Subscriber access provided by LOCK HAVEN UNIV
Article
A Coupling-and-Decoupling Approach Enables Palladium-Catalyzed Aerobic Bimolecular Carbocyclizations of Enediynes to 2,6-Diacylnaphthalenes Fei Ling, Yanjun Wan, Dongxu Wang, and Cheng Ma J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02870 • Publication Date (Web): 08 Mar 2016 Downloaded from http://pubs.acs.org on March 9, 2016
Just Accepted “Just Accepted” manuscripts have been peer-reviewed and accepted for publication. They are posted online prior to technical editing, formatting for publication and author proofing. The American Chemical Society provides “Just Accepted” as a free service to the research community to expedite the dissemination of scientific material as soon as possible after acceptance. “Just Accepted” manuscripts appear in full in PDF format accompanied by an HTML abstract. “Just Accepted” manuscripts have been fully peer reviewed, but should not be considered the official version of record. They are accessible to all readers and citable by the Digital Object Identifier (DOI®). “Just Accepted” is an optional service offered to authors. Therefore, the “Just Accepted” Web site may not include all articles that will be published in the journal. After a manuscript is technically edited and formatted, it will be removed from the “Just Accepted” Web site and published as an ASAP article. Note that technical editing may introduce minor changes to the manuscript text and/or graphics which could affect content, and all legal disclaimers and ethical guidelines that apply to the journal pertain. ACS cannot be held responsible for errors or consequences arising from the use of information contained in these “Just Accepted” manuscripts.
The Journal of Organic Chemistry is published by the American Chemical Society. 1155 Sixteenth Street N.W., Washington, DC 20036 Published by American Chemical Society. Copyright © American Chemical Society. However, no copyright claim is made to original U.S. Government works, or works produced by employees of any Commonwealth realm Crown government in the course of their duties.
Page 1 of 39
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 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Organic Chemistry
A Coupling-and-Decoupling Approach Enables Palladium-Catalyzed Aerobic Bimolecular Carbocyclizations of Enediynes to 2,6-Diacylnaphthalenes Fei Ling, Yanjun Wan, Dongxu Wang, and Cheng Ma* Department of Chemistry, Zhejiang University, 20 Yugu Road, Hangzhou 310027, China
ABSTRACT A formal palladium-catalyzed aerobic bimolecular carbocyclization reactions of (Z)-hexa-1,5-diyn-3-ene scaffolds has been successfully developed for the construction of 2,6-diacylnaphthalenes, wherein copper salts play a critical role to accomplish the oxygenative homo- and hetero-dimerization processes of readily accessible enediyne–carboxylic acids and esters, respectively. The enediyne dimerization protocol provides a flexible and regiospecific approach to a variety of functionalized naphthalenes with up to
six
differentiated
substituents
in
good
yields
by
using
a
directing-group-assisted
coupling-and-decoupling strategy. Mechanistic studies indicated that the two oxygen atoms being selectively incorporated into the crossover-annulation products of enediyne-carboxylic acid and ester directly originate from atmospheric molecular oxygen and H2O, respectively. INTRODUCTION Devising novel and efficient methods for the selective synthesis of polysubstituted naphthalene compounds is of great interest because of the prevalence of this structural motif in natural products and 1
ACS Paragon Plus Environment
The Journal of Organic Chemistry
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 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
bioactive molecular as well as industry values.1 In this content, the cycloaromatization and isomerization reactions of benzenoid enediynes provide a powerful tool for the construction of versatile naphthalene compounds. For instance, in light of mechanistic proposal for the formation of polymeric byproducts in the classic Bergman cyclization,2 the thermo-triggered isomerization and polymerization of acyclic enediynes was endeavored and has become as a promising strategy for the generation of conjugated aromatic polymers bearing naphthalene skeletons (Scheme 1a).3 Meanwhile, a set of elegant radical-induced polycyclizations of well-designed oligo-(phenylene-1,2-ethynylenes) have recently been established to deliver nano-scale aromatic ribbons.4 In addition to these radical-mediated cycloaromatization reactions, transition-metal-catalyzed cycloisomerization of enediynes have been notably investigated in the last decade, offering a variety of efficient methods to construct substituted naphthalene compounds as well as other aromatic molecules under mild reaction conditions (Scheme 1b).5,6 Despite significant progresses in their cycloisomerization and intramolecular cyclization reactions, very limited attentions have been devoted to the intermolecular carbocyclization of enediyne scaffolds, which would allow more flexible formations of substituted aromatics from simple substrates. To the best of our knowledge, there are only few precedents in literatures addressing the intermolecular [4 + 2] cyclization of enediyne compounds with C2 components like α-hydroxyketones7a and simple alkynes7b. In this case, given the multiple unsaturated C–C bonds of enediynes, a lot of troublesome problems associated with reaction selectivity8 have been regarded to be overcome besides the innate isomerization obstacle of this structural motif. Triggered by our previous results on the Pd/Cu-catalyzed aerobic [4 + 2] benzannulation between enediyne carboxylic compounds and internal alkynes,7b we have attempted to handle the dimerization reaction of enediynes9 and found that a class of 2,6-diacylnaphthalenes10 could be directly assembled through a formal palladium/copper-catalyzed intermolecular oxygenative carbocyclization of 2
ACS Paragon Plus Environment
Page 2 of 39
Page 3 of 39
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 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Organic Chemistry
enediyne skeletons (Scheme 1c).11 Remarkably, it appeared that copper salts play a critical role to control the reaction selectivity beyond an oxidant in the directing-group-assisted palladium-catalyzed aerobic cascade cyclization of enediyne-carboxylic acids 1 and enediyne-carboxylic esters 2.12 Scheme 1. Annulations of Acyclic Enediynes to Naphthalenes
RESULTS AND DISCUSSION Initial studies on enediyne homo-dimerization were started with readily accessible enediyne–acid 1a by using PdCl2 (10 mol %) as the catalyst in the presence of CuBr2 (20 mol %) in DMF under 1 atm of O2 (Table 1). While a sluggish conversion of 1a occurred at 35 oC, it appeared that 1a was too labile to be converted into a highly complex mixture involving naphthoic diacid 3a at elevated temperature (Table 1, entries 1 and 2). Switching CuBr2 to a set of other copper salts did not improve the product yield (Table 1, entries 3–7). After a lot of exhausting efforts on optimization of reaction conditions, a key breakthrough was ultimately achieved by identifying that not only the copper salts employed but also the amount of Cu co-catalyst is critical for completing a clear conversion of 1a to give naphthoic diacid 3a. In the presence 5 3
ACS Paragon Plus Environment
The Journal of Organic Chemistry
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 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 4 of 39
mol % of PdCl2 and CuBr2 (0.6 equiv), 1a underwent this dimerization-oxygenation cascade smoothly in DMF at 60 oC in O2 (1 atm), affording 3a in 82 % yield after 4 h (Table 1, entry 8). Nevertheless, further increasing the amount of CuBr2 from 0.6 equiv to 1.0 equiv would result in a decreasing yield (74 %) because of the generation of some undetermined by-products (Table 1, entry 9). In contrast, no desired product was detected in the absence of any palladium catalysts (Table 1, entry 10). Table 1. Optimization of Reaction of Acids 1a
entry
Cu salt (equiv)
t (h)
T (oC)
yield (%)b
1
CuBr2 (0.2)
8
35
7
2
CuBr2 (0.2)
8
60
22
3
Cu(OAc)2 (0.2)
8
60
trace
4
CuCl2 (0.2)
8
60
trace
5
Cu(OTf)2 (0.2)
8
60
13
6
CuBr (0.2)
8
60
trace
7
CuI (0.2)
8
60
15
8
CuBr2 (0.6)
4
60
82
9
CuBr2 (1.0)
3
60
74
10c
CuBr2 (0.2)
12
60
–
a
Unless otherwise noted, the reaction was carried out using 1a (0.1 mmol), PdCl2 (5 mol %), Cu salts in DMF (1.0 mL) b
c
under O2 (1 atm). Isolated yield. In the absence of PdCl2.
With the optimal reaction conditions in hand, the scope of the oxygenative homo-dimerization of acids 1 4
ACS Paragon Plus Environment
Page 5 of 39
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 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Organic Chemistry
was examined (Scheme 2). Accordingly, variation of substituents R1 or R2 of acids 1 indicated that a set of benzene rings with an electron-donating group (–Me) or an electron-withdrawing group (–CF3) as well as a halogen (–Br) were well tolerated to form a broad array of C2 symmetric naphthoic diacids potentially of interests in functional materials and supramolecular architectures.13 Due to the poor solubility of acids 3d, 3e, and 3f, their corresponding ester derivatives 3d’, 3e’, and 3f’ were produced as the products upon treatment with CH3I under basic conditions. Alkyl group (–C5H11) was also completely compatible with the catalytic systems to afford 3g in 79% yield. In addition, the benzene ring could be effectively replaced by other aromatic substituents like benzo[d][1,3]dioxol-5-yl to forge the desired naphthalene product 3h in good yield. Scheme 2. Oxygenative Homo-Dimerization of Acids 1a
a
The reaction was carried out on a 0.2 mmol scale of acids 1 with PdCl2 (5 mol %), and CuBr2 (0.6 equiv) in DMF (2.0 mL)
under O2 (1 atm) at 60 oC. The yields are of the isolated products.
Intriguingly, when subjecting enediyne–ester 2a to PdCl2 (5 mol %) and CuBr2 (0.6 equiv) in DMF at 60 o
C under oxygen atmosphere, a partially hydrolyzed product of 2,6-diacylnaphthalenes 4a was isolated in 5
ACS Paragon Plus Environment
The Journal of Organic Chemistry
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 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
Page 6 of 39
35% yield after 12 h (Table 2, entry 1).14 Reducing the amounts of copper salts improved the yield of 4a (Table 2, entry 2). Using 0.2 equiv of CuCl2 instead of CuBr2 not only sharply improved the product yield but also accelerated this transformation of 2a, giving access to 4a in 83 % yield after 6 h (Table 2, entry 3). However, replacing CuBr2 with a set of other copper salts disfavored the formation of product 4a. For examples, while a relatively lower yield of 4a was found with CuCl as the co-catalyst, Cu(OAc)2 only deliver traceless product (Table 2, entries 4 and 5). Further studies indicated that the reaction temperature had a little effect on this reaction, lowering or elevating the reaction temperature would decrease the yield of 4a (Table 2, entries 6 and 7). As expected, no desired product was detected in the absence of PdCl2, suggesting that palladium catalyst is critical to this transformation of enediyne–ester 2a (Table 2, entry 8). Table 2. Optimization of Reaction of 2aa
entry
Cu salt
t (h)
T (oC)
yield (%)b
1c
CuBr2
12
60
35
2
CuBr2
12
60
47
3
CuCl2
6
60
83
4
Cu(OAc)2
12
60
trace
5
CuCl
8
60
59
6
CuCl2
4
80
66
7
CuCl2
24
30
33
8c,d
CuCl2
12
60
–
a
Unless otherwise noted, the reaction was carried out using 2a (0.1 mmol), Pd-catalyst (5 mol %), Cu salts (0.2 equiv) in
6
ACS Paragon Plus Environment
Page 7 of 39
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 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Organic Chemistry
b
c
d
DMF (1.0 mL) under O2 (1 atm). Isolated yield. CuBr2 (0.6 equiv). Without PdCl2
A survey on the substrate scope of esters 2 was shown in Scheme 3. A variety of functional groups including halogen (4c’ and 4g), trifluoromethyl (4f’), and nitro groups (4h’) were applicable for the current catalytic system, providing good yields of the targeted naphthalene products 4. An alkyl group (1-pentyl) could be employed in this reaction to give 4b in 72% yield. Moreover, methyl ester 2d (R3 = R4 = Ph, R = Me) also underwent this reaction smoothly, affording 4d in good yield. In addition, the structure of 4h’ was unambiguously determined by single-crystal X-ray analysis. Scheme 3. Oxygenative Homo-Dimerization of Esters 2a
a
Unless otherwise noted, the reaction was carried out on a 0.2 mmol scale of acids 2 with PdCl2 (5 mol %), and CuCl2 (0.2
equiv) in DMF (2.0 mL) under O2 (1 atm) at 60 oC. The yields are of the isolated products.
Given the different reactivity of enediyne acid 1a and ester 2a upon treatment with CuBr2 in the Pd-catalyzed aerobic annulation reaction, we envisioned that the choice of suitable copper salts might enable a selective crossover-annulation of 1 and 2, which constituted a pair of ideal reaction partners for the construction of diverse substituted naphthalene products (Table 3). Thus a mixture of acid 1a and 7
ACS Paragon Plus Environment
The Journal of Organic Chemistry
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 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
ester 2b (3.0 equiv) was subjected to PdCl2 (5 mol %) and a set of Cu salts in DMF at 60 oC under 1 atm of O2. To our delight, using 0.2 equiv CuBr2 as the co-catalyst, cross-dimerization product 5ab was isolated in 67% yield, despite along with some homo-dimers of 3a and 4b (Table 3, entry 1). After screening a series of CuII and CuI slats, CuI turned out to be optimal, not only providing the highest yield but also inhibiting the generation of homo-dimers especially of 3a (Table 3, entries 2–5). Excess amounts of 2b could be recovered after the reaction, which is favorable to large-scale manipulation. Increasing the loading of CuI from 0.2 to 0.6 or 1.0 equiv could accelerate the conversion and afforded 5ab in 88% and 92% yield, respectively (Table 3, entries 6 and 7). Whereas raising the ratio of 1a to 2b prompted the homo-dimerization of 1a, the heterodimer 5ab was still obtained as the major product by using 2 equiv or even 1.5 equiv of ester 2b (Table 3, entries 8 and 9). It was also observed that an aqueous solvent system (DMF/H2O = 10:1) had a little influence on reaction outcomes (Table 3, entry 10). Notably, in the absence of Cu salts, a complicated mixture involving dimers 3a, 4b and 5ab could still be formed but in low yields without any selectivity (Table 3, entry 11). Nevertheless, no any productive conversions were observed in the absence of PdCl2 (Table 3, entry 12). All of these results clear indicated that Cu salts play an important role to facilitate this Pd-catalyzed aerobic crossover-annulation cascade selectively, presumably due to the difference in the coordinating ability of substrates and the product to copper ions as well as the ligand exchange of palladium catalyst with the counter ion of copper salts.15 Table 3. Optimization of Reaction of 1a and 2ba
8
ACS Paragon Plus Environment
Page 8 of 39
Page 9 of 39
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 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60
The Journal of Organic Chemistry
yield (%)c,d entry
b
Cu salt (equiv)
2b (equiv)
t (h) 3a/4b/5ab
1
3.0 (1.5)
CuBr2 (0.2)
3.5
15/5/67
2
3.0 (1.1)
CuCl2 (0.2)
2.0
16/7/59
3
3.0 (2.7)
Cu(OAc)2 (0.2)
12
