetrahedron,
2001, 57, 3809; (b) D. Prim, J. Campagne, D. Joseph and B. Andrioletti,
Tetrahedron, 2002, 58, 2041; (c) See also: J. Fischer, M. Schu¨rmann, M.
Mehring, U. Zachwieja and K. Jurkschat, Organometallics, 2006, 25,
2886.
10 K. S. Petrakis and T. L. Nagabhushan, J. Am. Chem. Soc., 1987, 109,
2831.
11 (a) S. Cacchi, F. Fabrizi, A. Goggiamani and D. Persiani, Org. Lett.,
2008, 10, 1597; (b) G. Bartoli, S. Cacchi, F. Fabrizi and A. Goggiamani,
Synlett, 2008, 2508; (c) S. Cacchi, G. Fabrizi, A. Goggiamani and A.
Sferrazza, Synlett, 2009, 973; (d) S. Cacchi, G. Fabrizi, A. Goggiamani
and A. Sferrazza, Synlett, 2009, 1277; (e) G. Fabrizi, A. Goggiamani,
A. Sferrazza and S. Cacchi, Angew. Chem. Int. Ed., 2010, 49, 4067.
12 S. Yasui, K. Shioji and A. Ohno, Heteroat. Chem., 1995, 6,
223.
13 (a) For selected references on aryl-aryl exchange between the palladium
center and phosphine ligands in Pd(II) complexes, see: K.-C. Kong and
C.-H. Cheng, J. Am. Chem. Soc., 1991, 113, 6313; (b) W. A. Hermann,
¨
C. Brobmer, K. Ofele, M. Beller and H. Fischer, J. Organomet. Chem.,
1995, 491, C1; (c) B. E. Segelstein, T. W. Butler and B. L. Chenard,
J. Org. Chem., 1995, 60, 12; (d) B. C. Hamann and J. F. Hartwig, J. Am.
Chem. Soc., 1998, 120, 3694; (e) S. Cacchi, G. Fabrizi, A. Goggiamani
and G. Zappia, Org. Lett., 2001, 3, 2539; (f) M. Phani Pavan, M.
Chakravarty and K. C. Kumara Swamy, Eur. J. Org. Chem., 2009,
5927.
14 For the synthesis of this class of compounds in the absence of palladium,
see: R. C. Moldovan, Rev. Chim. Bucharest, 2005, 56, 177.
15 M. K. Robinson, V. S. Kochurina and J. M. Hanna, Jr., Tetrahedron
Lett., 2007, 48, 7687.
4 A. Inoue, H. Shinokubo and K. Oshima, J. Am. Chem. Soc., 2003, 125,
1484.
16 M. P. Doyle and W. J. Bryker, J. Org. Chem., 1979, 44, 1572.
4520 | Org. Biomol. Chem., 2010, 8, 4518–4520
This journal is
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