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Tetrahedron 70 (2014) 880e885

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Tetrahedron

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Base-promoted N-alkylation using formamides as the N-sourcesin neat water

Wen-Xin Chen a, Cai-Yun Zhang a, Li-Xiong Shao a,b,*

aCollege of Chemistry and Materials Engineering, Wenzhou University, Chashan University Town, Wenzhou, Zhejiang Province 325035,People’s Republic of ChinabCollege of Chemistry and Life Sciences, Zhejiang Normal University, Jinhua, Zhejiang Province 321004, People’s Republic of China

a r t i c l e i n f o

Article history:Received 8 October 2013Received in revised form 2 December 2013Accepted 10 December 2013Available online 25 December 2013

Keywords:CeN bond formationAlkyl electrophilesFormamidesWaterGreen chemistry

* Corresponding author. Tel./fax: þ86 577 86689300wzu.edu.cn, shaolix@163.com (L.-X. Shao).

0040-4020/$ e see front matter � 2013 Elsevier Ltd.http://dx.doi.org/10.1016/j.tet.2013.12.031

a b s t r a c t

An efficient catalyst-free, alternative method for the CeN bond formation reaction of alkyl electrophilesusing formamides as the N-sources was achieved under mild conditions. The reaction possesses theadvantages of a broad range of substrates scope and wide functional group tolerance. It should also benoted that this process was performed using the environmentally benign water as the sole solvent, andhigh yield can also be achieved in ten-gram scale.

� 2013 Elsevier Ltd. All rights reserved.

1. Introduction

Amines are important moieties in various natural products andimportant synthetic targets with biological, pharmaceutical, andmaterials interest, etc.1 Therefore, CeN bond formation reactionbecomes unambiguously one of the most important reactions inmodern organic synthesis. During the past years, transition metals,such as copper, palladium, and rhodium catalyzed Ullmann,2 andBuchwaldeHartwig3 reactions have been thoroughly investigated.However, although great progress has been achieved, the presenceof heavy transition metal impurities in the final products still re-mains a major problem in such CeN bond formation reactions.Other traditional methods for the synthesis of amine derivativesincluding the direct nucleophilic amination between amines andalkyl halides,4 reduction of amides,5 and the reductive aminationprotocol,6 etc., of which the direct nucleophilic attack of amines toalkyl halides is the most straightforward procedure. However, themajor synthetic problem for this method is the use of complicatedcatalytic systems4 and the competing over-alkylation and theprevention of over-alkylation seems to be unavoidable whenhighly reactive amines are used.7 In addition, the above methodsare also limited by long reaction time and use of toxic, volatile, and

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flammable organic solvents. Therefore, development of highlyselective amination in environmentally benign medium undermild conditions within short reaction time still remains muchroom.

Recently, in our continuing program on the N-heterocycliccarbeneePd(II)e1-methylimidazole [NHCePd(II)eIm] complexcatalyzed amination reactions,8 we have reported that amides canact as efficient N-sources in the reaction with aryl chlorides toafford the corresponding anilines in moderate to almost quanti-tative yields at room temperature within 6 h. In addition, pre-liminary investigation on the reaction mechanism showed thatKNR2R3 may be the key intermediates for this amination reaction(Scheme 1).8c

Scheme 1. NHC-Pd(II)-Im complex catalyzed reaction of aryl chlorides with amides.

Table 2Reactions of benzylic chlorides 1 with N-formylmorpholine 2a under the optimalconditions

Entrya 1 (R1) Temp (�C) Yieldb (%)

1 1b (4-Me) 50 3b, 602 1b 80 3b, 963 1c (3-Me) 50 3c, 804 1d (2-Me) 50 3d, 815 1e (4-OMe) 50 3e, 646 1e 80 3e, 907 1f (3-OMe) 50 3f, 908 1g (4-tBu) 50 3g, 229c 1g 100 3g, 9810 1h (4-CN) 50 3h, 9211 1i (4-NO2) 50 3i, 9812 1j (4-Cl) 50 3j, 7613 1j 80 3j, 9314 1k (2-Cl) 50 3k, 9615 1l (4-F) 50 3l, 9016 1m (2-CN) 50 3m, 9917 1n 50 3n, 70

W.-X. Chen et al. / Tetrahedron 70 (2014) 880e885 881

Therefore, we envisioned that KNR2R3 may also act as efficientintermediates for CeN bond formation in the reaction with alkylelectrophiles via normal SN2 pathway. Herein, we report our initialresults on the amination reaction between alkyl electrophiles, suchas alkyl halides, tosylates, and mesylates with formamides in neatwater under mild conditions, providing a greener alternative forthe formation of CeN bonds.

2. Results and discussion

Initial examinations were carried out using benzyl chloride 2a(0.8 mmol) and N-formylmorpholine 3a (2.0 equiv) as the sub-strates inwater (1.0mL) at room temperature for 3 h to find the bestbase (Table 1, entries 1e7). As can be seem from Table 1, 31e42%yields of the desired product 3a can be obtained in the presence ofstrong bases, such as KOH, NaOH, and CsOH, among which KOHgave the best result (Table 1, entries 1e3). In the presence of otherweak bases, such as K2CO3, Na2CO3, KHCO3, and NaHCO3, no re-action occurred (Table 1, entries 4e7). Further studies showed thatwhen the reaction temperature was elevated to 50 �C, product 3acan be achieved in 89% yield (Table 1, entry 8), which was notdisturbed when the temperature was further increased to 60 �C(Table 1, entry 9). Therefore, the optimal reaction conditions wereestablished as that shown in Table 1, entry 8.

Table 1Optimization for the reaction conditions

Entrya Base Temp (�C) Yieldb (%)

1 KOH rt 422 NaOH rt 313 CsOH rt 404 K2CO3 rt NR5 Na2CO3 rt NR6 KHCO3 rt NR7 NaHCO3 rt NR8 KOH 50 899 KOH 60 90

a Reaction conditions: 1a (0.8 mmol), 2a (2.0 equiv), base (3.0 equiv), H2O(1.0 mL), 3 h

b Isolated yields.

18 1n 80 3n, 87

a Otherwise specified, all reactions were carried out using 1 (0.8 mmol), 2a(1.6 mmol), KOH (2.4 mmol) in H2O (1.0 mL) for 3 h.

b Isolated yields.c The reaction time is 12 h.

With the optimal reaction conditions in hand, we then first in-vestigated the reactions of a variety of benzylic chlorides 1 with N-formylmorpholine 2a to test the generality. As can be seen fromTable 2, regardless of electron-donating or electron-withdrawinggroups substituted benzylic chlorides 1bem as the substrates, allreactions proceeded smoothly to give the desired products 3 inhigh to almost quantitative yields under appropriate temperaturewithin 3e12 h (Table 2, entries 1e16). 1-Chloromethylnaphthalene1n was also a suitable substrate and 87% yield of product 3n wasachieved at 80 �C (Table 2, entry 18). It seems that electron-donating groups, such as 4-Me and 4-OMe attached on the phe-nyl rings of substrates 1 will retard the reactions to some extent,and elevated temperature was necessary (Table 2, entries 1, 2, and5, 6). In addition, although 4-tert-butylbenzyl chloride 1g was nota good substrate under the optimal conditions, the correspondingproduct 3g can be obtained in 98% yield at elevated temperature(100 �C) (Table 2, entries 8 and 9). Sterically hindered substituents,such as 2-Me, 2-Cl, and 2-CN attached on the phenyl rings of

benzylic chlorides almost had no effect on the reactions, giving thecorresponding products 3d, 3k, and 3m in good to almost quanti-tative yields (Table 2, entries 4, 14, and 16).

Inspired by the above results, we also carried out the aminationreactions of benzylic chlorides 1with other formamides, such as N-formylpiperidine 2b, N,N-dimethylformamide 2c, N,N-dieth-ylformamide 2d, and N-methylformanilide 2e under the optimalconditions. As can be seen from Table 3, all reactions performedvery well to give the desired products 3 in good to almost quanti-tative yields. The electronic effect of the substituents on the ben-zylic chlorides 1 did not affect the reactions. For example, whetherelectron-donating groups, such as OMe and Me or electron-withdrawing groups, such as F and CN were attached on the phe-nyl rings of benzylic chlorides, similar good to almost quantitativeyields were achieved.

In addition, the reactions between benzylic chlorides 1 andsecondary amide 2f were also investigated under the optimalconditions. To our pleasure, all reactions took place smoothly togive the mono-aminated products 3aaeaj as the sole ones in goodto high yields, implying its high selectivity toward such mono-amination reactions (Table 4).

In order to further investigate the substrate scope for this re-action, long-chain bromides 1oeq and pseudohalides, such asbenzylic tosylates 1reu and mesylates 1vey were also tested forthe reactions with N-formylmorpholine 2a. As can be seen fromTable 5, all reactions can also give the desired products 3 in mod-erate to high yields under similar conditions.

To develop such amination reaction using formamides as the N-sources in environmentally benignwater toward industrial vantagepoint, ten-gram scale reaction between benzyl chloride 1a(80 mmol) and N-formylmorpholine 2a (160 mmol) was also car-ried out under the optimal conditions (Scheme 2). It was found thatpure product 3a (13.3 g, 94%) can be obtained by simple normal

Table 3Reactions of benzylic chlorides 1 with formamides 2

Entrya 1 (R1) 2 Yieldb (%)

1 1a (H) 2b 3o, 81

2 1b (4-Me) 2b 3p, 843 1f (3-OMe) 2b 3q, 994 1h (4-CN) 2b 3r, 985 1i (4-NO2) 2b 3s, 986 1l (4-F) 2b 3t, 81

7c 1f 2c 3u, 90

8c 1n 2c 3v, 91

9 1f 2d 3w, 92

10 1n 2d 3x, 85

11c 1h 2e 3y, 99

12 1e (4-OMe) 2e 3z, 80

a Otherwise specified, all reactions were carried out using 1 (0.8 mmol), 2(1.6 mmol), KOH (2.4 mmol) in H2O (1.0 mL) at 50 �C for 3 h.

b Isolated yields.c The reaction temperature was 80 �C.

Table 4Reactions of benzylic chlorides 1 with secondary amide 2f

Entrya 1 (R1) Temp (�C) Yieldb (%)

1 1c (3-Me) 80 3aa, 752 1d (2-Me) 80 3ab, 783 1f (3-OMe) 50 3ac, 934c 1g (4-tBu) 100 3ad, 795 1h (4-CN) 50 3ae, 906 1i (4-NO2) 50 3af, 927 1j (4-Cl) 50 3ag, 868 1k (2-Cl) 50 3ah, 939 1l (4-F) 50 3ai, 95

10 1n 80 3aj, 79

a Otherwise specified, all reactions were carried out using 1 (0.8 mmol), 2f(1.6 mmol), KOH (2.4 mmol) in H2O (1.0 mL) for 3 h.

b Isolated yields.c The time was 6 h.

Scheme 2. Reaction of benzyl chloride 1a with N-formylmorpholine 2a in ten-gramscale.

Table 5Reactions of long-chain bromides and pseudohalides 1with N-formylmorpholine 2a

Entrya 1 Time (h) Yieldb (%)

1 12 3ak, 70

2 12 3al, 84

3 12 3am, 90

4 3 3a, 75

5 3 3f, 85

6 3 3c, 86

7 3 3l, 89

8 3 3a, 90

9 3 3c, 93

10 3 3f, 90

11 3 3l, 80

a All reactions were carried out using 1 (0.8 mmol), 2a (1.6 mmol), KOH(2.4 mmol) in H2O (1.0 mL) at 100 �C.

b Isolated yields.

W.-X. Chen et al. / Tetrahedron 70 (2014) 880e885882

W.-X. Chen et al. / Tetrahedron 70 (2014) 880e885 883

work-up processes, such as extraction by ethyl acetate, dried overanhydrous Na2SO4, filtered, and concentrated under reducedpressure.

3. Conclusion

In conclusion, we have developed the catalyst-free, CeN bondformation reactions using formamides as the N-sources in envi-ronmentally benignwater under mild conditions. The reactions cantolerate a broad scope of substrates. Under the optimal conditions,all reactions performed very well to give the corresponding mono-aminated products in good to almost quantitative yields, enrichinga convenient and alternative method for the formation of CeNbonds. It should be also pointed out that the reaction can also beperformed in ten-gram scale under the same conditions.

4. Experimental section

4.1. General remarks

1H and 13C NMR spectra were recorded on a Bruker Avance-300or 500 MHz spectrometer for solution in CDCl3 with tetrame-thylsilane (TMS) as an internal standard; J-values are in Hertz.Commercially obtained reagents were used without further puri-fication. Flash column chromatography was carried out usingHuanghai 300e400 mesh silica gel at increased pressure.

4.2. Experimental procedure

4.2.1. General procedure for the reactions between (pseudo)halides 1and formamides 2. KOH (2.4 mmol), H2O (1.0 mL), (pseudo)halides1 (0.8 mmol), and formamides 2 (1.6 mmol) were successivelyadded into a reaction tube. Then the reaction mixture was stirredunder the conditions shown in Tables 1e5. After the reactions werecompleted, the mixture was extracted by ethyl acetate, dried overanhydrous Na2SO4, filtered, concentrated under reduced pressure,and purified by flash chromatography to give products 3.

4.2.2. Scale-up reaction between benzyl chloride 1a and N-for-mylmorpholine 2a. KOH (13.5 g, 240 mmol), H2O (100 mL), benzylchloride 1a (0.93 mL, 80 mmol), and N-formylmorpholine 2a(16 mL, 160 mmol) were successively added into a round-bottomflask. Then the reaction mixture was stirred at 50 �C for 3 h. Afterthe reaction was completed, the mixture was extracted by ethylacetate, dried over anhydrous Na2SO4, filtered, concentrated underreduced pressure to give product 3a in 94% yield.

4.2.2.1. Compound 3a.4a Colorless liquid. 1H NMR (300 MHz,CDCl3, TMS) d 7.31e7.23 (m, 5H), 3.68 (t, J¼4.5 Hz, 4H), 3.47 (s, 2H),2.42 (t, J¼4.5 Hz, 4H). 13C NMR (75MHz, CDCl3) d 137.6, 129.0, 128.1,127.0, 66.8, 63.3, 53.5.

4.2.2.2. Compound 3b.9 Yellow solid. 1H NMR (500 MHz, CDCl3,TMS) d 7.20 (d, J¼8.1 Hz, 2H), 7.11 (d, J¼8.1 Hz, 2H), 3.70 (t, J¼4.5 Hz,4H), 3.45 (s, 2H), 2.42 (t, J¼4.5 Hz, 4H), 2.33 (s, 3H). 13C NMR(125 MHz, CDCl3) d 136.5, 134.5, 129.1, 128.9, 66.9, 63.1, 53.5, 21.0.

4.2.2.3. Compound 3c.10 Colorless liquid. 1H NMR (300 MHz,CDCl3, TMS) d 7.21e7.04 (m, 4H), 3.69 (t, J¼4.5 Hz, 4H), 3.44 (s, 2H),2.42 (t, J¼4.5 Hz, 4H), 2.34 (s, 3H). 13C NMR (75 MHz, CDCl3) d 137.7,137.5, 129.8, 128.0, 127.8, 126.1, 66.8, 63.4, 53.6, 21.3.

4.2.2.4. Compound 3d.11 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.24 (d, J¼6.6 Hz, 1H), 7.16e7.10 (m, 3H), 3.67 (t,J¼4.5 Hz, 4H), 3.44 (s, 2H), 2.42 (t, J¼4.5 Hz, 4H), 2.36 (s, 3H). 13C

NMR (125 MHz, CDCl3) d 137.5, 135.8, 130.2, 129.8, 127.1, 125.4, 67.0,61.2, 53.6, 19.1.

4.2.2.5. Compound 3e.9 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.22 (d, J¼8.4 Hz, 2H), 6.84 (d, J¼8.4 Hz, 2H), 3.78 (s,3H), 3.69 (t, J¼4.5 Hz, 4H), 3.43 (s, 2H), 2.41 (t, J¼4.5 Hz, 4H). 13CNMR (125 MHz, CDCl3) d 158.7, 130.2, 129.6, 113.5, 66.9, 62.7, 55.1,53.4.

4.2.2.6. Compound 3f.12 Yellow liquid. 1H NMR (500MHz, CDCl3,TMS) d 7.22 (t, J¼7.8 Hz, 1H), 6.91e6.80 (m, 2H), 6.77 (dd, J¼0.9,2.4 Hz, 1H), 3.78 (s, 3H), 3.69 (t, J¼4.5 Hz, 4H), 3.46 (s, 2H), 2.43 (t,J¼4.5 Hz, 4H). 13C NMR (125MHz, CDCl3) d 159.5, 139.3, 129.0, 121.3,114.5, 112.4, 66.9, 63.2, 55.0, 53.5.

4.2.2.7. Compound 3g.13 Colorless liquid. 1H NMR (300 MHz,CDCl3, TMS) d 7.32 (d, J¼8.1 Hz, 2H), 7.23 (d, J¼8.1 Hz, 2H), 3.68 (t,J¼4.5 Hz, 4H), 3.45 (s, 2H), 2.42 (t, J¼4.5 Hz, 4H), 1.31 (s, 9H). 13CNMR (75 MHz, CDCl3) d 149.8, 134.5, 128.8, 125.0, 66.8, 63.0, 53.5,34.3, 31.3.

4.2.2.8. Compound 3h.14 Yellow solid. 1H NMR (500 MHz, CDCl3,TMS) d 7.61 (d, J¼8.1 Hz, 2H), 7.48 (d, J¼8.1 Hz, 2H), 3.71 (t, J¼4.5 Hz,4H), 3.56 (s, 2H), 2.45 (t, J¼4.5 Hz, 4H). 13C NMR (125 MHz, CDCl3)d 143.6, 131.9, 129.3, 118.7, 110.7, 66.7, 62.5, 53.4.

4.2.2.9. Compound 3i.11 Yellow solid. 1H NMR (500 MHz, CDCl3,TMS) d 8.17 (d, J¼8.5 Hz, 2H), 7.54 (d, J¼8.5 Hz, 2H), 3.73 (t, J¼4.5 Hz,4H), 3.61 (s, 2H), 2.47 (t, J¼4.5 Hz, 4H). 13C NMR (125 MHz, CDCl3)d 147.0, 145.8, 129.3, 123.3, 66.7, 62.2, 53.4.

4.2.2.10. Compound 3j.11 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.29e7.24 (m, 4H), 3.70 (t, J¼4.5 Hz, 4H), 3.45 (s, 2H),2.42 (t, J¼4.5 Hz, 4H). 13C NMR (125 MHz, CDCl3) d 136.3, 132.7,130.3, 128.3, 66.9, 62.5, 53.4.

4.2.2.11. Compound 3k.15 Yellow liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.48 (dd, J¼1.0, 7.5 Hz,1H), 7.34 (dd, J¼1.5, 8.0 Hz,1H),7.23 (td, J¼7.5, 1.5 Hz, 1H), 7.18 (td, J¼7.5, 2.0 Hz, 1H), 3.71 (t,J¼4.5 Hz, 4H), 3.61 (s, 2H), 2.51 (t, J¼4.5 Hz, 4H). 13C NMR (125MHz,CDCl3) d 135.3, 134.3, 130.7, 129.4, 128.1, 126.5, 66.9, 59.5, 53.5.

4.2.2.12. Compound 3l.11 Yellow solid. 1H NMR (500MHz, CDCl3,TMS) d 7.30e7.27 (m, 2H), 7.01e6.98 (m, 2H), 3.70 (t, J¼4.5 Hz, 4H),3.45 (s, 2H), 2.42 (t, J¼4.5 Hz, 4H). 13C NMR (125MHz, CDCl3) d 161.6(d, J¼243.8 Hz), 133.4 (d, J¼3.2 Hz), 130.5 (d, J¼7.9 Hz), 114.9 (d,J¼21.0 Hz), 66.9, 62.5, 53.4.

4.2.2.13. Compound 3m. Colorless liquid. 1H NMR (300 MHz,CDCl3, TMS) d 7.65 (d, J¼7.5 Hz, 1H), 7.57e7.53 (m, 2H), 7.39e7.28(m,1H), 3.71 (t, J¼4.5 Hz, 4H), 3.69 (s, 2H), 2.51 (t, J¼4.5 Hz, 4H). 13CNMR (75 MHz, CDCl3) d 141.9, 132.9, 132.5, 130.0, 127.6, 117.7, 113.0,66.8, 60.8, 53.3. MS (ESI): 203 [MþH]þ; HRMS (ESI): calcd forC12H15N2O [MþH]þ: 203.1179; found: 203.1169. IR (neat) n 2160,1454, 1351, 1267, 1115, 1008, 913, 865, 763, 740, 701 cm�1.

4.2.2.14. Compound 3n.13 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 8.28 (d, J¼7.8 Hz, 1H), 7.83e7.81 (m, 1H), 7.75 (dd,J¼2.7, 6.9 Hz, 1H), 7.51e7.35 (m, 4H), 3.86 (s, 2H), 3.66 (t, J¼4.8 Hz,4H), 2.47 (t, J¼4.8 Hz, 4H). 13C NMR (125MHz, CDCl3) d 133.8, 133.4,132.5, 128.3, 128.0, 127.5, 125.7, 125.6, 125.0, 124.7, 67.0, 61.5, 53.7.

4.2.2.15. Compound 3o.4a Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.32e7.23 (m, 5H), 3.47 (s, 2H), 2.37 (t, J¼4.8 Hz, 4H),1.58 (pent, J¼5.4 Hz, 4H), 1.46e1.42 (m, 2H). 13C NMR (125 MHz,CDCl3) d 138.4, 129.2, 128.0, 126.8, 63.8, 54.4, 25.9, 24.3.

W.-X. Chen et al. / Tetrahedron 70 (2014) 880e885884

4.2.2.16. Compound 3p.9 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.20 (d, J¼8.0 Hz, 2H), 7.11 (d, J¼8.0 Hz, 2H), 3.43 (s,2H), 2.36 (t, J¼4.8 Hz, 4H), 2.33 (s, 3H), 1.57 (pent, J¼5.5 Hz, 4H),1.43e1.42 (m, 2H). 13C NMR (125 MHz, CDCl3) d 136.2, 135.3, 129.1,128.6, 63.5, 54.3, 25.9, 24.3, 21.0.

4.2.2.17. Compound 3q.16 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.20 (t, J¼8.0 Hz, 1H), 6.90e6.89 (m, 2H), 6.78e6.76(m, 1H), 3.79 (s, 3H), 3.44 (s, 2H), 2.36 (t, J¼5.5 Hz, 4H), 1.56(pent, J¼5.5 Hz, 4H), 1.43 (t, J¼5.5 Hz, 2H). 13C NMR (125 MHz,CDCl3) d 159.5, 140.2, 128.9, 121.4, 114.5, 112.2, 63.7, 55.0, 54.4,25.9, 24.3.

4.2.2.18. Compound 3r.17 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.59 (d, J¼8.1 Hz, 2H), 7.45 (d, J¼8.1 Hz, 2H), 3.50 (s,2H), 2.36 (t, J¼4.5 Hz, 4H), 1.60e1.55 (m, 4H), 1.45e1.43 (m, 2H). 13CNMR (125 MHz, CDCl3) d 144.7, 131.8. 129.3, 119.0, 110.4, 63.0, 54.4,25.7, 24.0.

4.2.2.19. Compound 3s.18 Yellow liquid. 1H NMR (500 MHz,CDCl3, TMS) d 8.16 (d, J¼8.8 Hz, 2H), 7.51 (d, J¼8.8 Hz, 2H), 3.55 (s,2H), 2.38 (t, J¼5.5 Hz, 4H), 1.59 (pent, J¼5.5 Hz, 4H), 1.45 (t,J¼5.5 Hz, 2H). 13C NMR (125MHz, CDCl3) d 147.0, 129.6,129.4,123.4,62.9, 54.6, 25.9, 24.1.

4.2.2.20. Compound 3t.5b Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.27 (dd, J¼5.7, 8.7 Hz, 2H), 6.98 (t, J¼8.7 Hz, 2H), 3.42(s, 2H), 2.34 (t, J¼4.5 Hz, 4H), 1.60e1.52 (m, 4H), 1.46e1.42 (m, 2H).13C NMR (125 MHz, CDCl3) d 161.8 (d, J¼243.0 Hz), 134.3 (d,J¼3.1 Hz), 130.6 (d, J¼7.8 Hz), 114.8 (d, J¼21.0 Hz), 63.0, 54.3, 25.9,24.3.

4.2.2.21. Compound 3u.19 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.22 (t, J¼7.5 Hz,1H), 6.89 (d, J¼7.5 Hz, 2H), 6.81e6.79(m, 1H), 3.80 (s, 3H), 3.43 (s, 2H), 2.26 (s, 6H). 13C NMR (125 MHz,CDCl3) d 159.6, 139.9, 129.1, 121.4, 114.3, 112.8, 64.1, 55.1, 45.1.

4.2.2.22. Compound 3v.20 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 8.24 (d, J¼7.8 Hz, 1H), 7.83e7.75 (m, 2H), 7.51e7.36(m, 4H), 3.78 (s, 2H), 2.27 (s, 6H). 13C NMR (125MHz, CDCl3) d 134.6,133.8, 132.4, 128.3, 127.9, 127.3, 125.9, 125.5, 125.0, 124.4, 62.4, 45.5.

4.2.2.23. Compound 3w.21 Colorless liquid. 1H NMR (300 MHz,CDCl3, TMS) d 7.20 (t, J¼7.5 Hz, 1H), 6.92e6.89 (m, 2H), 6.78e6.75(m, 1H), 3.78 (s, 3H), 3.53 (s, 2H), 2.51 (q, J¼7.2 Hz, 4H), 1.03 (t,J¼7.2 Hz, 6H). 13C NMR (75 MHz, CDCl3) d 159.5, 141.6, 128.9, 121.1,114.2, 112.1, 57.4, 55.0, 46.6, 11.6.

4.2.2.24. Compound 3x.22 Colorless liquid. 1H NMR (300 MHz,CDCl3, TMS) d 8.46e8.42 (m, 1H), 7.94e7.83 (m, 2H), 7.60e7.48 (m,4H), 4.07 (s, 2H), 2.69 (q, J¼6.9 Hz, 4H), 1.17 (t, J¼6.9 Hz, 6H). 13CNMR (75 MHz, CDCl3) d 135.6, 133.8, 132.5, 128.3, 127.5, 127.0, 125.6,125.4, 125.2, 124.6, 56.0, 46.9, 11.5.

4.2.2.25. Compound 3y.23 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.59 (d, J¼8.5 Hz, 2H), 7.34 (d, J¼8.5 Hz, 2H), 7.23 (dd,J¼7.5, 9.0 Hz, 2H), 6.76 (t, J¼7.5 Hz, 1H), 6.71 (d, J¼9.0 Hz, 2H), 4.57(s, 2H), 3.04 (s, 3H). 13C NMR (125 MHz, CDCl3) d 148.9, 144.7, 132.4,129.3, 127.4, 118.8, 117.6, 112.6, 110.8, 56.8, 39.0.

4.2.2.26. Compound 3z.24 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.18 (t, J¼8.0 Hz, 2H), 7.11 (d, J¼8.5 Hz, 2H), 6.81 (d,J¼8.5 Hz, 2H), 6.73 (d, J¼8.0 Hz, 2H), 6.68 (t, J¼8.0 Hz, 1H), 4.41(s, 2H), 3.71 (s, 3H), 2.92 (s, 3H). 13C NMR (125 MHz, CDCl3)d 158.5, 149.7, 130.8, 129.1, 127.9, 116.5, 113.9, 112.5, 55.9, 55.1,38.2.

4.2.2.27. Compound 3aa.25 Yellow liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.20 (t, J¼7.5 Hz, 1H), 7.16e7.12 (m, 4H), 7.06 (d,J¼7.5 Hz, 1H), 6.69 (t, J¼7.5 Hz, 1H), 6.60 (dd, J¼8.5, 1.0 Hz, 2H), 4.22(s, 2H), 3.92 (br, 1H), 2.32 (s, 3H). 13C NMR (125MHz, CDCl3) d 148.2,139.3, 138.2, 129.2, 128.4, 128.2, 127.9, 124.5, 117.4, 112.8, 48.2, 21.3.

4.2.2.28. Compound 3ab.26 Yellow solid. 1H NMR (500 MHz,CDCl3, TMS) d 7.29 (d, J¼7.5 Hz, 1H), 7.18e7.13 (m, 5H), 6.70 (t,J¼7.5 Hz, 1H), 6.59 (d, J¼8.0 Hz, 2H), 4.21 (s, 2H), 3.77 (br, 1H), 2.34(s, 3H). 13C NMR (125 MHz, CDCl3) d 148.2, 136.9, 136.2, 130.3, 129.2,128.1, 127.3, 126.1, 117.4, 112.6, 46.3, 18.8.

4.2.2.29. Compound 3ac.27 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.24 (t, J¼7.5 Hz, 1H), 7.17 (dd, J¼7.0, 8.5 Hz, 2H),6.95e6.92 (m, 2H), 6.80 (dd, J¼2.0, 8.5 Hz,1H), 6.73 (t, J¼7.0 Hz,1H),6.65 (d, J¼7.5 Hz, 2H), 4.29 (s, 2H), 3.78 (s, 3H). 13C NMR (125 MHz,CDCl3) d 159.8, 147.6, 140.7, 129.6, 129.2, 119.8, 118.0, 113.2, 113.1,112.7, 55.2, 48.5.

4.2.2.30. Compound 3ad.28 White solid. 1H NMR (500 MHz,CDCl3, TMS) d 7.36 (d, J¼8.5 Hz, 2H), 7.29 (d, J¼8.5 Hz, 2H), 7.16 (t,J¼8.0 Hz, 2H), 6.70 (t, J¼8.0 Hz, 1H), 6.62 (d, J¼8.0 Hz, 2H), 4.26 (s,2H), 3.94 (br, 1H), 1.31 (s, 9H). 13C NMR (125 MHz, CDCl3) d 150.1,148.2, 136.3, 129.2, 127.3, 125.5, 117.4, 112.7, 47.9, 34.4, 31.3.

4.2.2.31. Compound 3ae.29 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.56 (d, J¼8.5 Hz, 2H), 7.44 (d, J¼8.5 Hz, 2H), 7.15 (t,J¼7.5 Hz, 2H), 6.72 (t, J¼7.5 Hz, 1H), 6.56 (d, J¼7.5 Hz, 2H), 4.39 (s,2H), 4.15 (br, 1H). 13C NMR (125 MHz, CDCl3) d 147.3, 145.3, 132.3,129.2, 127.6, 118.8, 118.0, 112.8, 110.7, 47.6.

4.2.2.32. Compound 3af.24 Yellow liquid. 1H NMR (500 MHz,CDCl3, TMS) d 8.17 (d, J¼8.8 Hz, 2H), 7.52 (d, J¼8.8 Hz, 2H), 7.16 (dd,J¼9.0, 7.5 Hz, 2H), 6.74 (t, J¼7.5 Hz, 1H), 6.58 (dd, J¼9.0, 1.0 Hz, 2H),4.46 (s, 2H). 13C NMR (125 MHz, CDCl3) d 147.4, 147.2, 147.1, 129.3,127.7, 123.8, 118.2, 112.9, 47.6.

4.2.2.33. Compound 3ag.26 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.26e7.21 (m, 4H), 7.15e7.12 (m, 2H), 6.69 (t, J¼7.5 Hz,1H), 6.55 (d, J¼7.5 Hz, 2H), 4.21 (s, 2H), 3.96 (br, 1H). 13C NMR(125 MHz, CDCl3) d 147.7, 137.9, 132.7, 129.2, 128.65, 128.61, 117.7,112.8, 47.5.

4.2.2.34. Compound 3ah.26 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.36e7.32 (m, 2H), 7.16e7.12 (m, 4H), 6.69 (t, J¼7.5 Hz,1H), 6.55 (d, J¼7.5 Hz, 2H), 4.36 (s, 2H), 4.06 (br, 1H). 13C NMR(125 MHz, CDCl3) d 147.7, 136.6, 133.1, 129.4, 129.2, 128.9, 128.3,126.9, 117.7, 112.8, 45.8.

4.2.2.35. Compound 3ai.26 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 7.28e7.25 (dd, J¼8.5, 5.5 Hz, 2H), 7.14 (dd, J¼8.5,7.5 Hz, 2H), 6.98 (t, J¼8.5 Hz,1H), 6.57 (d, J¼8.0 Hz, 2H), 4.22 (s, 2H),3.94 (br, 1H). 13C NMR (125 MHz, CDCl3) d 162.0 (d, J¼243.5 Hz),147.9, 135.0 (d, J¼3.1 Hz), 129.2, 128.9 (d, J¼8.0 Hz), 117.7, 115.4 (d,J¼21.3 Hz), 112.8, 47.5.

4.2.2.36. Compound 3aj.25 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 8.03e8.01 (m, 1H), 7.86e7.84 (m, 1H), 7.77 (d,J¼8.0 Hz, 1H), 7.49e7.46 (m, 3H), 7.38 (t, J¼8.0 Hz, 1H), 7.17 (t,J¼7.5 Hz, 2H), 6.72 (t, J¼7.5 Hz, 1H), 6.62 (d, J¼7.5 Hz, 2H), 4.65 (s,2H), 3.90 (s, 1H). 13C NMR (125 MHz, CDCl3) d 148.1, 134.2, 133.8,131.4, 129.3, 128.7, 128.1, 126.3, 125.9, 125.8, 125.5, 123.5, 117.5,112.6, 46.3.

4.2.2.37. Compound 3ak.4c Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 3.73 (t, J¼4.5 Hz, 4H), 2.45 (t, J¼4.5 Hz, 4H), 2.33 (t,

W.-X. Chen et al. / Tetrahedron 70 (2014) 880e885 885

J¼7.5 Hz, 2H), 1.49 (pent, J¼7.5 Hz, 2H), 1.33e1.27 (m, 8H), 0.88 (t,J¼7.0 Hz, 3H). 13C NMR (125MHz, CDCl3) d 66.8, 59.1, 53.6, 31.7, 29.1,27.3, 26.4, 22.5, 13.9.

4.2.2.38. Compound 3al.30 Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 3.73 (t, J¼4.5 Hz, 4H), 2.45 (t, J¼4.5 Hz, 4H), 2.33 (t,J¼7.5 Hz, 2H), 1.50e1.46 (m, 2H), 1.33e1.27 (m, 6H), 0.88 (t,J¼7.0 Hz, 3H). 13C NMR (125MHz, CDCl3) d 66.8, 59.1, 53.7, 31.7, 27.1,26.4, 22.5, 13.9.

4.2.2.39. Compound 3am.4c Colorless liquid. 1H NMR (500 MHz,CDCl3, TMS) d 3.72 (t, J¼4.5 Hz, 4H), 2.44 (t, J¼4.5 Hz, 4H), 2.33 (t,J¼7.5 Hz, 2H), 1.50e1.47 (m, 2H), 1.29e1.28 (m, 10H), 0.88 (t,J¼7.0 Hz, 3H). 13C NMR (125 MHz, CDCl3) d 66.8, 59.1, 53.6, 31.7,29.4, 29.1, 27.4, 26.4, 22.5, 13.9.

Acknowledgements

Financial support from the Natural Science Foundation of Zhe-jiang Province (No. LY12B02012) and the Open Research Fund ofTop Key Discipline of Chemistry in Zhejiang Provincial Colleges andKey Laboratory of the Ministry of Education for Advanced CatalysisMaterials (Zhejiang Normal University) (No. ZJHX201305) is greatlyappreciated.

Supplementary data

Supplementary data associated with this article can be found inthe online version, at http://dx.doi.org/10.1016/j.tet.2013.12.031.These data include MOL files and InChiKeys of the most importantcompounds described in this article.

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