Copper-catalyzed phosphorylation of sp2 C-H bonds

Article abstract of DOI:10.1039/c4cc06246a

The phosphorylation of the ortho C-H bonds in benzamides containing an 8-aminoquinoline moiety as a bidentate directing group with H-phosphonates using copper as a catalyst under mild temperature conditions is described. This method shows high functional group compatibility and selectively gives mono-substituted products. This journal is

Full text of DOI:10.1039/c4cc06246a

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Copper-catalyzed phosphorylation of sp2
C–H bonds†
Cite this:DOI: 10.1039/c4cc06246a
Shan Wang, Rui Guo, Gao Wang, Shan-Yong Chen* and Xiao-Qi Yu*
Received 9th August 2014,
Accepted 1st September 2014
DOI: 10.1039/c4cc06246a
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The phosphorylation of the ortho C–H bonds in benzamides
containing an 8-aminoquinoline moiety as a bidentate directing
group with H-phosphonates using copper as a catalyst under mild
temperature conditions is described. This method shows high
functional group compatibility and selectively gives mono-substituted
products.
Aryl phosphonates and derivatives have found a wide range of
applications in medicinal chemistry,1 materials chemistry,2
and catalysis.3 Since the pioneering work developed by Hirao
and co-workers in 1981,4 the coupling of aryl halides or
pseudohalides with dialkyl phosphates has become one of the
most straightforward routes to construct C(sp2)–P bonds.5
Recently, the direct functionalization of carbon–hydrogen (C–H)
bonds has emerged as an atom-economical and environmentally
friendly synthetic method as it eliminates the need for prefunc-
tionalization of coupling partners.6 However, the direct forma-
Scheme 1 C–H phosphorylation reactions.
tion of C–P bonds through C–H activation is problematic because direct intermolecular arene C–H phosphorylation reaction has
of the strong coordinating character of phosphorus reagents.7,8 been reported. The use of a removable 8-aminoquinoline-based
Very recently, the Yu group and the Murakami group addressed amide as a directing group,17 originally developed by Daugulis in a
this problem by using a non-removable pyridine as the directing direct arylation reaction,17a was reported to have the potential for
group and a palladium reagent as the catalyst (Scheme 1, eqn (1) stabilizing high-valent Cu intermediates.18 As an outgrowth of
and (2)).9,10 A silver-catalyzed phosphonation of arenes bearing these studies, we hypothesized that an 8-aminoquinoline auxiliary
electron-withdrawing groups through a radical mechanism has would also affect the ortho-phosphonation of C(sp2)–H bonds.
also been developed (Scheme 1, eqn (3)).11 Herein, we present a
Initially, the optimization of the reaction between
method for direct C–H phosphorylation by using a removable N-(quinolin-8-yl)benzamide (1a) and diisopropyl phosphonate
amide as the directing group and copper(II) acetate as the catalyst (2a) started with 20 mol% of Cu(OAc)2, NMO and Ag2CO3 in
(Scheme 1, eqn (4)).
NMP at 120 1C for 12 h, giving a relatively low but promising
The use of low cost and toxicity copper reagents as catalysts for isolated yield of 30% (Table 1, entry 1). When the temperature
C–H bond activation is particularly attractive. Many good examples was increased to 140 1C, the yield of product 3a was reduced to
of the copper-catalyzed C–H functionalization reactions have been 23% (entry 2). We were strongly aware of the vital role the
reported.12–16 However, as far as we know, no copper-catalyzed temperature played in the reaction (entries 2–4). The tempera-
ture effect was investigated in detail (Table S2, ESI†) and 55 1C
Key Laboratory of Green Chemistry and Technology, Ministry of Education,
was proved to be the optimal temperature for this reaction
(entry 3). In view of the strong coordinating properties of
phosphorus reagents, the reaction was stirred at 15 1C for
College of Chemistry, Sichuan University, Chengdu, 610064, P. R. China.
E-mail: chensy@scu.edu.cn, xqyu@scu.edu.cn; Fax: +86-28-85415886;
Tel: +86-28-85415886
30 min before diisopropyl phosphonate was added, then the
mixture was transferred and the reaction was carried out at
† Electronic supplementary information (ESI) available. See DOI: 10.1039/
c4cc06246a
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Table 1 Optimization of the reaction conditionsa
Table 2 Copper-catalyzed phosphorylation of carboxylic acid derivativesa,b
Entry
T (1C)
Solvent
Additive
Yieldb (%)
1
2
3
4
120
140
55
10
55
55
55
55
NMP
NMP
NMP
NMP
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
Ag2CO3
—
30
23
59
NR
70
78
22
NR
5c
6c
7c
8c,d
NMP
DMSO
DMSO
DMSO
Ag2CO3
a
Reaction conditions: amide (0.2 mmol), Cu(OAc)2 (20 mol%), NMO
(2 equiv.), additive (2 equiv.), 4 Å MS (100 mg), solvent (0.8 mL) and
b
c
diisopropyl phosphonate (2 equiv.). Isolated yields. The mixture was
stirred at 15 1C for 30 min before diisopropyl phosphonate was added.
Then the reaction mixture was transferred and the reaction was carried
d
out at 55 1C immediately. Without Cu(OAc)2. NMO = N-methyl-
morpholine oxide. NMP = N-methyl pyrrolidone.
55 1C immediately, affording 3a in 70% yield (entry 5). The yield
was further improved to 78% when the solvent NMP was
replaced with DMSO (entry 6). The reaction yield became quite
low in the absence of Ag2CO3 (entry 7). No reaction could be
realized without Cu(OAc)2 (entry 8).
The effect of directing groups was next examined. The
reaction of N-methylamide (Fig. 1, A) with diisopropyl phos-
phonate failed, implying that the relatively acidic NH in 1a is
also assumed to exhibit great significance in the coupling.
When 1a was replaced by some structurally similar but mono-
dentate directing groups, no reaction took place, which suggested
that the N,N-bidentate directing group is essentially crucial for the
reaction to proceed (B–D). Furthermore, the utilization of the
N-benzylpicolinamide (E) or 2-(methylthio)aniline (F) moiety as
the bidentate directing group led to trace yields of the phos-
phorylation products. Accordingly, the reaction appears to be
more efficient upon using the 8-aminoquinoline motif as the
directing group.
a
Amide (0.2 mmol), HPO(OiPr)2 (2 equiv.), Cu(OAc)2 (20 mol%), NMO
With the optimized reaction conditions in hand, we next
examined the scope of a variety of benzoic acid derivatives
using the coupling partner 2a and obtained the isolated yields
with substrates 1a–1t (Table 2). Both electron-rich (1b, 1c, 1l, 1m)
b
(2 equiv.), Ag2CO3 (1 equiv.), DMSO (0.8 mL), 55 1C, 12 h. Isolated
yields.
and electron-deficient (1d–1k, 1n–1p) benzoic acid derivatives products were achieved in these cases. In addition, the reaction
are suitable substrates for providing cross-coupling products displayed an outstanding functional group tolerance, including
in moderate to good yields. Only ortho-monophosphonylated ethers (3c, 3m), halides (3d–3g, 3n–3p), esters (3k), nitriles (3j) and
nitro groups (3i). When the meta-substituted benzamides were used,
no matter what the electronic nature of the substituent is, most of
the phosphorylation proceeded selectively at the less sterically
hindered position (3l–3p). Furthermore, heterocyclic amides are
compatible with the reaction conditions. Both five- and six-
membered heterocyclic substrates remained reactive under these
conditions. Pyridine (1r) and thiofuran (1s) derivatives were con-
verted to monosubstituted products in synthetically useful yields.
This copper-catalyzed direct phosphorylation is also applicable to
vinylic C–H bonds (3t). To our delight, there was no significant loss
Fig. 1 Ineffective directing groups.
of yield when the reaction was scaled up at least tenfold (Scheme 2).
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reaction is unclear at this moment, it is likely that this
Cu-catalyzed phosphorylation reaction proceeds via Cu(III) inter-
mediates (Scheme S1, ESI†).20,21
In conclusion, we have developed a method for the direct,
auxiliary-assisted intermolecular C–H phosphorylation of non-
acidic benzamide b-C–H bonds. The reaction employs inexpensive
copper acetate under mild conditions. Moreover, the process
selectively gives only the mono-substituted products and demon-
strates excellent functional group tolerance. This method offers
a new and straightforward way for the preparation of ortho-
phosphonated benzoic acid derivatives. Further investigation of
the mechanism of the phosphorylation is in progress in our
laboratory.
Scheme 2 Preparative scale experiment.
Scheme 3 A control experiment in the presence of TEMPO.
This work was supported financially by the National Pro-
gram on Key Basic Research Project of China (973 Program,
2013CB328900) and the National Science Foundation of China
(Grant No. 21202107, 21321061 and J1103315).
Different dialkyl H-phosphonates and diaryl H-phosphonates
were also examined and most of the corresponding products were
obtained in moderate yields (3a, 4b, 4c, 4e). It seems that the
steric and electronic effect of the phosphonates profoundly
affected the rate and efficiency of the transformation. When the
phosphonate coupling partner was changed to the long aliphatic
chain dihexyl phosphonate, the equivalent of the phosphonate,
the reaction time had to be increased to afford the desired
product (4c) in the process. If diphenyl phosphonate as a phos-
phate reagent participated in the reaction, the transformation was
completely blocked because of the bulky benzene rings. Thus, the
diisopropyl phosphate was found to be the best partner for the
phosphorylation of N-(quinolin-8-yl)benzamide derivatives.
Taking into account the previous observation that Ag(I)-mediated
phosphorylation of indoles19 or N,N-diethylbenzamide11 with
H-phosphonates proceeds via a radical pathway, a control experi-
ment was carried out in the presence of the radical scavenger
2,2,6,6-tetramethylpiperidine N-oxide (TEMPO). The addition of
TEMPO did not decrease the yield of the model reaction
(Scheme 3). Furthermore, this reaction did not proceed in the
absence of copper catalyst (Table 1, entry 8). These results
indicate that no radical was involved in the catalytic cycle of
the phosphorylation (Table 3). Although the mechanism of the
Notes and references
1 (a) Q. Dang, Y. Liu, D. K. Cashion, S. R. Kasibhatla, T. Jiang,
F. Taplin, J. D. Jacintho, H. Li, Z. Sun, Y. Fan, J. DaRe, F. Tian,
W. Li, T. Gibson, R. Lemus, P. D. van Poelje, S. C. Potter and
M. D. Erion, J. Med. Chem., 2011, 54, 153; (b) X. Chen, D. J. Kopecky,
J. Mihalic, S. Jeffries, X. Min, J. Heath, J. Deignan, S. Lai, Z. Fu,
C. Guimaraes, S. Shen, S. Li, S. Johnstone, S. Thibault, H. Xu,
M. Cardozo, W. Shen, N. Walker, F. Kayser and Z. Wang, J. Med.
Chem., 2012, 55, 3837.
2 (a) H. R. Allcock, M. A. Hofmann, C. M. Ambler and R. V. Morford,
Macromolecules, 2002, 35, 3484; (b) H. Onouchi, T. Miyagawa,
A. Furuko, K. Maeda and E. Yashima, J. Am. Chem. Soc., 2005,
´
127, 2960; (c) C. Queffelec, M. Petit, P. Janvier, D. A. Knight and
B. Bujoli, Chem. Rev., 2012, 112, 3777.
3 (a) G. Helmchen and A. Pfaltz, Acc. Chem. Res., 2000, 33, 336;
(b) M. R. Netherton and G. C. Fu, Org. Lett., 2001, 3, 4295;
(c) N. Kataoka, Q. Shelby, J. P. Stambuli and J. F. Hartwig, J. Org.
Chem., 2002, 67, 5553; (d) C. W. Lim, O. Tissot, A. Mattison,
M. W. Hooper, J. M. Brown, A. R. Cowley, D. I. Hulmes and
A. Blacker, Org. Process Res. Dev., 2003, 7, 379; (e) W. Tang and
X. Zhang, Chem. Rev., 2003, 103, 3029; ( f ) G. Chelucci, G. Orru` and
G. A. Pinna, Tetrahedron, 2003, 59, 9471; (g) D. S. Surry and
S. L. Buchwald, Angew. Chem., Int. Ed., 2008, 47, 6338; (h) Y. Guo,
H. Fu, H. Chen and X. Li, Catal. Commun., 2008, 9, 1842; (i) Y. Li,
L. Q. Lu, S. Das, S. Pisiewicz, K. Junge and M. Beller, J. Am. Chem.
Soc., 2012, 134, 18325.
4 T. Hirao, T. Masunaga, Y. Ohshiro and T. Agawa, Synthesis, 1981, 56.
5 For reviews of C–P bond formation, see: (a) C. Baillie and J. Xiao,
Curr. Org. Chem., 2003, 7, 477; (b) F. M. J. Tappe, V. T. Trepohl and
M. Oestreich, Synthesis, 2010, 3037; (c) C. S. Demmer, N. Krogsgaard-
Larsen and L. Bunch, Chem. Rev., 2011, 111, 7981.
Table 3 Evaluation of different phosphorylation reagentsa,b
6 (a) C. I. Herrerias, X. Yao, Z. Li and C. J. Li, Chem. Rev., 2007, 107, 2546;
(b) X. Chen, K. M. Engle, D. H. Wang and J. Q. Yu, Angew. Chem., Int. Ed.,
2009, 48, 5094; (c) T. W. Lyons and M. S. Sanford, Chem. Rev., 2010,
110, 1147; (d) W. R. Gutekunst and P. S. Baran, Chem. Soc. Rev., 2011,
40, 1976; (e) L. McMurray, F. O’Hara and M. J. Gaunt, Chem. Soc. Rev.,
2011, 40, 1885; ( f ) E. M. Beccalli, G. Broggini, A. Fasana and
M. Rigamonti, J. Organomet. Chem., 2011, 696, 277.
7 (a) Y. Gao, G. Wang, L. Chen, P. Xu, Y. Zhao, Y. Zhou and L.-B. Han,
J. Am. Chem. Soc., 2009, 131, 7956; (b) C. Hou, Y. Ren, R. Lang, X. Hu,
C. Xia and F. Li, Chem. Commun., 2012, 48, 5181; (c) C.-B. Xiang,
Y. J. Bian, X.-R. Mao and Z.-Z. Huang, J. Org. Chem., 2012, 77, 7706;
(d) O. Berger, C. Petit, E. L. Deal and J.-L. Montchamp, Adv. Synth.
Catal., 2013, 355, 1361; (e) B. Yang, T.-T. Yang, X.-A. Li, J.-J. Wang
and S.-D. Yang, Org. Lett., 2013, 15, 5024; ( f ) X. Mi, M. Huang,
J. Zhang, C. Wang and Y. Wu, Org. Lett., 2013, 15, 6266.
a
Amide (0.2 mmol), HPO(OR2)2 (2 equiv.), Cu(OAc)2 (20 mol%), NMO
8 For phosphonation of aromatic C–H bonds using a stoichiometric
amount of a transition-metal complex, see: (a) V. I. Sokolov, L. L.
Troitskaya and O. A. Reutov, J. Organomet. Chem., 1980, 202, 58;
b
(2 equiv.), Ag2CO3 (1 equiv.), DMSO (0.8 mL), 55 1C, 12 h. Isolated
yields. HPO(OC6H13 2
c
)
(5 equiv.), 24 h.
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(b) C. Bolm, K. Wenz and G. Raabe, J. Organomet. Chem., 2002, 15 (a) G. Brasche and S. L. Buchwald, Angew. Chem., Int. Ed., 2008,
662, 23; (c) V. A. Stepanova, V. V. Dunina and I. P. Smoliakova,
Organometallics, 2009, 28, 6546.
9 C.-G. Feng, M. Ye, K.-J. Xiao, S. Li and J.-Q. Yu, J. Am. Chem. Soc.,
2013, 135, 9322.
10 C. Li, T. Yano, N. Ishida and M. Murakami, Angew. Chem., Int. Ed.,
2013, 52, 9801.
47, 1932; (b) R. Bernini, G. Fabrizi, A. Sferrazza and S. Cacchi, Angew.
Chem., Int. Ed., 2009, 48, 8078; (c) S. Ueda and H. Nagasawa, Angew.
Chem., Int. Ed., 2008, 47, 6411; (d) S. Ueda and H. Nagasawa, J. Org.
Chem., 2009, 74, 4272; (e) M. M. Guru, M. A. Ali and T. Punniyamurthy,
Org. Lett., 2011, 13, 1194; ( f ) H. Wang, Y. Wang, C. Peng, J. Zhang and
Q. Zhu, J. Am. Chem. Soc., 2010, 132, 13217.
11 X. Mao, X. Ma, S. Zhang, H. Hu, C. Zhu and Y. Cheng, Eur. J. Org. 16 (a) S. Zhang, P. Qian, M. Zhang, M. Hu and J. Cheng, J. Org. Chem.,
Chem., 2013, 4245.
2010, 75, 6732; (b) L. Chu, X. Yue and F.-L. Qing, Org. Lett., 2010,
12, 1644; (c) S. Ranjit, R. Lee, D. Heryadi, C. Shen, J. Wu, P. Zhang,
K.-W. Huang and X. Liu, J. Org. Chem., 2011, 76, 8999; (d) C. Dai,
Z. Xu, F. Huang, Z. Yu and Y.-F. Gao, J. Org. Chem., 2012, 77, 4414.
12 (a) A. E. Wendlandt, A. M. Suess and S. S. Stahl, Angew. Chem., Int.
Ed., 2011, 50, 11062; (b) Z. Li, D. S. Bohle and C.-J. Li, Proc. Natl.
Acad. Sci. U. S. A., 2006, 103, 8928; (c) I. Ban, T. Sudo, T. Taniguchi
and K. Itami, Org. Lett., 2008, 10, 3607; (d) W. Wang, F. Luo, S. Zhang 17 For selective use of 8-aminoquinone in direct C–H functionalizations,
and J. Cheng, J. Org. Chem., 2010, 75, 2415; (e) W. Wang, C. Pan,
F. Chen and J. Cheng, Chem. Commun., 2011, 47, 3978; ( f ) A. John
and K. M. Nicholas, J. Org. Chem., 2011, 76, 4158; (g) Q. Wang and
S. L. Schreiber, Org. Lett., 2009, 11, 5178; (h) A. E. King, L. M.
Huffman, A. Casitas, M. Costas, X. Ribas and S. S. Stahl, J. Am. Chem.
Soc., 2010, 132, 12068; (i) S. Usui, Y. Hashimoto, J. V. Morey,
A. E. H. Wheatley and M. Uchiyama, J. Am. Chem. Soc., 2007,
129, 15102; ( j) P. L. Holland, K. R. Rodgers and W. B. Tolman,
Angew. Chem., Int. Ed., 1999, 38, 1139.
see: (a) V. G. Zaitsev, D. Shabashov and O. Daugulis, J. Am. Chem. Soc.,
2005, 127, 13154; (b) B. V. S. Reddy, L. R. Reddy and E. J. Corey, Org.
Lett., 2006, 8, 3391; (c) D. Shabashov and O. Daugulis, J. Am. Chem.
Soc., 2010, 132, 3965; (d) W. R. Gutekunst, R. Gianatassio and
P. S. Baran, Angew. Chem., Int. Ed., 2012, 51, 7507; (e) L. D. Tran,
J. Roane and O. Daugulis, Angew. Chem., Int. Ed., 2013, 52, 6043;
( f ) G. He, S.-Y. Zhang, W. A. Nark, Q. Li and G. Chen, Angew. Chem.,
Int. Ed., 2013, 52, 11124; (g) F. Pan, P.-X. Shen, L.-S. Zhang, X. Wang
and Z.-J. Shi, Org. Lett., 2013, 15, 4758; (h) G. Shan, X. Yang, Y. Zong
and Y. Rao, Angew. Chem., Int. Ed., 2013, 52, 13606; (i) Y. Aihara and
N. Chatani, J. Am. Chem. Soc., 2014, 136, 898.
13 (a) X. Chen, X.-S. Hao, C. E. Goodhue and J.-Q. Yu, J. Am. Chem. Soc.,
2006, 128, 6790; (b) X. Chen, G. Dobereiner, X.-S. Hao, R. Giri,
N. Maugel and J.-Q. Yu, Tetrahedron, 2009, 65, 3085.
14 (a) H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2007, 129, 12404;
(b) H.-Q. Do, R. M. K. Khan and O. Daugulis, J. Am. Chem. Soc., 2008,
18 (a) T. Truong, K. Klimovica and O. Daugulis, J. Am. Chem. Soc., 2013,
135, 9342; (b) A. M. Suess, M. Z. Ertem, C. J. Cramer and S. S. Stahl,
J. Am. Chem. Soc., 2013, 135, 9797.
130, 15185; (c) H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2009, 19 H. Wang, X. Li, F. Wu and B. Wan, Synthesis, 2012, 941.
131, 17052; (d) H.-Q. Do and O. Daugulis, J. Am. Chem. Soc., 2011, 20 Silver mirror and/or silver black was observed after the reaction.
133, 13577; (e) I. Popov, S. Lindeman and O. Daugulis, J. Am. Chem. 21 Z. Wang, J. Ni, Y. Kuninobu and M. Kanai, Angew. Chem., Int. Ed.,
Soc., 2011, 133, 9286.
2014, 53, 3496.
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