Copper-catalyzed aerobic oxidative cross-coupling of arylamines and dialkylphosphites leading to...
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Copper-catalyzed aerobic oxidative cross-coupling of arylamines and dialkylphosphites leading to N-arylphosphoramidates Gao Wang, Qing-Ying Yu, Shan-Yong Chen ⇑ , Xiao-Qi Yu ⇑ Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China article info Article history: Received 7 May 2013 Revised 30 August 2013 Accepted 5 September 2013 Available online 12 September 2013 Keywords: Cross-coupling Copper salts N-arylphosphoramidates abstract An efficient method to generate N–P bonds directly from N–H and P–H bonds is described. Various aryl- amines and dialkylphosphites were directly oxidized to the corresponding N-arylphosphoramidates at room temperature in moderate to good yields by using an inexpensive catalyst–oxidant (CuBr/air) system. Ó 2013 Elsevier Ltd. All rights reserved. Phosphoramidates have found wide applications as structure motifs in bioactive compounds such as phosphoramidate- substituted nucleosides, N-phosphoryl amino acids, and N-phosphoryl peptides. 1 Phosphoramidates also play a significant role in organic synthesis. For example, N-arylphosphoramidates have been used for the preparation of imines 2 and various hetero- cycles such as quinazolinediones 3 , aziridines 4 , and azetidines. 5 Despite the increasing importance of phosphoramidates, only two standard procedures have been widely used in the laboratory. One route that forms phosphoramidates via the nucleophilic sub- stitution of phosphorochloridates or phosphorodichloridates with amines in the presence of a base (Scheme 1). 6,1g Another involves reactions of dialkyl or dibenzyl phosphites with amines using a halogen source like CCl 4 or other improved alternatives as activate agents (Scheme 1). 7 Other methods for the synthesis of phospho- ramidates include the oxidation of phosphate trimesters with I 2 in the presence of alkylamines and the reduction of nitroarenes with triethyl phophite followed by phosphorylation with triethyl phosphate. 8 These procedures have in common that they are based on the prefunctionalization–defunctionalization strategy. As results, these procedures use additional active agents or produce unde- sired by-products. Recently, there has been increasing emphasis on reducing the amount of toxic waste and byproducts arising from a chemical process. As an effort to develop green chemistry for chemical syn- thesis, a new concept of cross-dehydrogenative coupling was established. 9 To date, there is remarkable progress in the develop- ment of C–C, 10 N–N 11 , and P–P 12 bond forming reactions via dehydrogenative coupling. We envision that N–P bond may be formed via cross-dehydrogenative coupling. 13 We commenced our studies by examining the cross-coupling of diisopropyl phosphite with excess p-methylaniline at room tem- perature under air. In the absence of a catalyst, no desired product was observed. Using 10 mol % of CuBr 2 as the catalyst, 48% of de- sired product was obtained. After screening different copper salts, we found that CuBr performed the best (Table 1, entries 2–8). CuCl also facilitated the reaction, but was less efficient than CuBr (entry 4 vs entry 3). Other catalysts including Cu(OAc) 2 H 2 O, CuI, Cu(OTf) 2 , and Cu 2 O were inefficient or inactive. Attempts to use other transition-metal catalysts such as FeBr 3 and CoBr 2 were unsuccessful. Impressively, no desired product was observed under nitrogen (entry 9), indicating that oxygen is essential to this reac- tion. We then surveyed the effect of different solvents (entries 10– 14). When toluene was replaced with ethyl acetate as the solvent, we were pleased to find that the product could be obtained in 80% yield. The reaction gave low yields in EtOH, THF, and H 2 O. In the absence of a solvent, the reaction also performed, albeit with a 0040-4039/$ - see front matter Ó 2013 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.tetlet.2013.09.006 ⇑ Corresponding authors. Tel./fax: +86 28 85415886. E-mail address: [email protected] (X.-Q. Yu). CCl 4 Base P H O R 1 O R 1 O N H R 2 R 3 P N O R 1 O R 1 O R 2 R 3 P Cl O R 1 O R 1 O R 1 OH POCl 3 N H R 2 R 3 Base P N O R 1 O R 1 O R 2 R 3 P O R 1 O R 1 O Cl CCl 3 - CHCl 3 Scheme 1. The standard methods for the synthesis of phosphoramidates. Tetrahedron Letters 54 (2013) 6230–6232 Contents lists available at ScienceDirect Tetrahedron Letters journal homepage: www.elsevier.com/locate/tetlet
Transcript of Copper-catalyzed aerobic oxidative cross-coupling of arylamines and dialkylphosphites leading to...
Tetrahedron Letters 54 (2013) 6230–6232
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier .com/ locate / tet let
Copper-catalyzed aerobic oxidative cross-coupling of arylamines anddialkylphosphites leading to N-arylphosphoramidates
0040-4039/$ - see front matter � 2013 Elsevier Ltd. All rights reserved.http://dx.doi.org/10.1016/j.tetlet.2013.09.006
⇑ Corresponding authors. Tel./fax: +86 28 85415886.E-mail address: [email protected] (X.-Q. Yu).
CCl4Base
P HO
R1OR1O
NH
R2 R3
PO
R1OR1O
P ClO
R1OR1OR1OH
POCl3NH
R2 R3
BaseP N
O
R1OR1O
PO
R1OR1O Cl CCl3
- CHCl3
Scheme 1. The standard methods for the synthesis of phosphoramid
Gao Wang, Qing-Ying Yu, Shan-Yong Chen ⇑, Xiao-Qi Yu ⇑Key Laboratory of Green Chemistry and Technology, Ministry of Education, College of Chemistry, Sichuan University, Chengdu 610064, PR China
a r t i c l e i n f o
Article history:Received 7 May 2013Revised 30 August 2013Accepted 5 September 2013Available online 12 September 2013
Keywords:Cross-couplingCopper saltsN-arylphosphoramidates
a b s t r a c t
An efficient method to generate N–P bonds directly from N–H and P–H bonds is described. Various aryl-amines and dialkylphosphites were directly oxidized to the corresponding N-arylphosphoramidates atroom temperature in moderate to good yields by using an inexpensive catalyst–oxidant (CuBr/air)system.
� 2013 Elsevier Ltd. All rights reserved.
NR2
R3
R2
R3
ates.
Phosphoramidates have found wide applications as structuremotifs in bioactive compounds such as phosphoramidate-substituted nucleosides, N-phosphoryl amino acids, andN-phosphoryl peptides.1 Phosphoramidates also play a significantrole in organic synthesis. For example, N-arylphosphoramidateshave been used for the preparation of imines2 and various hetero-cycles such as quinazolinediones3, aziridines4, and azetidines.5
Despite the increasing importance of phosphoramidates, onlytwo standard procedures have been widely used in the laboratory.One route that forms phosphoramidates via the nucleophilic sub-stitution of phosphorochloridates or phosphorodichloridates withamines in the presence of a base (Scheme 1).6,1g Another involvesreactions of dialkyl or dibenzyl phosphites with amines using ahalogen source like CCl4 or other improved alternatives as activateagents (Scheme 1).7 Other methods for the synthesis of phospho-ramidates include the oxidation of phosphate trimesters with I2
in the presence of alkylamines and the reduction of nitroareneswith triethyl phophite followed by phosphorylation with triethylphosphate.8 These procedures have in common that they are basedon the prefunctionalization–defunctionalization strategy. As results,these procedures use additional active agents or produce unde-sired by-products.
Recently, there has been increasing emphasis on reducing theamount of toxic waste and byproducts arising from a chemicalprocess. As an effort to develop green chemistry for chemical syn-thesis, a new concept of cross-dehydrogenative coupling wasestablished.9 To date, there is remarkable progress in the develop-
ment of C–C,10 N–N11, and P–P12 bond forming reactions viadehydrogenative coupling. We envision that N–P bond may beformed via cross-dehydrogenative coupling.13
We commenced our studies by examining the cross-coupling ofdiisopropyl phosphite with excess p-methylaniline at room tem-perature under air. In the absence of a catalyst, no desired productwas observed. Using 10 mol % of CuBr2 as the catalyst, 48% of de-sired product was obtained. After screening different copper salts,we found that CuBr performed the best (Table 1, entries 2–8). CuClalso facilitated the reaction, but was less efficient than CuBr (entry4 vs entry 3). Other catalysts including Cu(OAc)2�H2O, CuI,Cu(OTf)2, and Cu2O were inefficient or inactive. Attempts to useother transition-metal catalysts such as FeBr3 and CoBr2 wereunsuccessful. Impressively, no desired product was observed undernitrogen (entry 9), indicating that oxygen is essential to this reac-tion. We then surveyed the effect of different solvents (entries 10–14). When toluene was replaced with ethyl acetate as the solvent,we were pleased to find that the product could be obtained in 80%yield. The reaction gave low yields in EtOH, THF, and H2O. In theabsence of a solvent, the reaction also performed, albeit with a
Table 1Copper-catalyzed cross-dehydrogenative coupling of p-methylaniline and diisopropylphosphatea
NH2 + PO
O iPrOiPrH P
O
O iPrOiPr
HN
Entry Catalyst (mol %) Solvent Yieldb (%)
1 — Toluene N.D.2 CuBr2 (10) Toluene N.D.3 CuBr (10) Toluene 544 CuCl (10) Toluene 455 Cu(OAc)2�H2O (10) Toluene 176 CuI (10) Toluene 67 Cu(OTf)2 (10) Toluene N.D.8 Cu2O (10) Toluene N.D.9b CuBr (10) Toluene N.D.10 CuBr (10) Ethyl acetate 8011 CuBr (10) EtOH 5212 CuBr (10) THF 6013 CuBr (10) H2O 3914c CuBr (10) — 4915 CuBr (2.5) Ethyl acetate 5416 CuBr (5) Ethyl acetate 8017 CuBr (20) Ethyl acetate 3218d CuBr (5) Ethyl acetate 78
a p-Methylaniline, 1.5 mmol; diisopropyl phosphite, 1 mmol; solvent, 1 mL;under air; at room temperature; 22 h; isolated yields.
b Under nitrogen.C No solvent.d 50 �C; 8 h.
Table 2Copper catalyzed cross-dehydrogenative coupling of arylamines and dialkylphosph-itesa
Ar NH2 + PO
ORORH P
O
OROR
HNAr
1 2 3
Product Yieldb
(%)Product Yieldb
(%)
PO
O iPrOiPr
HN
3a
64PO
OiPrOiPr
HN
3b
80
PO
OiPrOiPr
HN
3c
64PO
O iPrOiPr
HNF
3d65
PO
O iPrOiPr
HNCl
3e63 P
O
O iPrOi Pr
HN
Cl
3f
58
PO
O iPrOiPr
HNBr
3g
63PO
O iPrOiPr
HNMeO
3h
49
PO
OiPrOiPr
HN
3i
28 PO
O iPrOiPr
HN
Cl
3j
Trace
PO
O iPrOiPr
HNO2N
3kN.R.
PO
O iPrOiPr
HN
3l
49
PO
OiPrOiPrHN
3m
30
NP
O
OiPr
OiPr
3n
20(50c)
PO
OEtOEt
HN
3o64
PO
OnBuOnBu
HN
3p94
PO
OnBuOnBu
HNCl
3q75
PO
OnBuOnBu
HNBr
3r77
a 1, 1.5 mmol; 2, 1 mmol; ethyl acetate, 1 mL; CuBr, 5 mol %; under air; at roomtemperature; 22 h.
b Isolated yields.c N-methylaniline 5 mmol.
G. Wang et al. / Tetrahedron Letters 54 (2013) 6230–6232 6231
moderate yield (entry 14). Further, the catalyst loading wasscreened, and it was found that 5 mol % of CuBr was efficient to ob-tain a reasonable yield (entries 15–17 and entry 10). When thereaction was carried out at 50 �C, the yield decreased slightly (en-try 18). In summary, 5 mol % of CuBr in ethyl acetate, at room tem-perature, under air atmosphere were the optimized reactionconditions.
With optimized conditions in hand, we investigated the scopeof this transformation (Table 2). Various phosphoramidates wereproduced from arylamines and diisopropyl phosphite in moderateto good yields (3a–j). This reaction was tolerant of several func-tional groups. Both electron-rich and electron-deficient substrates(para or meta substituted) were well-tolerated. Arylamines bearingfluoro (3d), chloro (3e and 3f), or bromo (3g) groups were goodsubstrates, providing convenient handles for subsequent function-alization processes. Arylamines bearing an ortho substituent or astrong electron-withdraw substituent could not smoothly affordthe desired product (3i–k). The cross-coupling of a-naphthylaminewith diisopropyl phosphite produced 3l in 49% yield. Althoughalkylamines were not compatible with this method, benzylamineis an acceptable substrate (3m). Secondary arylamines were notgood substrates for this transformation. But increasing the loadingof N-methylaniline to 5:1 (amine/phosphate ratio), the corre-sponding product was obtained in an acceptable yield (3n). Inaddition to diisopropyl phosphite, other dialkyl phosphites includ-ing diethyl phosphite and di-n-butyl phosphite were also goodsubstrates for this cross-coupling reaction (3o–r). Interestingly,di-n-butyl phosphite performed more effectively and afforded thedesired product in higher yield than other dialkyl phosphites. Forexample, the reaction of p-methylanilide with di-n-butyl phos-phite, diisopropyl phosphite, and diethyl phosphite afforded thecorresponding phosphoramidates in 94%, 80%, and 64% yields,respectively (3p, 3b and 3o).
In conclusion, we have developed an efficient and greenmethod to prepare N-aryl-phosphoramidates via Cu-catalyzedcross-dehydrogenative coupling.
Acknowledgments
We are grateful for financial support from the National Programon Key Basic Research Project of China (973 Program,2013CB328900) and the National Science Foundation of China(Grant No. 21202107 and 20121001).
Supplementary data
Supplementary data (the detailed experimental procedures andcompounds characterization) associated with this article can be
6232 G. Wang et al. / Tetrahedron Letters 54 (2013) 6230–6232
found, in the online version, at http://dx.doi.org/10.1016/j.tetlet.2013.09.006.
References and notes
1. (a) Venkatachalam, T. K.; Goodman, P. A.; Qazi, S.; D’Cruz, O.; Uckun, F. M. Curr.Pharm. Design 2004, 10, 1713; (b) Venkatachalam, T. K.; Samuel, P.; Qazi, S.;Uckun, F. M. Bioorg. Med. Chem. 2005, 13, 5408; (c) Uckun, F. M.; Samuel, P.;Qazi, S.; Chen, C.; Pendergrass, S.; Venkatachalam, T. K. Antiviral Chem.Chemother. 2002, 13, 197; (d) Freel Meyers, C. L.; Borch, R. F. J. Med. Chem.2000, 43, 4319; (e) Roman, C. A.; Balzarini, J.; Meier, C. J. Med. Chem. 2010, 53,7675; (f) Ji, G. J.; Xue, C. B.; Zhao, Y. F. Synthesis 1988, 444; (g) Cai, Y. M.; Gao, X.;Huang, X. T.; Wang, T. J.; Zhao, Y. F. Chin. J. Org. Chem. 2006, 26, 1677; (h)Kortylewicz, Z. P.; Galardy, R. E. J. Med. Chem. 1990, 33, 263; (i) Mc Mahon, E. G.;Palomo, M. A.; Moore, W. M. Proc. Natl. Acad. Sci. U.S.A. 1991, 88, 703.
2. Ciufolini, M. A.; Spencer, G. O. J. Org. Chem. 1989, 54, 4739.3. Minami, T.; Ogata, M.; Hirao, I.; Tanaka, M.; Agawa, T. Synthesis 1982, 231.4. Yadav, L. D. S.; Rai, A.; Rai, V. K.; Awasthi, C. Tetrahedron Lett. 2008, 49, 68.
5. (a) Yadav, L. D. S.; Srivastava, V. P.; Patel, R. Tetrahedron Lett. 2008, 49, 5652; (b)Yadav, L. D. S.; Awasthi, C.; Rai, V. K.; Rai, A. Tetrahedron Lett. 2007, 48, 8037.
6. Li, S. O. J. Am. Chem. Soc. 1952, 74, 5959.7. (a) Atherton, F. R.; Openshaw, H. T.; Todd, A. R. J. Chem. Soc. 1945, 660; (b)
Gupta, A. K.; Acharya, J.; Dubey, D. K.; Kaushik, M. P. Synth. Commun. 2007, 37,3403.
8. (a) Nemer, M. J.; Ogilvie, K. K. Tetrahedron Lett. 1980, 21, 4149; (b) Haggam, R.;Conrad, J.; Beifuss, U. Tetrahedron Lett. 2009, 50, 6627.
9. (a) Li, C.-J.; Li, Z. Pure Appl. Chem. 2006, 78, 935–945; (b) Wendlandt, A. E.;Suess, A. M.; Stahl, S. S. Angew. Chem., Int. Ed. 2011, 50, 11062; (c) Liu, C.; Zhang,H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780.
10. (a) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. and references cited therein; (b) Li, Y.-Z.; Li, B.-J.; Lu, X.-Y.; Lin, S.; Shi, Z.-J. Angew. Chem., Int. Ed. 2009, 48, 3817; (c)Guo, X.; Yu, R.; Li, H.; Li, Z. J. Am. Chem. Soc. 2009, 131, 17387.
11. Zhang, C.; Jiao, N. Angew. Chem., Int. Ed. 2010, 49, 6174.12. Zhou, Y.; Yin, S.; Gao, Y.; Zhao, Y.; Goto, M.; Han, L.-B. Angew. Chem., Int. Ed.
2010, 49, 6852.13. During the preparation of this manuscript, Mizuno et al reported a Cu-
catalyzed coupling reaction between dialkylphosphites and cyclic amides. SeeJin, X.; Yamaguchi, K.; Mizuno, N. Org. Lett. 2013, 15, 418.
