ORGANIC

LETTERS

Pd(II)-Catalyzed ortho-Arylation of XXXX

Vol. XX, No. XX
Aryl Phosphates and Aryl Hydrogen 000–000

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
[email protected]

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 C H activation reactions have attracted Nitrogen-containing directing groups such as amides,2
a great deal of attention and demonstrated their synthetic imines,3 and N-heterocycles4 are most commonly used.
usefulness for ortho C H functionalizations by not only In recent years, C H activation using carboxyl and hy-
C C bond but also C heteroatom bond formation.1 droxyl directing groups has been extensively studied.5,6

(1) For selected recent reviews on Pd-catalyzed C H activations, see: (4) Selected examples of pyridine derivatives: (a) Li, Y.; Li, B.-J.;
(a) Engle, K. M.; Mei, T.-S.; Wasa, M.; Yu, J.-Q. Acc. Chem. Res. 2012, Wang, W.-H.; Huang, W.-P.; Zhang, X.-S.; Chen, K.; Shi, Z.-J. Angew.
45, 782. (b) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. Chem., Int. Ed. 2011, 50, 2115. (b) Chernyak, N.; Dudnik, A. S.; Huang,
(c) Wencel-Delord, J.; Dr€ oge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. C.; Gevorgyan, V. J. Am. Chem. Soc. 2010, 132, 8270. (c) Hull, K. L.;
2011, 40, 4740. (d) Cho, S. H.; Kim, J. Y.; Kwak, J.; Chang, S. Chem. Lanni, E. L.; Sanford, M. S. J. Am. Chem. Soc. 2006, 128, 14047. (d)
Soc. Rev. 2011, 40, 5068. (e) Lyons, T. W.; Sanford, M. S. Chem. Rev. Kalyani, D.; Dick, A. R.; Anani, W. Q.; Sanford, M. S. Org. Lett. 2006,
2010, 110, 1147. (f) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem. Commun. 2010, 8, 2523. (e) Itami, K.; Mitsudo, K.; Kamei, T.; Koike, T.; Noka,o, T.;
46, 677. (g) Satoh, T.; Miura, M. Chem.;Eur. J. 2010, 16, 11212. Yoshida, J.-i. J. Am. Chem. Soc. 2000, 122, 12013. Oxazoline deriva-
(h) Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. tives: (f) Li, B.; Devaraj, K.; Darcel, C.; Dixneuf, P. H. Green Chem.
2009, 48, 9792. (i) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. 2012, 14, 2706. (g) Chen, X.; Li, J.-J.; Hao, X.-S.; Goodhue, C. E.; Yu,
Angew. Chem., Int. Ed. 2009, 48, 5094. J.-Q. J. Am. Chem. Soc. 2006, 128, 78. (h) Giri, R.; Wasa, M.; Breazzano,
(2) For selected examples of carboxylic amides, see: (a) Rakshit, S.; S. P.; Yu, J.-Q. Org. Lett. 2006, 8, 5685. (i) Giri, R.; Chen, X.; Yu, J.-Q.
Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem. Soc. 2011, 133, Angew. Chem., Int. Ed. 2005, 44, 2112.
2350. (b) Guimond, N.; Gouliaras, C.; Fagnou, K. J. Am. Chem. Soc. (5) For selected examples of carboxyl groups, see: (a) Ackermann, L.;
2010, 132, 6908. (c) Shi, Z.; Cui, Y.; Jiao, N. Org. Lett. 2010, 12, 2908. Pospech, J. Org. Lett. 2011, 13, 4153. (b) Wang, D.-H.; Engle, K. M.;
(d) Nishikata, T.; Lipshutz, B. H. Org. Lett. 2010, 12, 1972. (e) Kim, Shi, B.-F.; Yu, J.-Q. Science 2010, 327, 315. (c) Engle, K. M.; Wang, D.-H.;
B. K.; Jang, C.; Lee, D. J.; Youn, S. W. Chem.;Asian. J. 2010, 5, 2336. Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49, 6169. (d) Engle, K. M.; Wang,
(f) Tobisu, M.; Ano, Y.; Chatani, N. Org. Lett. 2009, 11, 3250. (g) Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 14137. (e) Shi, B.-F.; Zhang,
D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 7190. Y.-H.; Lam, J. K.; Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132,
(h) Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130, 14058. 460. (f) Xiao, B.; Xu, J.; Gong, T.-J.; Dai, J.-J.; Yi, J.; Liu, L. J. Am. Chem.
(i) Li, B.-J.; Tian, S.-L.; Fang, Z.; Shi, Z.-J. Angew. Chem., Int. Ed. 2008, Soc. 2010, 132, 468. (g) Tetsuya, S.; Masahiro, M. Synthesis 2010, 3395.
47, 1115. (j) Shi, Z.; Li, B.; Wan, X.; Cheng, J.; Fang, Z.; Cao, B.; Qin, C.; (h) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
Wang, Y. Angew. Chem., Int. Ed. 2007, 46, 5554. (k) Tsang, W. C. P.; 6097. (i) Wang, D.-H.; Mei, T.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2008, 130,
Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560. 17676. (j) Mei, T.-S.; Giri, R.; Maugel, N.; Yu, J.-Q. Angew. Chem., Int.
(l) Zaitsev, V.; Dauglulis, O. J. Am. Chem. Soc. 2005, 127, 4156. Ed. 2008, 47, 5215. (k) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9,
Sulfonoamides: (m) Dai, H.-X.; Stepan, A. F.; Plummer, M. S.; Zhang, 1407. (l) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;
Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222. (n) Garcı́a-Rubia, Kamer, P. C. J.; de Vries, J. G.; van Leewen, P. W. N. M. J. Am. Chem.
A.; Array as, R. G.; Carretero, J. C. Angew. Chem., Int. Ed. 2009, 48, Soc. 2002, 124, 1586. (m) Miura, M.; Tsuda, T.; Satoh, T.; Pivsa-Art, S.;
6511. Nomura, M. J. Org. Chem. 1998, 63, 5211.
(3) For selected examples of oximes, see: (a) Neufeldt, S. R.; Sanford, (6) For selected examples of hydroxyl groups, see: (a) Lu, Y.; Leow,
M. S. Org. Lett. 2010, 12, 532. (b) Sun, C.-L.; Liu, N.; Li, B.-J.; Yu, D.-G.; D.; Wang, X.; Engle, K. M.; Yu, J.-Q. Chem. Sci. 2011, 2, 967. (b) Wang,
Wang, Y.; Shi, Z.-J. Org. Lett. 2010, 12, 184. (c) Thirunavukkarasu, V. S.; X.; Lu, Y.; Dai, H.-X.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 12203.
Parthasarathy, K.; Cheng, C.-H. Angew. Chem., Int. Ed. 2008, 47, 9462. (c) Lu, Y.; Wang, D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010,
(d) Desai, L. V.; Malik, H. A.; Sanford, M. S. Org. Lett. 2006, 8, 1141. 132, 5916.

10.1021/ol400732q r XXXX American Chemical Society

Scheme 1. Arylation of Organophosphates Table 1. Optimizing Reaction Conditions with 1a and 1ba
temp conv
entry substrate base (°C) solvent (%)b

1 1a 90 DCE 72 (52)c
2 1a Li2CO3 90 DCE 0
3 1a Cs2CO3 90 DCE 0
4 1a K3PO4 90 DCE 0
5 1a Na2CO3 90 DCE 88 (55)c
6 1a Na2CO3 90 DCE 0d
7 1a Na2CO3 90 dioxane 16
8 1a Na2CO3 90 PhCF3 0
Nonetheless, there is still a need to search for new efficient 9 1a Na2CO3 90 DMF 0
functional groups to direct ortho-selective C H cleavage, 10 1a Na2CO3 90 xylene 0
11 1b 110 DCE 59 (57)c
which will make a considerable impact in synthetic ap-
12 1b Na2CO3 110 DCE 61 (60)c
plications. As such, our group has recently focused on 13 1b Na2CO3 110 dioxane 14
utilizing organophosphates as the directing group in C H 14 1b Na2CO3 110 toluene 16
activation reactions.7 15 1b Na2CO3 110 t
BuOH 0
Organophosphates are the main building block in DNA a
Conditions: 0.15 mmol of 1, 2 equiv of Ph2IOTf, 10 mol % of
and RNA. They are also important constituents in many Pd(TFA)2, 1.5 equiv of base in 1 mL of solvent for 15 h. b Conversion
cofactors that are essential for life and biological activities, of starting material 1, based on crude NMR. c Isolated yield. d 20 mol %
as well as the basis of many agrochemicals such as insecti- of DMSO was added.
cides and herbicides. Moreover, they are very useful func-
tional groups in organic synthesis,8 given their numerous pathway. Herein, we report the development of the orga-
synthetic applications, especially in the area of cross- nophosphates as the ortho-directing group for C H acti-
coupling.9 Additionally, we have also been interested in vated arylation via Pd(II)/Pd(IV) catalysis (Scheme 1).
the possibility of Pd insertion to the C;H bond via the We began our studies with diethyl o-tolyl phosphate (1a)
chelation of a PdO bond with Pd(II) through weak as the substrate, which can be easily synthesized from
coordination. By utilizing this property, we hope to synthe- commercially available o-cresol and diethyl chlorophos-
size biaryl compounds, well-known to be major moieties in phate. As shown, when 1a was reacted with Ph2IOTf
natural products. (2 equiv) using Pd(TFA)2 (10 mol %) in 1,2-dichloroethane
The common pathway for such C C bond formations at 90 °C for 15 h, 72% of the starting material was reacted
to produce biaryl compounds generally included the to give the phenylated product 2a along with unidentified
Pd(II)/Pd(0) catalytic cycle, and thus often required the side products (Table 1, entry 1). As such, a low isolated
presence of an oxidant to regenerate the catalyst.1i Recent yield of only 52% was obtained. In the presence of various
studies using Ar2IOTf or Ar2IBF4 suggested the use of bases such as Li2CO3, Cs2CO3, or K3PO4, the reaction did
iodonium salts as a great alternative for such reactions.5f,10 not occur (entries 2 4). The introduction of Na2CO3
In this case, the iodonium salt can serve as the arylating (entry 5) not only increased the conversion to 88% but
agent as well as the oxidant, whereby the reaction inter- also greatly reduced the side reactions as studied in the
mediate will then go through a Pd(II)/Pd(IV) catalytic crude NMR analysis. However, the isolated yield of 2a
gave only an unsatisfactory 55% yield. The addition of
(7) (a) Chan, L. Y.; Kim, S.; Ryu, T.; Lee, P. H. Chem. Commun. 2013 20 mol % DMSO to stabilize the Pd catalyst also did not
DOI: 10.1039/C3CC41107A. (b) Meng, X.; Kim, S. Org. Lett. 2013 DOI:
10.1021/ol400565r. help (entry 6).11 Changing the solvent to 1,4-dioxane,
(8) For reviews on phosphorous organic catalysts, see: (a) Honjo, T.; trifluorotoluene, DMF, or xylene only worsened the reac-
Phipps, R. J.; Rauniyar, V.; Toste, F. D. Angew. Chem., Int. Ed. 2012, 51, tion (entries 7 10). We then proposed a more bulky
9684. (b) Terada, M. Synthesis 2010, 12, 1929. (c) Terada, M. Chem.
Commun. 2008, 4097. phosphate 1b, hoping that the substrate will be thermally
(9) For phosphates as a coupling partner in CCR reactions, see: more stable toward the reaction than the diethyl phosphate
(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.;
derivatives. Indeed, 1b proved to be more stable with almost
Verboom, W. Org. Biomol. Chem. 2012, 10, 5443. (c) Ackermann, L.; quantitative isolated yield for each reaction. Nonetheless,
Barf€ usser, S.; Pospech, J. Org. Lett. 2010, 12, 724. (d) Gauthier, D.; the reaction of 1b was relatively slow with low conversion of
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. the starting material even at 110 °C (entries 11 15). Further
(f) Guo, J.; Harling, J. D.; Steel, P. G.; Woods, T. M. Org. Biomol. Chem. attempts to change Pd(TFA)2 to Pd(OTf)2, PdCl2, and
2008, 6, 4053. (g) Ebran, J.-P.; Hansen, A. L.; Gøgsig, T. M.; Skrydstrup,
T. J. Am. Chem. Soc. 2007, 129, 6931. other Pd catalysts were also unsuccessful.
(10) (a) Daugulis, O.; Do, H.-Q.; Shabashov, D. Acc. Chem. Res. As further exemplified in Table 2, a few examples
2009, 42, 1074. (b) Kalyani, D.; Deprez, N. R.; Desai, L. V.; Stanford, of ortho- or meta-alkyl substituted phosphates were
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, (11) Brasche, G.; Garcı̈a-Fortanet, J.; Buchwald, S. L. Org. Lett.
A. R.; Hull, K. L.; Sanford, M. S. J. Am. Chem. Soc. 2004, 126, 2300. 2008, 10, 2207.

B Org. Lett., Vol. XX, No. XX, XXXX

Table 2. Initial Studies of ortho-Arylation Using Table 4. Substrate Scope for ortho-Selective Arylation via a
Organophosphates 3a 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
entry base (°C) solvent (%)b

1 Na2CO3 rt DCE messy

2 rt DCE 27c
3 rt DCE 54 Scheme 2. Arylation of Monophosphoric Acid 5c with Various
4 80 DCE 95 (85)d Aryl Iodonium Salts
5 80 DME 50
6 80 dioxane messy
7 110 DCE 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 (3a 3f), 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 (entry 1), and a more reactive Pd(TFA)2 proved to be a
starting material in nearly all cases. Nevertheless, these better catalyst as compared to Pd(OAc)2 (entries 2, 3). 1c
results strongly suggest the presence of the chelation of the was shown to work best at 80 °C in 1,2-dichloroethane
PdO bond with a Pd(II)-catalyst which promotes ortho- (entries 4 6) with high conversion (95%) and good isolated
arylation. yield (85%). However, decomposition was observed when
We next turned our attention to monophosphoric acid the reaction was carried out at 110 °C (entry 7).
as the directing group for C H activated alkenylation Table 4 summarized the substrate scope for ortho-
and started our studies using methyl o-tolyl hydrogen arylation under the standard optimized conditions. For
phosphate (1c) as a model compound. To our delight, facile purification, the crude arylated monophosphoric
the reactivity was increased significantly, as the reaction acids were first methylated using TMS-diazomethane
can proceed even at ambient temperature (entries 2, 3) as to afford the respective methyl phosphate esters 6a 6l.
shown in Table 3. The presence of Na2CO3 was unnecessary As seen, substrates 6a 6f, bearing alkyl at the ortho- or
Org. Lett., Vol. XX, No. XX, XXXX C
meta-position, significantly facilitate arylation. For meta- The regioselectivity is noteworthy especially for aryl iodo-
substituted substrates, arylation occurred at the less nium salts that contained a para- or meta-substituent.
hindered position as predicted. When the reaction was In conclusion, we have developed simple yet efficient
performed with alkoxyl substituents, substrates 6g and 6h reaction conditions for introducing different function-
were too reactive and gave low isolated yields. Although alized aryl groups at the ortho-position via the use of
substrates 6e, 6j, and 6k with electron-withdrawing hal- monophosphoric acid as the directing group.
ogens are tolerant toward the standard conditions, the
reaction rate is relatively slower. The selectivity for unsub- Acknowledgment. We gratefully acknowledge the start-
stituted 6l was not well-controlled as well. 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- Supporting Information Available. Experimental pro-
tives just by varying the iodonium salts. As shown in cedures and full spectroscopic data for all new com-
Scheme 2, 5c reacted cleanly with a list of [Mes I pounds. This material is available free of charge via the
Ar]OTf iodonium salts to furnish the desired products Internet at http://pubs.acs.org.
7a 7f in high yields.5f,10 Various functional groups
such as ester, fluoride, and amide are also compatible. The authors declare no competing financial interest.

D Org. Lett., Vol. XX, No. XX, XXXX