Pd(II)-catalyzed ortho-arylation of aryl phosphates and aryl hydrogen phosphates with diaryliodonium triflates

Article abstract of DOI:10.1021/ol400732q

Functionalized biaryl compounds were successfully synthesized using phosphates as the ortho-directing group in the Pd(II)/Pd(IV) catalytic cycle.

Full text of DOI:10.1021/ol400732q

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Pd(II)-Catalyzed ortho-Arylation of
Aryl Phosphates and Aryl Hydrogen
Phosphates with Diaryliodonium Triflates
Li Yan Chan, Lilian Cheong, and Sunggak Kim*
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical
Sciences, Nanyang Technological University, Singapore 637371, Singapore
sgkim@ntu.edu.sg
Received March 19, 2013
ABSTRACT
Functionalized biaryl compounds were successfully synthesized using phosphates as the ortho-directing group in the Pd(II)/Pd(IV) catalytic cycle.
Pd-catalyzed CÀH activation reactions have attracted
a great deal of attention and demonstrated their synthetic
usefulness for ortho CÀH functionalizations by not only
CÀC bond but also CÀheteroatom bond formation.1
Nitrogen-containing directing groups such as amides,2
imines,3 and N-heterocycles4 are most commonly used.
In recent years, CÀH activation using carboxyl and hy-
droxyl directing groups has been extensively studied.5,6
(1) For selected recent reviews on Pd-catalyzed CÀH activations, see:
(a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012,
45, 782. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215.
(4) Selected examples of pyridine derivatives: (a) Li, Y.; Li, B.-J.;
Wang, W.-H.; Huang, W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J. Angew.
Chem., Int. Ed. 2011, 50, 2115. (b) Chernyak, N.; Dudnik, A. S.; Huang,
C.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132, 8270. (c) Hull, K. L.;
Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047. (d)
Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006,
8, 2523. (e) Itami, K.; Mitsudo, K.; Kamei, T.; Koike, T.; Noka,o, T.;
Yoshida, J.-i. J. Am. Chem. Soc. 2000, 122, 12013. Oxazoline deriva-
tives: (f) Li, B.; Devaraj, K.; Darcel, C.; Dixneuf, P. H. Green Chem.
2012, 14, 2706. (g) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu,
J.-Q. J. Am. Chem. Soc. 2006, 128, 78. (h) Giri, R.; Wasa, M.; Breazzano,
S. P.; Yu, J.-Q. Org. Lett. 2006, 8, 5685. (i) Giri, R.; Chen, X.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2005, 44, 2112.
(5) For selected examples of carboxyl groups, see: (a) Ackermann, L.;
Pospech, J. Org. Lett. 2011, 13, 4153. (b) Wang, D.-H.; Engle, K. M.;
Shi, B.-F.;Yu, J.-Q. Science2010, 327, 315. (c)Engle, K. M.;Wang, D.-H.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49, 6169. (d) Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 14137. (e) Shi, B.-F.;Zhang,
Y.-H.; Lam, J. K.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
460. (f) Xiao, B.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem.
Soc. 2010, 132, 468. (g) Tetsuya, S.; Masahiro, M. Synthesis 2010, 3395.
(h) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
6097. (i) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130,
17676. (j) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int.
Ed. 2008, 47, 5215. (k) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9,
1407. (l) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;
Kamer, P. C. J.; de Vries, J. G.; van Leewen, P. W. N. M. J. Am. Chem.
Soc. 2002, 124, 1586. (m) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.;
Nomura, M. J. Org. Chem. 1998, 63, 5211.
€
(c) Wencel-Delord, J.; Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev.
2011, 40, 4740. (d) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem.
Soc. Rev. 2011, 40, 5068. (e) Lyons, T. W.; Sanford, M. S. Chem. Rev.
2010, 110, 1147. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010,
46, 677. (g) Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212.
(h) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed.
2009, 48, 9792. (i) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q.
Angew. Chem., Int. Ed. 2009, 48, 5094.
(2) For selected examples of carboxylic amides, see: (a) Rakshit, S.;
Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133,
2350. (b) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc.
2010, 132, 6908. (c) Shi, Z.; Cui, Y.; Jiao, N. Org. Lett. 2010, 12, 2908.
(d) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010, 12, 1972. (e) Kim,
B. K.; Jang, C.; Lee, D. J.; Youn, S. W. Chem.;Asian. J. 2010, 5, 2336.
(f) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250. (g) Wang,
D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190.
(h) Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058.
(i) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008,
47, 1115. (j) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.;
Wang, Y. Angew. Chem., Int. Ed. 2007, 46, 5554. (k) Tsang, W. C. P.;
Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560.
(l) Zaitsev, V.; Dauglulis, O. J. Am. Chem. Soc. 2005, 127, 4156.
Sulfonoamides: (m) Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang,
Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222. (n) Garcıa-Rubia,
ꢀ
A.; Arrayas, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48,
6511.
(3) For selected examples of oximes, see: (a) Neufeldt, S. R.; Sanford,
M. S. Org. Lett. 2010, 12, 532. (b) Sun, C.-L.; Liu, N.; Li, B.-J.; Yu, D.-G.;
Wang, Y.; Shi, Z.-J. Org. Lett. 2010, 12, 184. (c) Thirunavukkarasu, V. S.;
Parthasarathy, K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2008, 47, 9462.
(d) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141.
(6) For selected examples of hydroxyl groups, see: (a) Lu, Y.; Leow,
D.; Wang, X.; Engle, K. M.; Yu, J.-Q. Chem. Sci. 2011, 2, 967. (b) Wang,
X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 12203.
(c) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
132, 5916.
r
10.1021/ol400732q
XXXX American Chemical Society

Table 1. Optimizing Reaction Conditions with 1a and 1ba
Scheme 1. Arylation of Organophosphates
temp
conv
(%)b
entry
substrate
base
(°C)
solvent
1
1a
1a
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
À
90
90
DCE
72 (52)c
2
Li2CO3
Cs2CO3
K3PO4
DCE
0
3
90
DCE
0
4
90
DCE
0
5
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
Na2CO3
À
90
DCE
88 (55)c
6
90
DCE
0d
7
90
dioxane
PhCF3
DMF
16
8
90
0
9
90
0
Nonetheless, there is still a need to search for new efficient
functional groups to direct ortho-selective CÀH cleavage,
which will make a considerable impact in synthetic ap-
plications. As such, our group has recently focused on
utilizing organophosphates as the directing group in CÀH
activation reactions.7
10
11
12
13
14
15
90
xylene
DCE
0
110
110
110
110
110
59 (57)c
Na2CO3
Na2CO3
Na2CO3
Na2CO3
DCE
61 (60)c
dioxane
toluene
tBuOH
14
16
0
Organophosphates are the main building block in DNA
and RNA. They are also important constituents in many
cofactors that are essential for life and biological activities,
as well as the basis of many agrochemicals such as insecti-
cides and herbicides. Moreover, they are very useful func-
tional groups in organic synthesis,8 given their numerous
synthetic applications, especially in the area of cross-
coupling.9 Additionally, we have also been interested in
the possibility of Pd insertion to the C;H bond via the
chelation of a PdO bond with Pd(II) through weak
coordination. Byutilizing thisproperty, we hope tosynthe-
size biaryl compounds, well-known to be major moieties in
natural products.
The common pathway for such CÀC bond formations
to produce biaryl compounds generally included the
Pd(II)/Pd(0) catalytic cycle, and thus often required the
presence of an oxidant to regenerate the catalyst.1i Recent
studies using Ar2IOTf or Ar2IBF4 suggested the use of
iodonium salts as a great alternative for such reactions.5f,10
In this case, the iodonium salt can serve as the arylating
agent as well as the oxidant, whereby the reaction inter-
mediate will then go through a Pd(II)/Pd(IV) catalytic
a Conditions: 0.15 mmol of 1, 2 equiv of Ph2IOTf, 10 mol % of
Pd(TFA)2, 1.5 equiv of base in 1 mL of solvent for 15 h. b Conversion
of starting material 1, based on crude NMR. c Isolated yield. d 20 mol %
of DMSO was added.
pathway. Herein, we report the development of the orga-
nophosphates as the ortho-directing group for CÀH acti-
vated arylation via Pd(II)/Pd(IV) catalysis (Scheme 1).
We began our studies with diethyl o-tolyl phosphate (1a)
as the substrate, which can be easily synthesized from
commercially available o-cresol and diethyl chlorophos-
phate. As shown, when 1a was reacted with Ph2IOTf
(2 equiv) using Pd(TFA)2 (10 mol %) in 1,2-dichloroethane
at 90 °C for 15 h, 72% of the starting material was reacted
to give the phenylated product 2a along with unidentified
side products (Table 1, entry 1). As such, a low isolated
yield of only 52% was obtained. In the presence of various
bases such as Li2CO3, Cs2CO3, or K3PO4, the reaction did
not occur (entries 2À4). The introduction of Na2CO3
(entry 5) not only increased the conversion to 88% but
also greatly reduced the side reactions as studied in the
crude NMR analysis. However, the isolated yield of 2a
gave only an unsatisfactory 55% yield. The addition of
20 mol % DMSO to stabilize the Pd catalyst also did not
help (entry 6).11 Changing the solvent to 1,4-dioxane,
trifluorotoluene, DMF, or xylene only worsened the reac-
tion (entries 7À10). We then proposed a more bulky
phosphate 1b, hoping that the substrate will be thermally
more stable toward the reaction than the diethyl phosphate
derivatives. Indeed, 1b proved to be more stable with almost
quantitative isolated yield for each reaction. Nonetheless,
the reaction of 1b was relatively slow with low conversion of
the starting material even at 110 °C (entries 11À15). Further
attempts to change Pd(TFA)2 to Pd(OTf)2, PdCl2, and
other Pd catalysts were also unsuccessful.
(7) (a) Chan, L. Y.; Kim, S.; Ryu, T.; Lee, P. H. Chem. Commun. 2013
DOI: 10.1039/C3CC41107A. (b) Meng, X.; Kim, S. Org. Lett. 2013 DOI:
10.1021/ol400565r.
(8) For reviews on phosphorous organic catalysts, see: (a) Honjo, T.;
Phipps, R. J.; Rauniyar, V.; Toste, F. D. Angew. Chem., Int. Ed. 2012, 51,
9684. (b) Terada, M. Synthesis 2010, 12, 1929. (c) Terada, M. Chem.
Commun. 2008, 4097.
(9) For phosphates as a coupling partner in CCR reactions, see:
(a) Trost, B. M.; Czabaniuk, L. C. J. Am. Chem. Soc. 2012, 134, 5778. (b)
Nikishkin, N. I.; Huskens, J.; Assenmacher, J.; Wilden, A.; Modolo, G.;
Verboom, W. Org. Biomol. Chem. 2012, 10, 5443. (c) Ackermann, L.;
€
Barfusser, S.; Pospech, J. Org. Lett. 2010, 12, 724. (d) Gauthier, D.;
Beckendrof, S.; Gøgsig, T. M.; Lindhardt, A. T.; Skrydstrup, T. J. Org.
Chem. 2009, 74, 3536. (e) Steel, P. G.; Wood, T. M. Synthesis 2009, 3897.
(f) Guo, J.; Harling, J. D.; Steel, P. G.; Woods, T. M. Org. Biomol. Chem.
2008, 6, 4053. (g) Ebran, J.-P.; Hansen, A. L.; Gøgsig, T. M.; Skrydstrup,
T. J. Am. Chem. Soc. 2007, 129, 6931.
As further exemplified in Table 2, a few examples
of ortho- or meta-alkyl substituted phosphates were
(10) (a) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res.
2009, 42, 1074. (b) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Stanford,
M. S. J. Am. Chem. Soc. 2005, 127, 7330. (c) Dick, A. R.; Kampf, J. W.;
Sanford, M. S. J. Am. Chem. Soc. 2005, 127, 12790. (d) Daugulis, O.;
Zaitsev, V. G. Angew. Chem., Int. Ed. 2005, 44, 4046. (e) Desai, L. V.;
Hull, K. L.; Stanford, M. S. J. Am. Chem. Soc. 2004, 126, 9542. (f) Dick,
A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300.
(11) Brasche, G.; Garcıa-Fortanet, J.; Buchwald, S. L. Org. Lett.
2008, 10, 2207.
B
Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Initial Studies of ortho-Arylation Using
Organophosphates 3a
Table 4. Substrate Scope for ortho-Selective Arylation via a
Monophosphoric Acid Directing Groupa,b
a Conditions: 0.15 mmol of 3, 2 equiv of Ph2IOTf, 10 mol % of
Pd(TFA)2, in 1 mL of 1,2-dichloroethane at 110 °C for 15 h. b Reaction
was carried out in 90 °C with 1.5 equiv of Na2CO3. c Recovery yield of
starting material 3.
Table 3. Optimizing Reaction Conditionsa
a Conditions: (i) 0.15 mmol of 5, 2 equiv of Ph2IOTf, 10 mol % of
Pd(TFA)2, in 1 mL of 1,2-dichloroethane at 80 °C for 15 h. (ii) 5 equiv of
TMSCHN2 in 0.5 mL of MeOH at rt for 30 min. b Isolated yield is based
on the yield over two steps. c Recovery yield of methylated starting
material 5. d Reaction was carried out at 110 °C. e 1.2 equiv of Ph2IOTf
was used instead. f Yield of diarylated product.
temp
conv
(%)b
entry
base
(°C)
solvent
1
2
3
4
5
6
7
Na2CO3
rt
DCE
messy
27c
À
À
À
À
À
À
rt
DCE
Scheme 2. Arylation of Monophosphoric Acid 5c with Various
Aryl Iodonium Salts
rt
DCE
54
80
80
80
110
DCE
95 (85)d
50
DME
dioxane
DCE
messy
messy
a Conditions: 0.15 mmol of 1, 2 equiv of Ph2IOTf, 10 mol % of
Pd(TFA)2, 1.5 equiv of base in 1 mL of solvent for 15 h. b Conversion of
starting material 1c, based on crude NMR. c 10 mol % of Pd(OAc)2 was
used instead. d Isolated yield after methylation with TMSCHN2.
demonstrated (3aÀ3f), which reacted to give moderate
yields of the phenylated products. The initial studies of
ortho-arylation were not as satisfactory, as the reaction
was slow with the recovery of a substantial amount of the
starting material in nearly all cases. Nevertheless, these
results strongly suggest the presence of the chelation of the
PdO bond with a Pd(II)-catalyst which promotes ortho-
arylation.
We next turned our attention to monophosphoric acid
as the directing group for CÀH activated alkenylation
and started our studies using methyl o-tolyl hydrogen
phosphate (1c) as a model compound. To our delight,
the reactivity was increased significantly, as the reaction
can proceed even at ambient temperature (entries 2, 3) as
shown in Table 3. The presence of Na2CO3 was unnecessary
(entry 1), and a more reactive Pd(TFA)2 proved to be a
better catalyst as compared to Pd(OAc)2 (entries 2, 3). 1c
was shown to work best at 80 °C in 1,2-dichloroethane
(entries 4À6) with high conversion (95%) and good isolated
yield (85%). However, decomposition was observed when
the reaction was carried out at 110 °C (entry 7).
Table 4 summarized the substrate scope for ortho-
arylation under the standard optimized conditions. For
facile purification, the crude arylated monophosphoric
acids were first methylated using TMS-diazomethane
to afford the respective methyl phosphate esters 6aÀ6l.
As seen, substrates 6aÀ6f, bearing alkyl at the ortho- or
Org. Lett., Vol. XX, No. XX, XXXX
C

meta-position, significantly facilitate arylation. For meta-
substituted substrates, arylation occurred at the less
hindered position as predicted. When the reaction was
performed with alkoxyl substituents, substrates 6g and 6h
were too reactive and gave low isolated yields. Although
substrates 6e, 6j, and 6k with electron-withdrawing hal-
ogens are tolerant toward the standard conditions, the
reaction rate is relatively slower. The selectivity for unsub-
stituted 6l was not well-controlled as well.
The regioselectivity is noteworthy especially for aryl iodo-
nium salts that contained a para- or meta-substituent.
In conclusion, we have developed simple yet efficient
reaction conditions for introducing different function-
alized aryl groups at the ortho-position via the use of
monophosphoric acid as the directing group.
Acknowledgment. We gratefully acknowledge the start-
up and FYP grants from Nanyang Technological University.
Even so, the reaction can be further expanded by
introducing a diverse range of functionalized aryl deriva-
tives just by varying the iodonium salts. As shown in
Scheme 2, 5c reacted cleanly with a list of [MesÀIÀ
Ar]OTf iodonium salts to furnish the desired products
7aÀ7f in high yields.5f,10 Various functional groups
such as ester, fluoride, and amide are also compatible.
Supporting Information Available. Experimental pro-
cedures and full spectroscopic data for all new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX