Palladium-catalyzed ortho-alkenylation of aryl hydrogen phosphates using a new mono-phosphoric acid directing group

Article abstract of DOI:10.1039/c3cc41107a

A highly efficient Pd-catalyzed ortho-alkenylation is reported using a mono-phosphoric acid-directing group for the first time. This phosphoric acid-directing group is successfully utilized for the synthesis of various alkenylated products and offers a new approach to transition-metal-catalyzed C-H activation. The Royal Society of Chemistry 2013.

Full text of DOI:10.1039/c3cc41107a

ChemComm
View Article Online
View Journal
COMMUNICATION
Palladium-catalyzed ortho-alkenylation of aryl
hydrogen phosphates using a new mono-phosphoric
Cite this: DOI: 10.1039/c3cc41107a
acid directing group†
Li Yan Chan,a Sunggak Kim,*a Taekyu Ryub and Phil Ho Lee*b
Received 9th February 2013,
Accepted 2nd April 2013
DOI: 10.1039/c3cc41107a
www.rsc.org/chemcomm
A highly efficient Pd-catalyzed ortho-alkenylation is reported using
a mono-phosphoric acid-directing group for the first time. This
phosphoric acid-directing group is successfully utilized for the
synthesis of various alkenylated products and offers
approach to transition-metal-catalyzed C–H activation.
a new
Scheme 2 Alkenylation of organophosphate derivatives.
Over the years, chemists have pursued approaches to activate and
functionalize the inert C–H bond.1 In the late 1960s, Fujiwara and
Moritani successfully connected alkenes and arenes together via
Pd(II) catalysis,2,3 which brought a breakthrough in C–H activa-
tion. In the recent methods, such C–H activation reactions have
been impressively enhanced by the use of directing groups or
ligands to control the selectivity. The most widely used directing
together with their synthetic and biological importance led us to
study the Pd-catalyzed ortho-alkenylation (Scheme 2).
To study the effectiveness of the phosphoric acid-based
directing groups in the C–H activation, we first began our studies
with dimethyl o-tolyl phosphate (1a) as seen in Table 1.15
groups in Pd(II)-catalyzed C–H activation reactions utilize Table 1 Optimization of reaction conditions using 1a
carboxylic derivatives4–6 along with N-heterocycles.7–9
Phosphoric acid and its derivatives are important consti-
tuents of living organisms and have also been widely exploited as
organic catalysts10 and coupling partners in Pd-catalyzed cross-
coupling reactions.11 Organophosphoric acid-based directing
groups have been used in ortho-metalation-induced migration
of the dialkylphosphoryl group as shown in Scheme 1.12,13
As far as we know, these have not been used in the transition-
metal-catalyzed C–H activation reactions.14 In addition, in terms
of the structural versatility, organophosphoric acid derivatives
would have another advantage over carboxylic acid derivatives.
Our interest in phosphoric acid derivatives as directing groups
Entry
Substrate
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1c
1c
1c
1c
1c
1c
1c
1c
1c
1c
Na2S2O8
CuO
Ag2CO3
AgOAc
AgOAc
BQ
Cu(OAc)2
Ag2O
Ag2CO3
AgOAc
Na2S2O8
BQ
DCE
DCE
DCE
DCE
Dioxane
DCE
DCE
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
Dioxane
tBuOH
DCE
0
0
0
0
0
0
o5
0
9
o5
10
11
12
13
14
15
16
17
18
19
20
0
0
0
0
61
44
54
CuO
Cu(OAc)2
Ag2CO3
Ag2O
AgOAc
AgOAc
AgOAc
AgOAc
Scheme 1 ortho-Metalation of organophosphates.
100 (80)c
26
46 (30)d
0
a Division of Chemistry and Biological Chemistry, School of Physical and
Mathematical Sciences, Nanyang Technological University, 637371, Singapore.
E-mail: sgkim@ntu.edu.sg
Toluene
a
0.15 mmol of 1, 2 equiv. of ethyl acrylate, 10 mol% of Pd(OAc)2,
b Department of Chemistry, Kangwon National University, Chuncheon 200-701,
b
3 equiv. of oxidant in 1 mL of solvent at 110 1C for 15 h. NMR yield.
c
d
Republic of Korea. E-mail: phlee@kangwon.ac.kr
Isolated yield after methylation with TMSCHN2. 2-Chloroethyl
methyl o-tolyl phosphate.
† Electronic supplementary information (ESI) available. See DOI: 10.1039/c3cc41107a
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.

View Article Online
Communication
ChemComm
Table 2 Substrate scope for ortho-selective alkenylationa
Reaction of 1a with ethyl acrylate (2 equiv.) using Pd(OAc)2
(10 mol%) and Na2S2O8 oxidant (3 equiv.) in 1,2-dichloroethane
at 110 1C for 15 h did not occur and the starting 1a was
recovered (entry 1). Varying the oxidizing agent or changing
the solvent did not affect the reaction (entries 2–5). To
strengthen the directing ability of the phosphoryl group
towards the palladium intermediate, methyl o-tolyl phenyl-
phosphoramidate (1b) was chosen, but our attempts at ortho-
alkenylation via C–H activation under various conditions were
totally unsuccessful (entries 6–10). Inspired by recent reports
on the hydroxyl-directed C–H activations using carboxyl,4
hydroxyl,16 and removable silanol groups,17 together with a
weak coordination concept,1a our attention was next paid to
methyl o-tolyl hydrogen phosphate (1c). When 1c was treated
with ethyl acrylate (2 equiv.) and Cu(OAc)2 (3 equiv.) in the
presence of 10 mol% Pd(OAc)2 in 1,4-dioxane at 110 1C for 15 h,
61% of the desired alkenylated product 2c was observed (entry 14),
suggesting that the mono-phosphoric acid functionality is crucial
in aiding weak coordination of the Pd catalyst with the substrate.
To search for the optimum conditions, various oxidants were
then screened. The reaction was relatively sensitive to the
choice of oxidants used, and Na2S2O8, BQ, and CuO were totally
ineffective (entries 11–13). The oxidants, Ag2CO3 and Ag2O, gave
moderate conversion of the starting mono-phosphoric acid 1c
(entries 15 and 16). To our delight, AgOAc turned out to be the
most effective oxidant and resulted in the complete consumption
of 1c to yield the alkenylated product cleanly (entry 17). Among
the solvents tested, 1,4-dioxane gave the best result (entries 18–20).
Furthermore, the addition of a base (Li2CO3 and Na2CO3) and an
amino acid ligand such as Boc-Val-OH (20 mol%) did not influence
the reaction.4a,16b Therefore, the remaining reactions were carried
out with ethyl acrylate (2 equiv.) and AgOAc (3 equiv.) using
Pd(OAc)2 (10 mol%) in 1,4-dioxane at 110 1C for 15 h.18
a
Conditions: (i) 0.15 mmol of 3, 2 equiv. of ethyl acrylate, 10 mol% of
Pd(OAc)2, 3 equiv. of AgOAc in 1 mL of 1,4-dioxane at 110 1C for 15 h.
(ii) 5 equiv. of TMSCHN2 in 0.5 mL of MeOH at r.t. for 30 min. Isolated
b
yield is based on the yield over 2 steps. Recovery yield of methylated
c
starting material 3. 1.2 equiv. of ethyl acrylate was used instead.
d
As summarized in Table 2, various substrates were applied to
the standard conditions to determine the scope and limitations
of the present method. For the facile purification, the crude
alkenyl mono-phosphoric acids were methylated using TMS-
diazomethane to afford the corresponding methyl esters 4a–o.
Substrates 3a–i containing electron-donating alkyl or alkoxy
groups at the ortho- or meta-positions promoted alkenylation
considerably (4a–i). Naphthyl derivatives 3j–k worked well too.
However, biaryl derivative 3l was less reactive and the alkenylated
product 4l was isolated in 66% yield along with the starting
material (17%). As expected, meta-substituted substrates under-
went alkenylations regio-selectively at the sterically less hindered
position. When unsubstituted 3m was subjected to the standard
conditions in the presence of 1.2 equiv. of ethyl acrylate, the
desired alkenylated product was isolated in 55% yield together
with the dialkenylated product (16%) and the starting material
(14%). Although fluoride-substituent 3n is completely compatible
under these mild reaction conditions, the reaction was signifi-
cantly slowed down and gave the alkenylated product 4n in less
than 50% yield. Interestingly, even when an electron-withdrawing
ester group was located at the ortho-position, the reaction
proceeded smoothly but hydrolysis of the product occurred,
yielding the respective phenol 4o almost quantitatively. Appar-
ently, dephosphorylation occurred upon acidic workup.19
Yield of dialkenylated product.
The usefulness of this methodology is not limited to only
ethyl acrylate. As demonstrated in Scheme 3, the scope of the
Scheme 3 Alkenylation of mono-phosphoric acid 3c with various alkenes.
c
Chem. Commun.
This journal is The Royal Society of Chemistry 2013

View Article Online
ChemComm
Communication
´
M. R. Gagne, G. C. Lloyd-Jones and K. I. Booker-Milburn, Angew.
Chem., Int. Ed., 2009, 48, 1830.
alkenylation is broad and various electron-deficient alkenes
and styrene derivatives could be successfully employed in the
ortho-alkenylation. Vinyl sulfone and vinyl phosphate reacted
with mono-phosphoric acid 3c to furnish the corresponding
alkenyl phosphates 5b and 5c in 77% and 78% yields, respec-
tively. Similarly, phenyl vinyl ketone (5h) also worked well.
Styrene and its derivatives (5d–g) were also efficient acceptors
toward the palladium intermediate. However, the present
method did not work well with allylbenzene and ethyl vinyl
ether.
In conclusion, we have demonstrated the effectiveness of the
mono-phosphoric acid-directing group in the Pd(II)-catalyzed
ortho-alkenylation of aryl hydrogen phosphates for the first
time. The reaction provides various alkenylated products in
high yields and its scope is broad. Further studies on applica-
tions of various phosphoryl derivatives as new directing groups
in C–H activations are underway.
7 For pyridine derivatives, see: (a) Y. Li, B.-J. Li, W.-H. Wang,
W.-P. Huang, X.-S. Zhang, K. Chen and Z.-J. Shi, Angew. Chem., Int.
Ed., 2011, 50, 2115; (b) N. Chernyak, A. S. Dudnik, C. Huang and
V. Gevorgyan, J. Am. Chem. Soc., 2010, 132, 8270; (c) K. L. Hull,
E. L. Lanni and M. S. Sanford, J. Am. Chem. Soc., 2006, 128, 14047.
8 For oxazoline derivatives, see: (a) B. Li, K. Devaraj, C. Darcel and
P. H. Dixneuf, Green Chem., 2012, 14, 2706; (b) X. Chen, J.-J. Li,
X.-S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc., 2006,
128, 78; (c) R. Giri, M. Wasa, S. P. Breazzano and J.-Q. Yu, Org. Lett.,
2006, 8, 5685.
9 For references on other directing groups, see (i) sulfonoamides:
(a) H.-X. Dai, A. F. Stepan, M. S. Plummer, Y.-H. Zhang and J.-Q. Yu,
´
´
J. Am. Chem. Soc., 2011, 133, 7222; (b) A. Garcıa-Rubia, R. G. Arrayas
and J. C. Carretero, Angew. Chem., Int. Ed., 2009, 48, 6511 (ii) oximes:
(c) S. R. Neufeldt and M. S. Sanford, Org. Lett., 2010, 12, 532;
(d) C.-L. Sun, N. Liu, B.-J. Li, D.-G. Yu, Y. Wang and Z.-J. Shi, Org.
Lett., 2010, 12, 184; (e) V. S. Thirunavukkarasu, K. Parthasarathy and
C.-H. Cheng, Angew. Chem., Int. Ed., 2008, 47, 9462 (iii) carbonates
and esters: ( f ) B. Xiao, Y. Fu, J. Xu, T.-J. Gong, J.-J. Dai, J. Yi and
L. Liu, J. Am. Chem. Soc., 2010, 132, 468.
10 For reviews on phosphorous-derived organic catalysts, see:
(a) M. Terada, Synthesis, 2010, 1929; (b) M. Terada, Chem. Commun.,
2008, 4097; (c) T. Honjo, R. J. Phipps, V. Rauniyar and F. D. Toste,
Angew. Chem., Int. Ed., 2012, 51, 9684.
11 For phosphates as coupling partner in CCR reactions, see:
(a) B. M. Trost and L. C. Czabaniuk, J. Am. Chem. Soc., 2012,
134, 5778; (b) N. I. Nikishkin, J. Huskens, J. Assenmacher,
A. Wilden, G. Modolo and W. Verboom, Org. Biomol. Chem., 2012,
10, 5443; (c) P. G. Steel and T. M. Wood, Synthesis, 2009, 3897;
(d) J. Guo, J. D. Harling, P. G. Steel and T. M. Woods, Org. Biomol.
Chem., 2008, 6, 4053; (e) J.-P. Ebran, A. L. Hansen, T. M. Gøgsig and
T. Skrydstrup, J. Am. Chem. Soc., 2007, 129, 6931.
SK acknowledges the financial support from Nanyang Technol-
ogical University and PHL thanks the NCRL (2012-0001245) funded
by the National Research Foundation of Korea.
Notes and references
1 For recent reviews on Pd-catalyzed C–H activations, see:
(a) K. M. Engle, T.-S. Mei, M. Wasa and J.-Q. Yu, Acc. Chem. Res.,
2012, 45, 788; (b) C. S. Yeung and V. M. Dong, Chem. Rev., 2011,
¨
111, 1215; (c) J. Wencel-Delord, T. Droge, F. Liu and F. Glorius,
Chem. Soc. Rev., 2011, 40, 4740; (d) C.-L. Sun, B.-J. Li and Z.-J. Shi, 12 (a) M. Watanabe, M. Date, K. Kawanishi, M. Tsukazaki and
Chem. Commun., 2010, 46, 677; (e) T. W. Lyons and M. S. Sanford,
Chem. Rev., 2010, 110, 1147; ( f ) S. H. Cho, J. Y. Kim, J. Kwak and
S. Chang, Chem. Soc. Rev., 2011, 40, 5068.
2 (a) I. Moritani and Y. Fujiwara, Tetrahedron Lett., 1967, 8, 1119;
(b) Y. Fujiwara, I. Moritani, S. Danno, R. Asano and S. Teranishi,
J. Am. Chem. Soc., 1969, 91, 7166; (c) C. Jia, T. Kitamura and
Y. Fujiwara, Acc. Chem. Res., 2001, 34, 633.
S. Furukawa, Chem. Pharm. Bull., 1989, 37, 2564; (b) B. Dhawan
and D. Redmore, J. Org. Chem., 1986, 51, 179; (c) L. S. Melvin,
Tetrahedron Lett., 1981, 22, 3375; (d) C. J. Rohbogner, G. C. Clososki
and P. Knochel, Angew. Chem., Int. Ed., 2008, 47, 1503;
´
´
(e) V. Y. Rodrıguez, M. A. del Aguila, M. J. Iglesias and F. Lopez
Ortiz, Tetrahedron, 2012, 68, 7355.
13 For organophosphonate derivatives, see: (a) H. e. Hajjouji,
´ ´ ´
E. Belmonte, J. Garcıa-Lopez, I. Fernandez, M. J. Iglesias, L. Roces,
3 For reviews of the Heck reactions, see: (a) R. F. Heck, Acc. Chem. Res.,
1979, 12, 146; (b) R. F. Heck, Org. React., 1982, 27, 345; (c) I. P.
Beletskaya and A. V. Cheprakov, Chem. Rev., 2000, 100, 3009;
(d) A. B. Dounay and L. E. Overman, Chem. Rev., 2003, 103, 2945.
4 For carboxylic acids in Pd(II)-catalyzed C–H activations, see:
´
´
S. Garcıa-Granda, A. E. Laghdach and F. Lopez Ortiz, Org. Biomol.
´
´
Chem., 2012, 10, 5647; (b) I. Fernandez, P. O. Burgos, G. R. Gomez,
´
´
C. Bled, S. Garcıa-Granda and F. Lopez Ortiz, Synlett, 2007, 611;
(c) L. Dashan and S. Trippett, Tetrahedron Lett., 1983, 24, 2039.
(a) D.-H. Wang, K. M. Engle, B.-F. Shi and J.-Q. Yu, Science, 2010, 14 For the use of phosphinites and phosphites as directing groups, see:
327, 315; (b) K. M. Engle, D.-H. Wang and J.-Q. Yu, Angew. Chem., Int.
Ed., 2010, 49, 6169; (c) K. M. Engle, D.-H. Wang and J.-Q. Yu, J. Am.
Chem. Soc., 2010, 132, 14137; (d) Y.-H. Zhang, B.-F. Shi and J.-Q. Yu,
Angew. Chem., Int. Ed., 2009, 48, 6097; (e) M. Miura, T. Tsuda,
T. Satoh, S. Pivsa-Art and M. Nomura, J. Org. Chem., 1998,
63, 5211; ( f ) B. Xiao, T.-J. Gong, J. Xu, Z.-J. Liu and L. Liu, J. Am.
Chem. Soc., 2011, 133, 1466.
5 For carboxylic amides, see: (a) Y. Ano, M. Tobisu and N. Chatani,
Org. Lett., 2012, 14, 354; (b) Y. Ano, M. Tobisu and N. Chatani,
J. Am. Chem. Soc., 2011, 133, 12984; (c) S. Rakshit, C. Grohmann,
T. Besset and F. Glorius, J. Am. Chem. Soc., 2011, 133, 2350;
(d) T. Nishikata and B. H. Lipshutz, Org. Lett., 2010, 12, 1972;
(a) L. N. Lewis and J. F. Smith, J. Am. Chem. Soc., 1986, 108, 2728;
(b) S. Oi, S.-i. Watanabe, S. Fukita and Y. Inoue, Tetrahedron Lett.,
2003, 44, 8665; (c) J. C. Lewis, J. Wu, R. G. Bergman and J. A. Ellman,
Organometallics, 2005, 24, 5737; (d) R. B. Bedford, S. J. Coles,
M. B. Hursthouse and M. E. Limmert, Angew. Chem., Int. Ed.,
2003, 42, 112.
15 For Pd(II)-catalyzed ortho-functionalization of phenols, see:
(a) Y. Kawamura, T. Satoh, M. Miura and M. Nomura, Chem. Lett.,
1999, 961; (b) T. Satoh, Y. Kawamura, M. Miura and M. Nomura,
Angew. Chem., Int. Ed., 1997, 36, 1740; (c) T. Satoh, J.-i. Inoh,
Y. Kawamura, Y. Kawamura, M. Miura and M. Nomura, Bull. Chem.
Soc. Jpn., 1998, 71, 2239.
(e) M. Tobisu, Y. Ano and N. Chatani, Org. Lett., 2009, 11, 3250; 16 (a) X. Wang, Y. Lu, H.-X. Dai and J.-Q. Yu, J. Am. Chem. Soc., 2010,
( f ) M. Wasa and J.-Q. Yu, J. Am. Chem. Soc., 2008, 130, 14058;
(g) B.-J. Li, S.-L. Tian, Z. Fang and Z.-J. Shi, Angew. Chem., Int. Ed.,
2008, 47, 1115; (h) V. G. Zaitsev and O. Dauglulis, J. Am. Chem. Soc.,
2005, 127, 4156; (i) M. D. K. Boele, G. P. F. Van Strijdonck, A. H. M.
de Vries, P. C. J. Kamer, J. G. Vries and P. W. N. M. van Leeuwen,
J. Am. Chem. Soc., 2002, 124, 1586.
6 For carbamates and ureas, see: (a) T.-J. Gong, B. Xiao, Z.-J. Liu,
J. Wan, J. Xu, D.-F. Luo, Y. Fu and L. Liu, Org. Lett., 2011, 13, 3235;
(b) C. Feng and T.-P. Loh, Chem. Commun., 2011, 47, 10458;
132, 12203; (b) Y. Lu, D.-H. Wang, K. M. Engle and J.-Q. Yu, J. Am.
Chem. Soc., 2010, 132, 5916; (c) Y. Lu, D. Leow, X. Wang, K. M. Engle
and J.-Q. Yu, Chem. Sci., 2011, 2, 967; (d) B. Xiao, T.-J. Gong, Z.-J. Liu,
J.-H. Liu, D.-F. Luo, J. Xu and L. Liu, J. Am. Chem. Soc., 2011,
133, 9250.
17 (a) C. Huang, B. Chattopadhyay and V. Gevorgyan, J. Am. Chem. Soc.,
2011, 133, 12406; (b) C. Huang, N. Ghavtadze, B. Chattopadhyay and
V. Gevorgyan, J. Am. Chem. Soc., 2011, 133, 17630; (c) C. Wang and
H. Ge, Chem.–Eur. J., 2011, 17, 14371.
(c) X. Zhao, C. S. Yeung and V. M. Dong, J. Am. Chem. Soc., 2010, 18 Additional data for optimization of reaction conditions are included
132, 5837; (d) T. Nishikata, A. R. Abela, S. Huang and B. H. Lipshutz, in the ESI†.
J. Am. Chem. Soc., 2010, 132, 4978; (e) R. B. Bedford, R. L. Webster 19 (a) T. Yamada, K. Takemura, J.-i. Yoshida and S. Yamago, Angew.
and C. J. Mitchell, Org. Biomol. Chem., 2009, 7, 4853; ( f ) C. E.
Houlden, M. Hutchby, C. D. Bailey, J. G. Ford, S. N. G. Tyler,
Chem., Int. Ed., 2006, 45, 7575; (b) R. Holzwarth, R. Bartsch,
´
Z. Cherkaoui and G. Solladie, Eur. J. Org. Chem., 2005, 3536.
c
This journal is The Royal Society of Chemistry 2013
Chem. Commun.