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One-Step Palladium- and Phenylsilane-ActivatedAmidation of Solid-Supported Ally Esters

One-Step Palladium- and Phenylsilane-ActivatedAmidation of Solid-Supported Ally Esters

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36



ONE-STEP PALLADIUM- AND PHENYLSILANE-ACTIVATED AMIDATION

Building blocks

O



O

H2N



R1



O



OH



O

OH



OH

H2N



OH



NH2



NH2



3,6,9



2,5,8



1,4,7

Building blocks

R2NHR3:

N

1



Pyrrolidine



2



Morpholine



3



Diethylamine



4



Tetrahydrofurylamine



5



NAcetylethylenediamine



9



Tyramine



10



Cyxlohexylamine



11



Benzylamine



12



4(Aminomethyl)pyridine



NH2 13



4-Bromobenzylamine



O

N

H3C



CH3



N



OH



H2N



H2 N



H 2N



O



Phenethylamine



6



H2N

O



N



H2N



H2N

1-(3Aminopropyl)imidazole



8



4-(2HN

Aminoethyl)morpholine 2



14



N



N



1



1.1.1



NH2



H2N



Br



CH3



7



1.1



N



N 15



O



16



Aniline



H2N



p-Anisidine



H2N



4-Nitroaniline



H2N



CH3

O

O

N+

O−



PROCEDURE



General Procedure for the Synthesis of Resin 4–6



Route 1



PL-FMP resin (2-(4-formyl-3-methoxyphenoxy)ethyl polystyrene HL, loading: 1.00 mmol/g substitution, 100–200 mesh, Novabiochem) was swollen

with DMF (20 mL/mmol) (note 1) at room temperature, and then trimethyl

orthoformate (TMOF, 5 mL/mmol), 2 equiv. of amino allyl ester (note 2),



PROCEDURE



37



and 1.5 equiv. of DIEA were added into the resin mixture. The reaction

was allowed to agitate overnight at room temperature. After that, the reaction was washed with DMF (2×), and then a solution of AcOH in DMF

(10 mL/mmol of 2:98 AcOH:DMF) and 4 equiv. of NaB(OAc)3 H were

added. The reaction mixture was allowed to agitate for 3 h. The reaction

was sequentially washed with DMF (2×), THF (2×), and DCM (3×), and

then additional DCM (10 mL/mmol) was added. To the resin mixture in

DCM were added 5 equiv. of benzoyl chloride and 10 equiv. of DIEA at

room temperature. After 30 min of shaking, the product resin was washed

with the same sequence as above, finishing with a MeOH wash before drying under vacuum at room temperature overnight. The resin was finally

dried under a flow of argon. The loading of the resin was checked by TFA

cleavage, based on its purity and yield (note 3).



1.1.2



Route 2



The acid resins 1–3 (2 g, ∼1.0 mmol/g substitution, note 4) were swollen

with 15 mL of DMF at room temperature for 5 min, and 5 equiv. of allyl

bromide and 5 equiv. of CsF were added into the resin mixture. The reaction

was allowed to agitate overnight. After that, the reaction was washed with

DMF (2×), THF (3×), and DCM (4×). The allyl ester resins 4–6 were

then dried under high vacuum and checked by TFA cleavage. The products

had purities in the range 90–96% and were obtained in yields of 96–100%

(note 5).



1.2



General Procedure for the Synthesis of Resins 7–9



A 48-compound array was constructed from a matrix of three R2 allyl esters

crossed with 16 R3 amines and anilines. The process was carried out using

commercially available IRORI MicroKans [1] and employed Rf-encoded

split pool synthesis technology (note 6). The reactions were performed

on a 0.02-mmol scale (0.02 mmol per microkan) in anhydrous DCM at

room temperature for 24 h with 10 equiv. of amines or anilines, 20 equiv.

of PhSiH3 , and 0.05 equiv. of Pd(PPh3 )4 . After that, the microkans were

pooled together and washed with DMF (2×), THF (3×), and DCM (4×). All

microkans were dried under high vacuum pump and sorted into an IRORI

cleavage station. The final products 10 were cleaved into 96-well plates

using a solution of 30% TFA in DCM (2 mL per microkan). The solvent was

removed under high vacuum, and the products were directly analyzed by



38



ONE-STEP PALLADIUM- AND PHENYLSILANE-ACTIVATED AMIDATION



TABLE 1



Purity and Yield Data for 48-Compound Automation Library

Product Characterization (10)a



Entry

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

16

17

18

19

20

21

22

23

24

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

41

42



Resin



Amines or Anilines



MH+



Purity (%)



Yield (%)



4

4

4

4

4

4

4

4

4

4

4

4

4

4

4

4

5

5

5

5

5

5

5

5

5

5

5

5

5

5

5

5

6

6

6

6

6

6

6

6

6

6



Pyrrolidine

Morpholine

Diethylamine

Tetrahydrofurylamine

N -Acetylethylenediamine

Phenethylamine

1-(3-Aminopropyl)imidazole

4-(2-Aminoethyl)morpholine

Tyramine

Cyclohexylamine

Benzylamine

4-(Aminomethyl)pyridine

4-Bromobenzylamine

Aniline

p-Anisidine

4-Nitroaniline

Pyrroline

Morpholine

Diethylamine

Tetrahydrofurylamine

N -Acetylethylenediamine

Phenethylamine

1-(3-Aminopropyl)imidazole

4-(2-Aminoethyl)morpholine

Tyramine

Cyclohexylamine

Benzylamine

4-(Aminomethyl)pyridine

4-Bromobenzylamine

Aniline

p-Anisidine

4-Nitroaniline

4-Nitroaniline

Pyrroline

Morpholine

Diethylamine

Tetrahydrofurylamine

N -Acetylethylenediamine

Phenethylamine

1-(3-Aminopropyl)imidazole

4-(2-Aminoethyl)morpholine

Tyramine



309.20

325.17

311.25

339.24

340.20

359.26

363.30

368.30

375.30

337.25

345.22

346.23

424.14



90

99

27(53b)

90

72

95

77

84

86

20(67b)

85

87

95

Only acid

Only acid

Only acid

86

94

7 (14b)

97

98

86

94

97

86

52(73b)

85

89

85

Only acid

Only acid

Only acid

100

97

37(67b)

99

100

98 (0c)

99

99

98

92



73

72

74

68

68

64

65

49

61

67

50

62

55

0

0

0

71

47

56

43

42

61

54

55

35

64

64

38

51

0

0

0

56

83

71

69

54

92 (0c)

91

80

58

56



315.20

331.23

317.37

345.40

346.10

365.33

369.35

374.10

381.33

343.32

351.29

352.29

430.13



247.10

263.20

249.24

277.29

278.10

297.10

301.26

306.10

313.10

275.32



(continued )



DISCUSSION



TABLE 1



39



(Continued )

Product Characterization (10)a



Entry

43

44

45

46

47

48



Resin



Amines or Anilines



MH+



Purity (%)



Yield (%)



6

6

6

6

6

6



Cyclohexylamine

Benzylamine

4-(Aminomethyl)pyridine

4-Bromobenzylamine

Aniline

p-Anisidine



283.26

284.27

362.17



99

100

99

Only acid

Only acid

Only acid



72

66

52

0

0

0



a Overall isolated yield after cleavage. All products were analyzed by LC-MS and flow 1 H

NMR spectroscopy.

b ◦

60 C in DMF for 24 h.

c Without the addition of both PhSiH and Pd(Ph P) , or one of them.

3

3 4



flow nuclear magnetic resonance (NMR) and liquid chromatography–mass

spectrometry (LC-MS). The overall yield was calculated based on the initial

loading of the resins.

2 DISCUSSION

An allyl ester is a commonly utilized protecting group that can be used

with many acid- or base-labile linkers [2]. The procedure described here

illustrates a practical and efficient method using a Pd(0)/PhSiH3 system to

convert resin-bound allyl esters to amides [3, 4]. The reaction can typically

be carried out in a single step at room temperature. A systematic investigation of amine and aniline inputs has demonstrated that, in general, primary

amines and unhindered secondary amines give excellent yields of amides

with high purity. Additional experiments have indicated that the best solvent for this method is DMF or NMP. Furthermore, the reaction is typically

carried out using 5 equiv. of amine and 10 equiv. of PhSiH3 .

Direct analyses of the cleaved products (HPLC and LC-MS) indicated

that all reactions proceeded cleanly, with the major side product being

the unprotected carboxylic acid. With an increase in steric congestion of

the amine component, more severe conditions were required to drive reactions to completion (i.e., higher reaction temperatures and the use of additional equivalents of amines). Reactions with anilines were disappointing,

with few amide products obtained and high recovery of the unprotected

acids observed even under more forcing reaction conditions. No product

was formed in the reaction without addition of both PhSiH3 and catalytic



40



ONE-STEP PALLADIUM- AND PHENYLSILANE-ACTIVATED AMIDATION



Pd(Ph3 P)4 reagents, as shown in our control experiment, entry 38. Solidphase array results are provided in Table 1.

This methodology has been recently used in a solid-phase sequence to

prepare a 10,000-compound library directed at the identification of protease

inhibitors.

NOTES

1. Dimethylformamide (DMF), trimethyl orthoformate (TMOF), amino N,N -diisopropylethylamine (DIEA), acetic acid (AcOH), sodium triacetoxy-borohydride

(NaB(OAc)3 H), tetrahydrofuran (THF), dichloromethane (DCM), benzoyl chloride,

trifluoroacetic acid (TFA), allyl bromide, cesium fluoride (CsF), phenylsilane (PhSiH3 ),

tetrakis(triphenylphosphine)palladium(0) (Pd(PPh3 )4 ), and all the diversity amines were

purchased from Aldrich Chemical Company, Inc.

2. Amino allyl esters were synthesized according to the following procedure: to a solution of

amino acid (NH2 R1 COOH) in allyl alcohol (5 mL/mmol) was added chlorotrimethylsilane

(TMSCl, 5 equiv.). The reaction was stirred overnight and concentrated. The product was

dried for three days under high vacuum at room temperature, and then loaded onto the

resin without purification.

3. The cleaved products had purities in the range 95–100% by high performance liquid

chromatography (HPLC), and the resin loadings were 0.8–0.9 mmol/g.

4. The resin-bound N -benzoyl carboxylic acids (1–3) could be easily prepared through

standard procedures.

5. A general method to protect carboxylic acids as their allyl ester group on solid support

is described in Route 2.

6. The synthesis, cleavage, and analysis can be carried out manually or automated using

combichem processes.



REFERENCES

1. Lee H, Sarko CR. Analysis of a combinatorial library synthesized using a split-and-pool

Irori MicroKan method for development and production. In: Kyranos JN High throughput

analysis for early drug discovery. San Diego, CA: Elsevier; 2004. pp. 37–56.

2. Guib´e F. Allylic protecting groups and their use in a complex environment—Part II:

Allylic protecting groups and their removal through catalytic palladium π -allyl methodology. Tetrahedron 1998;54(13):2967–3042.

3. Ruan Z, Lawrence M, Cooper C. Phenylsilane as an active amidation reagent for the

preparation of carboxamides and peptides. Tetrahedron Lett 2006;47(43):7649–7651.

4. Dessolin M, Guillerez M-G, Thieriet N, Guib´e F, Loffet A. New allyl group acceptors for

palladium catalyzed removal of allyic protections and transacylation of allyl carbamates.

Tetrahedron Lett 1995;36(32):5741–5744.



CHAPTER 4

SOLID-PHASE REACTIONS OF POLYMER-BOUND

ARENESULFONATES WITH ARYL GRIGNARD REAGENTS

Kwangyong Park and Chul-Hee Cho

School of Chemical Engineering and Materials Science, Chung-Ang University,

Dongjak-Gu, Seoul, Korea



Library synthesis route



Building blocks



Solid-Phase Organic Syntheses, Volume 2: Solid-Phase Palladium Chemistry, First Edition.

Edited by Peter J. H. Scott.

© 2012 John Wiley & Sons, Inc. Published 2012 by John Wiley & Sons, Inc.



41



42



SOLID-PHASE REACTIONS OF POLYMER-BOUND ARENESULFONATES



TABLE 1



Preparation of Polymer-Bound Sulfonates 2a



Component

Loading level of 2 (mmol/g)

Yield (%)

a



a



b



c



d



0.630

82



0.652

84



0.589

78



0.639

85



The isolated yields of arenesulfonate resin 2 were determined by elemental analysis (EA).



1



PROCEDURE



1.1 General Procedure for the Preparation of Polymer-Bound

Arenesulfonates (2)

The hydroxyethylmethyl resin 1 (5.0 g, 4.55 mmol; note 1) and Et3 N

(3.1–3.3 mL, ∼23 mmol) were swollen in CH2 Cl2 (50 mL). A solution

of appropriate arenesulfonyl chloride (∼18 mmol) in CH2 Cl2 (30 mL) was

added at ice bath temperature. After stirring for 48 h at room temperature, the resulting resin was isolated by filtration through a sintered glass

filter and rinsed with CH2 Cl2 (×3), MeOH (×3), 0.1 N HCl (×2), water

(×3), and MeOH (×3). The resin was dried under vacuum to give the

desired arenesulfonate resin 2 (note 2, Table 1). Before using the resins

2 for the next step, they were treated with methyl iodide (0.85–0.90 mL,

∼14 mmol) and Et3 N (2.2–2.3 mL, ∼16 mmol) for 3 h to protect the

remaining hydroxy groups as methoxy groups.



1.2 General Procedure for the Preparation of Polymer-Bound

Biphenylsulfonates (4)

The 4-bromobenzenesulfonate resin 2d (2.5 g, 1.6 mmol) was swollen in

DME (38 mL) for 5 min. The reaction was then treated with Pd(PPh3 )4

(172–174 mg, ∼0.15 mmol; note 3), 2.0 M aqueous Na2 CO3 (1.6 mL),

and arylboronic acid (∼5.3 mmol) in a small amount of EtOH/DME at

room temperature. After 30 h of heating, 30% H2 O2 (0.10 mL) was added

to the mixture at room temperature, and the reaction mixture was stirred for

10 min. The resulting resin 4 was filtered and washed several times with

MeOH and CH2 Cl2 . The resin was dried under vacuum to give the desired

biphenylsulfonate resin 4.



DISCUSSION



TABLE 2

Component

2a

2b

2c

4a

4b

a



43



Solid-Phase Synthesis of Biphenyls 3 and Terpheyls 5a

a



b



c



d



e



3a (68%)

3e (73%)

3i (66%)

5a (59%)b

5b (57%)b



3b (72%)

3f (78%)

3j (70%)

5b (63%)b

5e (58%)b



3c (62%)

3g (64%)









3d (70%)

3h (81%)



5c (62%)b

5f (55%)b









5d (58%)b

5g (66%)b



Isolated yields based on the loading level of 2a–2c.

yields of the isolated products based on the loading level of 2d.



b Overall



1.3 General Procedure for the Cross-Coupling Reaction of

Polymer-Bound Arenesulfonates (2) or Biphenylsulfonates (4) with

Aryl Grignard Reagents

To a stirred solution of polymer-bound sulfonate 2 or 4 (0.26 mmol) and

dppfNiCl2 (53–54 mg, ∼0.08 mmol; note 4) in THF (8.0 mL) was slowly

added appropriate aryl Grignard reagent (∼2.6 mmol) at room temperature

under Ar atmosphere. The reaction mixture was heated at reflux for 24 h (2)

or 15 h (4) and cooled to room temperature. Additional Grignard reagent

(∼1.3 mmol) was added to the solution. The mixture was heated at reflux

for 24 h (2) or 15 h (4) and cooled to room temperature. The reaction

mixture was filtered and washed several times with Et2 O. The resulting

organic solution was treated with 1.0% aqueous HCl, water, and brine; dried

over MgSO4 ; and concentrated in vacuo. The crude product was purified

by either column chromatography or preparative high performance liquid

chromatography (HPLC) using ethyl acetate/hexane as the eluent system to

afford the corresponding product 3 or 5 (note 5, Table 2).

2 DISCUSSION

To accommodate the growing number of reactions on solid supports, new

linker units continue to be reported in this chapter. At present, linker units

are typically grouped according to the functionality left at the “cleavage

site” in the target molecule and are normally designed as traditional

(polar functionality remains after the cleavage) or traceless (hydrogen

residue remains after the cleavage) linkers. The polar functionality left

from traditional linkers eventually limits the scope of investigating the



44



SOLID-PHASE REACTIONS OF POLYMER-BOUND ARENESULFONATES



structure/activity relationships. Therefore, the development of traceless

linker strategies that enable the release of unfunctionalized hydrocarbons

from the polymer support represents an important challenge in SPOS [1].

For this reason, the traceless cleavage of C–Si and C–N bonds has been

extensively studied, and traceless strategies based on the cleavage of C–S

bonds have also been investigated [2]. Traceless multifunctional cleavage

linker systems, allowing the introduction of certain atoms or molecular

fragments at the original linking site during the cleavage step, are of

particular interest, as they allow for the additional diversification of the

library with the release of the target compound [3].

Here, we describe that the nickel-catalyzed reactions between

polymer-bound arenesulfonates and aryl Grignard reagents produce

unfunctionalized biphenyls and terphenyls in good yields through reductive

cleavage/coupling of the C–S bond. Arenesulfonates 2 underwent the

cleavage/cross-coupling reactions with 15 equiv. of Grignard reagents in the

presence of dppfNiCl2 to produce the desired unfunctionalized biphenyls 3

in good isolated yields within 48 h. Polymer-bound biphenylsulfonates 4

were also allowed to undergo the reaction to produce terphenyls 5 [4].

The more conjugated biphenylsulfonates 4 showed better reactivity toward

the nickel catalyst than the benzenesulfonates 2a and 2b. This traceless

multifunctional cleavage strategy appears to be a powerful tool for the

preparation of nonfunctionalized hydrocarbon libraries [5].

WASTE DISPOSAL INFORMATION

All toxic materials were disposed of in accordance with Prudent Practices

in the Laboratory (Washington, D.C.: National Academy Press, 1995).



APPENDIX

4-tert-Butylbiphenyl (3a) was prepared by the reaction of 3a (0.414 g,

0.261 mmol) with 4a (3.92 mL, 3.91 mmol) in the presence of dppfNiCl2

(53.4 mg, 0.078 mmol). The crude compound was purified by preparative

HPLC (CH3 CN) to give 5a (37.6 mg, 68.5%) as a white solid: melting

point (mp) 46–47◦ C (uncorrected); 1 H NMR (300 MHz, CDCl3 ) δ = 1.36

(s, 9H), 7.32 (t, J = 7.30 Hz, 1H), 7.39–7.49 (m, 4H), 7.52–7.61 (m, 4H);

13

C NMR (75 MHz, CDCl3 ) δ = 31.5 (×3), 34.6, 126.0 (×2), 127.1 (×2),

127.2, 127.3 (×2), 129.0 (×2), 138.6, 141.4, 150.6; HRMS (EI, 70 eV)

calcd for C16 H18 (M+ ), 210.1409, found 210.1405.



APPENDIX



45



4-Methyl-4 -tert-butylbiphenyl (3b) was prepared by the reaction of

3a (0.414 g, 0.261 mmol) with 4b (1.96 mL, 3.91 mmol) in the presence

of dppfNiCl2 (53.4 mg, 0.078 mmol). The crude compound was purified

by preparative HPLC (CH3 CN) to give 5b (42.1 mg, 71.8%) as a white

solid: mp 75–76◦ C (uncorrected); 1 H NMR (300 MHz, CDCl3 ) δ = 1.36

(s, 9H), 2.39 (s, 3H), 7.24 (d, J = 8.48 Hz, 2H), 7.45 (d, J = 8.73 Hz,

2H), 7.49 (d, J = 8.48 Hz, 2H), 7.53 (d, J = 8.73 Hz, 2H); 13 C NMR

(75 MHz, CDCl3 ) δ = 21.2, 31.5 (×3), 34.6, 125.9 (×2), 126.9 (×2), 127.1

(×2), 129.7 (×2), 137.0, 138.5, 138.6, 150.2; HRMS (EI, 70 eV) calcd for

C17 H20 (M+ ), 224.1565, found 224.1546.

4-tert-Butyl-4 -methoxybiphenyl (3c) was prepared by the reaction of

3a (0.414 g, 0.261 mmol) with 4c (7.84 mL, 3.91 mmol) in the presence

of dppfNiCl2 (53.4 mg, 0.078 mmol). The crude compound was purified

by column chromatography (Et2 O:n-hexane = 1:10) to give 5c (38.8 mg,

61.9%) as ivory solid: mp 127–128◦ C (uncorrected); 1 H NMR (300 MHz,

CDCl3 ) δ = 1.36 (s, 9H), 3.84 (s, 3H), 6.97 (d, J = 8.9 Hz, 2H), 7.44

(d, J = 8.73 Hz, 2H), 7.50 (d, J = 8.73 Hz, 2H); 7.53 (d, J = 8.9 Hz,

2H); 13 C NMR (75 MHz, CDCl3 ) δ = 31.5, 34.6 (×3), 55.4, 114.3 (×2),

125.9 (×2), 126.6 (×2), 128.3 (×2), 133.9, 138.2, 149.9, 159.3; HRMS

(EI, 70 eV) calcd for C17 H20 O (M+ ), 240.1514, found 240.1510.

3,5-Dimethyl-4 -tert-butylbiphenyl (3d) was prepared by the reaction

of 3a (0.414 g, 0.261 mmol) with 4d (7.84 mL, 3.91 mmol) in the presence

of dppfNiCl2 (53.4 mg, 0.078 mmol). The crude compound was purified

by preparative HPLC (CH3 CN) to give 5d (43.3 mg, 69.6%) as a colorless

oil; 1 H NMR (300 MHz, CDCl3 ) δ = 1.34 (s, 9H), 2.35 (s, 6H), 6.95 (s,

1H), 7.19 (s, 2H), 7.43 (d, J = 8.56 Hz, 2H), 7.50 (d, J = 8.73 Hz, 2H);

13

C NMR (75 MHz, CDCl3 ) δ = 21.5 (×2), 31.5 (×3), 34.6, 125.2 (×2),

125.8 (×2), 127.1 (×2), 128.9 (×2), 138.4, 138.8, 141.4, 150.3; HRMS

(EI, 70 eV) calcd for C18 H22 (M+ ), 238.1721, found 238.1711.

2-Phenylnaphthalene (3e) was prepared by the reaction of 3b (0.400 g,

0.261 mmol) with 4a (3.92 mL, 3.91 mmol) in the presence of dppfNiCl2

(53.4 mg, 0.078 mmol). The crude compound was purified by column chromatography (Et2 O:n-hexane = 1:10) to give 5e (38.8 mg, 72.8%) as a

white solid: mp 108–109◦ C (uncorrected); 1 H NMR (300 MHz, CDCl3 )

δ = 7.33–7.42 (m, 1H), 7.43–7.53 (m, 4H), 7.69–7.77 (m, 3H), 7.82–7.93

(m, 3H), 8.04 (s, 1H); 13 C NMR (75 MHz, CDCl3 ) δ = 125.9, 126.1, 126.2,

126.6, 127.6, 127.7 (×2), 127.9, 128.5, 128.7, 129.1 (×2), 132.9, 134.0,

138.9, 141.4; HRMS (EI, 70 eV) calcd for C16 H12 (M+ ), 204.0939, found

204.0917.

2-p-Tolylnaphthalene (3f) was prepared by the reaction of 3b (0.400 g,

0.261 mmol) with 4b (1.96 mL, 3.91 mmol) in the presence of dppfNiCl2



46



SOLID-PHASE REACTIONS OF POLYMER-BOUND ARENESULFONATES



(53.4 mg, 0.078 mmol). The crude compound was purified by column chromatography (Et2 O:n-hexane = 1:10) to give 5f (44.3 mg, 77.7%) as a white

solid: mp 89–91◦ C (uncorrected); 1 H NMR (300 MHz, CDCl3 ) δ = 2.39

(s, 3H), 7.33 (d, J = 7.89 Hz, 2H), 7.49–7.54 (m, 2H), 7.71 (d, J =

8.23 Hz, 2H), 7.83 (dd, J = 1.84 Hz, 1H), 7.91–7.99 (m, 3H), 8.15 (s,

1H); 13 C NMR (75 MHz, CDCl3 ) δ = 21.2, 125.7, 125.8, 126.0, 126.5,

127.5 (×2), 127.9 (×2), 128.4, 128.6, 129.9 (×2), 132.8, 134.0, 137.4,

138.5, 138.8; HRMS (EI, 70 eV) calcd for C17 H14 (M+ ), 218.1096, foundp

218.1066.

2-p-Methoxyphenylnaphthalene (3g) was prepared by the reaction of

3b (0.400 g, 0.261 mmol) with 4c (7.84 mL, 3.91 mmol) in the presence

of dppfNiCl2 (53.4 mg, 0.078 mmol). The crude compound was purified

by column chromatography (Et2 O:n-hexane = 1:10) to give 5g (39.0 mg,

63.7%) as a white solid: mp 139–140◦ C (uncorrected); 1 H NMR (300 MHz,

CDCl3 ) δ = 3.88 (s, 3H), 7.03 (d, J = 8.72 Hz, 2H), 7.42–7.53 (m, 2H),

7.67 (d, J = 8.73 Hz, 2H), 7.72 (dd, J = 1.85 Hz, 1H), 7.84–7.91 (m,

3H), 7.99 (s, 1H); 13 C NMR (75 MHz, CDCl3 ) δ = 55.5, 114.5 (×2), 125.3,

125.7, 125.9, 126.5, 127.9, 128.3, 128.6, 128.7 (×2), 132.6, 133.9, 134.0,

138.4, 159.6; HRMS (EI, 70 eV) calcd for C17 H14 O (M+ ), 234.1045, found

234.1033.

3,5-Dimethylphenylnaphthalene (3h) was prepared by the reaction of

3b (0.400 g, 0.261 mmol) with 4d (7.84 mL, 3.91 mmol) in the presence

of dppfNiCl2 (53.4 mg, 0.078 mmol). The crude compound was purified by

preparative HPLC (CH3 CN) to give 5h (49.1 mg, 81.0%) as a white solid:

mp 68–69◦ C (uncorrected); 1 H NMR (300 MHz, CDCl3 ) δ = 2.41 (s, 6H),

7.02 (s, 1H), 7.34 (s, 2H), 7.42–7.53 (m, 2H), 7.73 (dd, J = 1.68 Hz, 1H),

7.82–7.92 (m, 3H), 8.02 (s, 1H); 13 C NMR (75 MHz, CDCl3 ) δ = 21.5

(×2), 125.6 (×2), 126.0, 126.0, 126.0, 126.4, 127.9, 128.4, 128.5, 129.3,

132.9, 134.0, 138.6 (×2), 139.1, 141.4; HRMS (EI, 70 eV) calcd for C18 H16

(M+ ), 232.1252, found 232.1233.

1-Dimethylamino-5-phenylnaphthalene (3i) was prepared by the reaction of 3c (0.443 g, 0.261 mmol) with 4a (3.92 mL, 3.91 mmol) in the

presence of dppfNiCl2 (53.4 mg, 0.078 mmol). The crude compound was

purified by column chromatography (Et2 O:n-hexane = 1:10) to give 5i

(42.7 mg, 66.1%) as a colorless oil, which rapidly changed to brown in air;

1

H NMR (300 MHz, CDCl3 ) δ = 2.92 (s, 6H), 7.09 (d, J = 7.56 Hz, 1H),

7.29–7.57 (m, 9H), 8.30 (d, J = 8.40 Hz, 1H); 13 C NMR (75 MHz, CDCl3 )

δ = 45.5 (×2), 114.3, 121.5, 124.0, 124.9, 126.0, 127.2, 127.4, 128.4 (×2),

129.5, 130.4 (×2), 133.3, 141.0, 141.6, 151.1; HRMS (EI, 70 eV) calcd for

C18 H17 N (M+ ), 247.1361, found 247.1358.

1-Dimethylamino-5-(p-tolyl)naphthalene (3j) was prepared by the reaction of 3c (0.443 g, 0.261 mmol) with 4b (1.96 mL, 3.91 mmol) in the



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