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Different behaviors of a Cu catalyst in amine solvents: Controlling N and O reactivities of amide Yu Yamane, Koichiro Miyazaki, and Takashi Nishikata ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.6b02309 • Publication Date (Web): 26 Sep 2016 Downloaded from http://pubs.acs.org on September 26, 2016

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ACS Catalysis

Different behaviors of a Cu catalyst in amine solvents: Controlling N and O reactivities of amide Yu Yamane, Koichiro Miyazaki, Takashi Nishikata* †

Graduate School of Science and Engineering, Yamaguchi University, 2-16-1 Tokiwadai, Ube, Yamaguchi, 755-8611, Japan

ABSTRACT. Controlling the reactivity of the nitrogen or oxygen nucleophile of an amide group to form C–N or C–O bonds by tuning reaction conditions is one of the most challenging issues in the use of amides in organic synthesis. Both nucleophiles in the amide group can individually participate in reactions, and most reactions employ a substrate-controlled methodology to achieve selectivity. However, in the reaction of -bromoamides and acrylates, we successfully controlled the reactivity of the nitrogen or oxygen nucleophile of the amide group to afford a lactam via carboamidation or an iminolactone via carbooxygenation, using a copper catalyst system with an appropriate base.

KEYWORDS. amide, lactam, iminolactone, cyclization, copper Introduction

The amide group is a highly useful functional group in pharmaceuticals and organic synthesis.1,2 The amide group is termed an ambident nucleophile, i.e., it contains both nitrogen and oxygen nucleophiles. This property is extremely attractive for heterocycle synthesis, such as lactams and iminolactones; however, the control of the nucleophile selectivity is not well studied (Scheme 1A). Impressive work was reported by Kornblum et al. in 1955, who observed predominantly amide Oattack in the reaction of 2-pyridone and ethyl iodide in the presence of a silver salt, by which 2-

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ethoxypyridine was produced.3 In that reaction, the in situ generation of a carbenium species as the electrophile affected the amide oxygen reactivity. 4,5 Later, results of experiments on amide reactivities led to the establishment of the hard and soft acids and bases theory (HSAB) by Pearson.6-9 The Marcus theory also provided useful information regarding the behavior of ambident nucleophiles.10,11 However, these theoretical predictions have not led to the development of practical organic reactions with ambident nucleophile control because amibident reactivities are sensitive to reaction conditions. Current empirical hypotheses for amide reactivity are still somewhat controversial but may be generalized because of the following reasons: 1) neutral amides lead to a mixture of products arising from O- and N-attack,12,13 2) amide anions lead to predominantly N-functionalized products,14 and 3) the reaction of an amide and a strong carbocation or carbenium ion, which are generated with the aid of strong Lewis acids such as silver salts, lead to O-attack (Scheme 1B).3-5,

15,16

However, despite these observations, a general

methodology for the control of the ambident reactivities of amides in organic synthesis has not yet been established.17-19 During our studies on the development of Cu-catalyzed functionalized tertiary alkyl radical reactions,20,21 we have extensively investigated the potential of radical chemistry to control amide nitrogen and oxygen nucleophiles. We envisioned that if the reaction of an α-bromoamide and acrylate could be made to proceed via the corresponding lactamization or iminolactonization through atom-transfer radical addition (ATRA)22-25 followed by cyclization, this could be a new methodology for a convenient divergent synthesis of heterocycles from the same molecule (Scheme 1C). Herein, we report our findings on the reactivities of amide nitrogen and oxygen, which we hope will further our understanding of amide chemistry.

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Scheme 1. The reaction of an amide compound Results and Discussion To investigate the control of amide N- and O-nucleophilicity, we performed the reaction of αbromoamide 1 with acrylate 2 to produce lactam 3 or iminolactone 4 as a model reaction, wherein vicinal C–C and C–N or C–O bonds are installed via carboamidation or carbooxygenation (Table 1). Recently, we reported that the copper-catalyzed reaction of styrenes and α-bromoesters provides tertiary alkylative olefinations in good yields via ATRA22-25 followed by dehydrohalogenation,20,21 which involves a single-electron transfer process with a Cu(I) catalyst. Since α-bromoamides (instead of esters) and acrylates (instead of styrenes) did not react under the copper-catalyzed conditions, we did not expect any products from this reaction. During our


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continuous study of α-bromoamides, we found that the reaction of 1a and 2a in an amine solvent gave a mixture of the cyclized products 3a and 4a in 85% yield with a 28:72 ratio (Entry 1). This result encouraged us to develop the controlled N- vs. O-cyclization reaction of amides. The reaction mechanism will be discussed in detail later but, briefly, this reaction involves radical reactions, as indicated by the fact that the reaction is strongly inhibited by the addition of radical inhibitors such as 2,2,6,6-tetramethyl piperidine 1-oxyl (TEMPO) and 2,6-bis(1,1-dimethylethyl)4-methylphenol (BHT). We screened various copper salts as catalysts, and the product ratios do not significantly change (Entries 1–3). When primary alkylamines are used as the solvent, Ncyclization predominates over O-cyclization (Entries 4–6). Increasing the amount of copper is effective, affording the product in 75% yield at 90:10 ratio (Entry 7). This behavior of amides (i.e., N-attack versus O-attack) in cyclizations is unclear from previous individual N- or Ocyclizations,26,27 but N-cyclizations are more likely to proceed via the generation of an amide anion. Knapp reported that silyl imidates selectively undergo N-cyclizations leading to lactams in the halocyclization of amides,28,29 whereas Li reported the divergent cyclization of amide using amidyl radicals, wherein lone-pair repulsion of the amide nitrogen or oxygen is very important for the selective production of lactams or lactones.30 Previous alkylation reactions of neutral amides gave a mixture of products arising from N- vs O-attack,12,13 whereas amide anions typically react at the nitrogen.14, 17-19 Therefore, additional strong amine bases were added to the reaction mixture to generate an amide anion, which could undergo N-cyclization. 1,1,3,3-Tetramethylguanidine (TMG) affords the best result compared with 1,8-diazabicycloundec-7-ene (DBU), triazabicyclodecene (TBD), and other amines (Entries 8-11). The addition of K3PO4 is necessary for obtaining high yields of 3a, probably due to the necessity of a strongly basic reaction mixture, but BnBu3NBr, which improves the solubility of added chemicals, does not play an important role


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in this reaction (Entry 12). The yield of 3a is slightly increased at 80 °C (Entry 13), but good results were not obtained at other temperatures. Surprisingly, when the solvent was switched to toluene from an amine, O-cyclization (iminolactonization) giving 4a was predominant (Entry 14). To obtain N-cyclizations, strongly basic conditions in a protic polar solvent were required, whereas slightly weak basic conditions in a non-polar solvent were suitable for O-cyclizations. Indeed, weak bases, such as tri- and dialkylamines, were effective for obtaining 4a in excellent yields and selectivities (Entries 15 and 16). Unlike urea derivatives,31,32 amides in transition metal-catalyzed cross-couplings typically react at the nitrogen to produce N-substituted products,2 and reaction at the oxygen is rare.33


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Table 1. Optimization of the reaction conditions.

a

All reactions were conducted with 0.50 mmol 1a (1 equiv), 0.75 mmol 2a (1.5 equiv), 10 mol% CuX, 20 mol% BnBu3NBr, 5 mol% TPMA, and base in solvent (1.0 mL) at 100 °C for 20 h. Yields were determined by 1H NMR analysis. bDetermined by GC-MS analysis. c15 mol% of CuBrSMe2 and 7.5 mol% of TPMA were used. dWithout BnBu3NBr. eIsolated yield. fReaction was conducted at 80 °C.

We examined the substrate scope of the divergent cyclizations under the optimized conditions (Table 2). The cyclization of 1a proceeds with a broad range of acryl amides and esters (2a–2p) leading to lactamization (3b–3p) and iminolactonization (4b–4p) in excellent yields with almost perfect selectivities. Secondary amides possessing an n-butyl (2b) or 2-pyridylmethyl group (2c)


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afforded the corresponding lactam (3b or 3c) and iminolactone (4b or 4c) under each set of optimal conditions in good yields with excellent selectivities. The reaction product 4c was not stable enough to isolate; thus, the corresponding lactone was generated and isolated in moderate yield. Acryl amides possessing various substituted aromatic rings (2d-2i) also underwent both of the cyclizations in good yields and excellent selectivities. These functional group compatibilities may be useful in the synthesis of more complex molecules containing these cyclic moieties. In the iminolactonizations, steric and electronic effects did not affect the yields and selectivities but the sterically bulky 2e and electron-poor 2h decreased product yields in the lactamizations (3e and 3h). The negative effect of steric bulkiness was also observed in the lactamization of tertiary amides 2j and 2l. The sterically bulky Et2N and i-Pr2N moieties of 2j and 2l affected the yields of 3j and 3l, respectively, whereas the sterically less hindered tertiary amide 2k provided 3k in good yield. When the reaction of 2j was performed under the optimal conditions, the yield was ca. 60% but the selectivity is 3j:4j = 87:13. To improve this selectivity, different conditions were examined; we found that slightly increased amounts of Cu and ligand gave 62% yield and a selectivity of 3j:4j = 98:2. Similar effects were expected in the synthesis of 3l, but the results were not improved. Methacryl amide 2m possessing a bulky C=C bond underwent iminolactonization, but the corresponding lactamization was sluggish. The use of acryl esters (2n–2p) afforded good results, though ethyl acrylate 2n gave the product in only moderate yield, probably due to the polymerization or oligomerization of the acrylate. We examined various conditions to improve the yield of 3n and found that using N,N,N',N'-tetrakis(2-pyridylmethyl) ethylene diamine (TPEN) as the ligand affords the best results. Decreasing selectivities were observed in the iminolactonization of 2b–2i, 2k, and 2n–2p under optimal conditions, but the use of i-Pr2NEt instead of i-Pr2NH


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improves the results. Therefore, the selectivity of the iminolactonization was not dependent on the structure of 2, but on the amine used. Table 2. Reaction of 1a with acrylate derivatives 2. O

Ph N

X

O

Me Me

3 Lactam 3 Yiled (%)a 3:4b O

Ph N

N O

O

O

O

n-Bu

O

Ph N

O

Me Me

O

2c

O ArHN

Ph N

O

Me Me

iPr N iPr

4c 80% (58%) >99:1

Ar Me Me

3d (Ar=Ph) 90% (85%) >99:1 3e (Ar=o-An) 67% (68%)d 98:2 3f (Ar=m-An) 91% (87%) 99:1 3g (Ar=p-An) 88% (81%) >99:1 3h (Ar=p-AcPh) 55% (51%) >99:1 3i (Ar=p-IPh) 76% (76%) >99:1

O

H N

ArHN

2d (Ar=Ph)

2e (Ar=o-An)

2f (Ar=m-An)

2g (Ar=p-An)

2h (Ar=p-AcPh)

2i (Ar=p-IPh)

i-Pr

4d (Ar=Ph) 93% (84%)d, e 97:3 4e (Ar=o-An) 85% (69%)d, e >99:1 4f (Ar=m-An) 92% (92%)d, e 98:2 4g (Ar=p-An) 91% (90%)d, e >99:1 4h (Ar=p-AcPh) 86% (83%)d, e 97:3 4i (Ar=p-IPh) 94% (95%)e 98:2

O

O

Ph N

NPh

Me Me

2k

4k 83% (75%)e 98:2 O iPr N iPr

2l

O

O

NPh

Me Me

4l 90% (88%) >99:1 OMe

Me N

O

NPh

N O

2m

3m trace O

Me Me

O

O

Me Me

RO

NPh

N

Me Me

OMe Ph N O

O

4j 97% (87%) >99:1

i-Pr N

O

N Me Me

O

Ph N

3l 18%c 52:48

NPh

Et N Et

N

Me Me

O O

O

3k 88% (75%) >99:1 NPh

Iminolactone 4 Yiled (%)a 4:3b

O

Ph N

N

O O

Et

O

NPh

4

O

Et N

2j

Me Me

HN 2-PyCH 2

O

Me Me

O O

Ph N

NPh

Me Me

Substrate 2

3j 62% (58%)c, d 98:2

4b 84% (83%)e >99:1

2-PyCH 2 NH

3c 71% (66%) >99:1

Et N Et

O n-Bu N H

2b

O

Me Me

4a 94% (80%) >99:1

H N

Me Me

3b 71% (61%) 98:2

HN 2-PyCH 2

O

2a

Ph N

NPh

N

Me Me

n-Bu N H

O O

N

3a 86% (75%) 98:2

Lactam 3 Yiled (%)a 3:4b

O

O

O

iPr2NH (1.5 equiv) toluene, 100°C

O

2

Iminolactone 4 Yiled (%)a 4:3b

Substrate 2

O

CuI (10 mol%) O TPMA (5 mol%) X BnBu3NBr (20 mol%) X

CuBr·SMe2 (15 mol%) TPMA (7.5 mol%) Me Me TMG (10 mol%) NHPh Br + K3PO4 (1.0 equiv) O tert-butylamine, 80°C 1a

O

Me Me

4m 96% (84%) >99:1 O

O

O

RO RO

NPh

O Me Me

Me Me

3n (R=Et) 52% (42%)d, f >99:1

2n (R=Et)

4n (R=Et) 72% (61%)d, e 98:2

3o (R=Cy) 76% (61%) >99:1

2o (R=Cy)

4o (R=Cy) 71%e >99:1

3p (R=tBu) 71% (69%) 98:2

2p (R=tBu)

4p (R=tBu) 73% (69%)e 98:2

Lactamization: 1a (0.5 mmol), 2 (0.75 mmol), CuBrSMe2 (15 mol%), TPMA (7.5 mol%), K3PO4 (1.0 equiv), and TMG (10 mol%) in tert-butylamine (1.0 mL) at 80 °C for 20 h. Iminolactonization: 1a (0.5 mmol), 2 (0.75 mml), CuI (10 mol%), TPMA (5 mol%), Bu3BnNBr (20 mol%), and iPrNH2 (1.5 equiv) in toluene (1.0 mL) at 100 °C for 20 h. a NMR yields (isolated yields in parentheses). bThe ratios of 3:4 were determined by crude GC-MS. cReaction conditions: 1a (0.5 mmol), 2 (0.75 mml), CuBrSMe2 (20 mol%), TPMA (10 mol%), K3PO4 (1.0 equiv) in secbutylamine (0.5 mL) at 80 °C for 20 h. dGPC yield. eUsing iPr2NEt instead of iPr2NH. fUsing CuBrSMe2 (30 mol%) and TPEN (15 mol%).


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We next investigated the reactivities of -bromoamides (1b–1l) with 2a. As shown in Table 3, debromination of 1 (leading to hydrogenated 1) or elimination of bromide (leading to methacrylates) are problematic side reactions, but the desired products 3 or 4 were obtained in moderate-to-good yields and selectivities under optimal or modified conditions. The tendencies of the yields and selectivities were generally similar to the reactivities of 2, i.e., a wide range of bromoamides 1 with electron-donating or -withdrawing groups can be applied to this reaction. For example, the reactions of sterically bulky 1b, 1f, 1j, and 1k tended to show decreased yields of the lactams 3q, 3u, 3y, and 3z, respectively. 1l possessing a secondary alkyl structure also reacted with 2a to give lactam 3aa and iminolactone 4aa in moderate to good yields with excellent selectivities under slightly modified conditions. In the reactions of 1j and 1l, diastereomers were obtained, but the reactions were not selective. Interestingly, the N-alkyl substituted -bromoamide 1m provides only iminolactone 4ab under each set of optimized conditions (Scheme 2).


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Table 3. Reaction of 2a with -bromoamide derivatives 1.

Lactamization: 1 (0.5 mmol), 2a (0.75 mmol), CuBrSMe2 (15 mol%), TPMA (7.5 mol%), K3PO4 (1.0 equiv), and TMG (10 mol%) in tert-butylamine (1.0 mL) at 80 °C for 20 h. Iminolactonization: 1a (0.5 mmol), 2a (0.75 mml), CuI (10 mol%), TPMA (5 mol%), Bu3BnNBr (20 mol%), and iPrNH2 (1.5 equiv) in toluene (1.0 mL) at 100 °C for 20 h. aNMR yields (isolated yields in parentheses). bThe ratios of 3:4 were determined by crude GC-MS. cUsing CuI (15 mol%) and TPMA (7.5 mol%). dUsing CuI (20 mol%) and TPMA (10 mol%). eGPC yield. fUsing iPr2NEt instead of i Pr2NH. gReaction was conducted at 100 °C. hUsing Cy2NH instead of iPr2NH.

OMe

OMe

HN

Me

O O

Me N Cy 4ab

CuBr·SMe2 (15 mol%) TPMA (7.5 mol%) TMG (10 mol%) K3PO4 (1.0 equiv)

Me Br

Me

H N

1m +

CuI (10 mol%) TPMA (5 mol%) BnBu3NBr (20 mol%) iPr2NEt (1.5 equiv)

H N

toluene, 100°C, 20h

O

tert-butylamine, 80°C 20h

HN

Me

O O

Me N Cy 4ab

O 66% (45% GPC Yield) 3:4 = 1:>99

OMe 2g

75% NMR Yield 4:3 = >99:1

Scheme 2. Reaction of 1 m and 2g.


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This result indicates that the acidity of the NH group plays an important role in the cyclizations. Conversely, in the reaction of 1n and 2q (Scheme 3), the size of the molecule did not affect the selectivity but the yields were only moderate. We also performed a gram-scale synthesis of 3a and 4a (Scheme 4). In each case, the products were obtained with good yields and selectivities.

H

Me Br

Me

CuBr·SMe2 (15 mol%) TPMA (7.5 mol%) TMG (10 mol%) K3PO4 (1.0 equiv)

H N

O

O O

Me tert-butylamine, 80°C Me 20h

Ph 1n

3ac: 38% (3ac:4ac=>20:1)

N O Ph

+

CuI (10 mol%) TPMA (5 mol%) BnBu3NBr (20 mol%) iPr2NEt (2.0 equiv)

H

H

O

toluene, 100°C, 20h

O

O O

Me Me

2q

4ac: 57% (3ac:4ac=1:>20)

O N

Ph

Scheme 3. Reaction of cholesterol derivatives 2q.

O

O N

O NPh

Me Me

O 3a

CuBr·SMe2 (15 mol%) TPMA (7.5 mol%) TMG (10 mol%) K3PO4 (1.0 equiv) tert-butylamine, 80°C 20h 80% (3a:4a =98:2)

1a 5 mmol + 2a 7.5 mmol

CuI (10 mol%) TPMA (5 mol%) BnBu3NBr (20 mol%) iPr2NEt (1.5 equiv) toluene, 100°C, 20h 91% (3a:4a =6:94)

N

O O

Me Me

NPh 4a

Scheme 4. Gram-scale synthesis.


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The obtained nitrogen- and oxygen-containing products possessing various active functional groups were easily converted into a wide range of derivatives using conventional organic reactions (Schemes 5–8). The reduction of lactam 3a with LiAlH4 afforded the corresponding amine compound 5 in 70% yield (Scheme 5). Conversely, iminolactone 4a reacted with NaBH4 to produce the ring-expanded product 6 in 94% yield (Scheme 6).

Scheme 5. Reduction of 3a.

Scheme 6. Reduction of 4a. Moreover, 3w and 4i, possessing Csp2–Br bonds, underwent Suzuki-Miyaura and Sonogashira coupling reactions to afford the corresponding arylated and 1-alkenylated products in good yields, respectively (Scheme 7 and 8). These results showed that our cyclization reaction is a powerful technique for synthesizing nitrogen-containing building blocks.

O N

O

I

N 3w

O

O

Pd(PPh3)4 (5 mol%) K2CO3 (4 equiv) PhB(OH)2 (1.5 equiv) THF/H2O (3:1) 80 °C, 18h

Ph

N O

N

O

7: 75% yield

Scheme 7. Suzuki–Miyaura coupling of 3w.


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Scheme 8. Sonogashira reaction of 4i. We performed several control experiments to investigate the mechanism of our reaction (Schemes 9–11). We initially suspected that copper-catalyzed or -mediated reactions undergo lactamization via the formation of an iminolactone as an intermediate.34 However, such exchange reactions were not observed (Scheme 9). The iminolactonization of 1d and 2a in the presence of lactam 3a provided the corresponding iminolactones 4s and 3a, respectively (Scheme 10). Scheme 9. Cyclization test under each set of optimized conditions.

Scheme 10. Iminolactonization in the presence of lactam 3a. Similarly, the lactamization of 1d and 2a in the presence of iminolactone 4a provided the corresponding lactams 3s and 4a, respectively (Scheme 11). We monitored each reaction to check


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the selectivity during the cyclization reaction but substrate and product distributions were not changed under each optimzal conditions. Although simple perturbation can generate unidentified chemical species in situ that are capable of switching the cyclization process, no such chemical species were generated during the reaction.

Scheme 11. Lactamization in the presence of iminolactone 4a.

The observed behaviors in the cyclization of amides (i.e., N-attack versus O-attack) are not easily understood based on HSAB theory. The mechanism of the current reaction, which is proposed based on the control experiments, is illustrated in Scheme 12. The reaction begins with a single-electron transfer to α-bromoamide 1 to produce alkyl radical species A. After A is generated, an addition reaction with acrylate 2 occurs to give alkyl radical intermediate B. In the lactamization reaction under strong base conditions, B reacts with Cu(II) and K3PO4 to produce copper amide species C. It is well known that the reaction of an amide with a copper salt in the presence of K3PO4 as a base can generate a copper amide complex.35 The intermediate C undergoes oxidative cyclization with copper to generate metallacycle D. Hartwig et al. have reported that a carbon-amide bond is formed from the reaction of an alkyl radical species and a copper amide, followed by reductive elimination36. Although we failed to detect the Cu(III) intermediate D in our studies37, the lactam 3 and Cu(I) could be formed via reductive elimination of D. Conversely, the intermediate B under weak base conditions undergoes radical cyclization to produce E. According to previous reports,3-5,15,16 amide oxygens favorably react with carbocations. However, the


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generation of an α-carbocation from B by oxidation with a Cu(II) species is considered to be unfavorable due to stability issues. Therefore, the addition of a carbon-centered radical species to a carbonyl group is another reaction pathway and is a typical radical reaction.33,

38

Finally,

iminolactone 4 is obtained after the oxidation of E with Cu(II) followed by proton elimination.

Scheme 12. Proposed mechanism. Conclusion In conclusion, we accomplished highly selective lactamization and iminolactonization cyclization reactions by controlling ambident amide reactivities using a copper salt. A key to the success of this selective reaction is to use basic conditions. Amide nitrogen reactivity is favorable under strong base conditions to form lactam 3, whereas amide oxygen reactivity is favorable under weak base conditions to form iminolactone 4. Further investigation, including mechanistic experiments designed to trap active copper intermediates, are underway in our group and will be reported in due course.


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EXPERIMENTAL SECTION All reactions were carried out under nitrogen (99.95%) atmosphere. For TLC analyses precoated Kieselgel 60 F254 plates (Merck, 0.25 mm thick) were used; for column chromatography Silica Flash® P60 (SiliCycle, 40-63 μm) was used. Visualization was accomplished by UV light (254 nm), 1H and

13

C NMR spectra were obtained by using a JEOL 500 MHz NMR spectrometer.

Chemical shifts for 1H NMR were described in parts per million (chloroform as an internal standard δ = 7.26 ppm) in CDCl3, unless otherwise noted. Chemical shifts for

13

C NMR were

expressed in parts per million in CDCl3 as an internal standard (δ = 77.16 ppm), unless otherwise noted. High resolution mass analyses were obtained using a ACQUITY UPLC/ TOF-MS for ESI. Anhydrous toluene were purchased from Kanto Chemical Co., Ltd. Other chemicals obtained from TCI, Sigma-Aldrich and Wako and Copper salts obtained from Sigma-Aldrich and Wako were used directly as supplied. Lactamization reaction General Procedure for the lactamization Reaction: 1 (0.50 mmol), 2 (0.75 mmol), CuBr･SMe2 (0.075 mmol), TPMA (0.038 mmol) and K3PO4 (0.50 mmol) were sequentially added to the dram vial equipped with a stir bar and a screw cap. Tert-butyl amine (1.0 mL) and 1,1,3,3Tetramethylguanidine (0.05 mmol) was added to a dram vial. The resulting mixture vigorously stirred under nitrogen atmosphere (purity 99.95%) for 20 h at 80 °C. After this time, the contents of the flask were filtered through the plug of silica gel, and then concentrated by rotary evaporation. The yield was determined by 1H NMR analysis (internal standard 1,1,2,2-Tetrachloroethane). The crude residue was purified by flash chromatography, eluting with hexane/EtOAc to afford the product 3.


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ACS Catalysis

Iminolactonization reaction General Procedure for the iminolactonization Reaction: 1 (0.50 mmol), 2 (0.75 mmol), CuI (0.050 mmol), TPMA (0.025 mmol) and BnBu3NBr (0.50 mmol) were sequentially added to the dram vial equipped with a stir bar and a screw cap. Dried toluene (1.0 mL) and iPr2NH (0.10 mmol) was added to a dram vial. The resulting mixture vigorously stirred under nitrogen atmosphere (purity 99.95%) for 20 h at 100 °C. After this time, the contents of the flask were filtered through the plug of silica gel, and then concentrated by rotary evaporation. The yield was determined by 1H NMR analysis (internal standard 1,1,2,2-Tetrachloroethane). The crude residue was purified by flash chromatography, eluting with hexane/EtOAc to afford the product 4. ASSOCIATED CONTENT Supporting Information Supporting Information includes experimental details and compounds data. This material is available free of charge via the Internet at http://pubs.acs.org/.

AUTHOR INFORMATION Corresponding Author Takashi Nishikata E-mail: [email protected]

ACKNOWLEDGMENT Financial support provided by program to disseminate tenure tracking system, MEXT, Japan. REFERENCES


ACS Catalysis

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(1) Amination and Formation of sp2 C-N Bonds, Taillefer, M.; Ma, D. Eds.; Springer, New York: 2014. (2) Catalyzed Carbon-Heteroatom Bond Formation, Yudin, A. K. Ed.; Wiley-VCH: Weinheim, 2011. (3) Kornblum, N.; Smiley, R. A.; Blackwood, R. K.; Iffland, D. C. J. Am. Chem. Soc. 1955, 77, 6266- 6269. (4) Hopkins, G. C.; Jonak, J. P.; Minnemeyer, H. J.; Tieckelmann, H. J. Org. Chem. 1967, 32, 4040- 4044. (5) Chung, N. H.; Tieckelmann, N. J. Org. Chem. 1970, 35, 2517- 2520. (6) Pearson, R. G. J. Am. Chem. Soc. 1963, 85, 3533- 3539. (7) Pearson, R. G. J. Chem. Educ. 1968, 45, 581- 587. (8) Pearson, R. G. J. Chem. Educ. 1968, 45, 643- 648. (9) Pearson, R. G. Chemical Hardness; Wiley-VCH: Weinheim, 1997. (10) Breugst, M.; Zipse, H.; Guthrie, J. P.; Mayr, H. Angew. Chem., Int. Ed. 2010, 49, 51655169. (11) Marcus, R. A. Pure Appl. Chem. 1997, 69, 13- 30. (12) Challis, B.C.; Challis, J. In The Chemistry of Amides; Zabicky, J., Ed.; Interscience Publisher: London, UK, 1970; pp 731- 858. (13) Stirling, C. J. M. J. Chem. Soc. 1960, 255- 262.


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(14) Döpp, D.; Döpp, H. Houben-Weyl Methods of Organic Chemistry, 4th ed.; Thieme: Stuttgart, Germany, 1985; Vol. E5, pp 934- 1135. (15) Koch, T. H.; Sluski, R. J.; Moseley, R. H. J. Am. Chem. Soc. 1973, 95, 3957- 3963. (16) Anderson, D. R.; Keute, J. S.; Koch, T. H.; Moseley, R. H. J. Am. Chem. Soc. 1977, 99, 6332- 6340. (17) Martin, B.; Tokuyasu, T.; Mayr, H. J. Org. Chem. 2010, 75, 5250- 5258. (18) Martin, B.; Mayr, H. J. Am. Chem. Soc. 2010, 132, 15380- 15389. (19) Cheng, Y. A.; Yu, W. Z.; Yeung, Y.-Y. Angew. Chem., Int. Ed. 2015, 54, 12102- 12106. (20) Nishikata, T.; Noda, Y.; Fujimoto, R.; Sakashita, T. J. Am. Chem. Soc. 2013, 135, 1637216375. (21) Nishikata, T.; Ishida, S.; Fujimoto, R. Angew. Chem., Int. Ed. 2016, 55, 10008- 10012. (22) (a) Pintauer, T.; Matyjaszewski, K. Chem. Soc. Rev. 2008, 37, 1087- 1097. (b) Eckenhoff , W. T.; Pintauer, T. Catal. Rev. 2010, 52, 1- 59. (23) Matyjaszewski, K.; Tsarevsky, N. V.; Braunecker, W. A.; Dong, H.; Huang, J.; Jakubowski, W.; Kwak, Y.; Nicolay, R.; Tang, W.; Yoon, J. A. Macromolecules. 2007, 40, 7795- 7806. (24) Jakubowski, W.; Min, K.; Matyjaszewski, K. Macromolecules. 2006, 39, 39- 45. (25) Jakubowski, W.; Matyjaszewski, K. Macromolecules. 2005, 38, 4139- 4146. (26) Robin, S.; Rousseau, G. Tetrahedron 1998, 54, 13681-13886.


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ACS Catalysis

Insert Table of Contents Graphic and Synopsis Here O

lactam R' O R'

3 N-attack 99% N-selective

EWG 2 NHR

NR EWG

Cu cat.

NR

Br 1

R' iminolactone

O EWG

4 O-attack 99% O-selective


Different Behaviors of a Cu Catalyst in Amine ... - ACS Publications

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