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The temperature-controlled divergent hydroamination cyclization [2+2]-cycloaddition cascade reactions of homopropargylic amines with 2-butynedioates: Direct access to the pyrrolo-b-cyclobutene and dihydro-1H- azepines Xinhong Li, Songmeng Wang, Shengli Li, Kangming Li, Xin Mo, Lingyan Liu, Weixing Chang, and Jing Li J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02730 • Publication Date (Web): 08 Jan 2019 Downloaded from http://pubs.acs.org on January 12, 2019

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The Journal of Organic Chemistry

The temperature-controlled divergent hydroamination cyclization

[2+2]-cycloaddition

cascade

reactions

of

homopropargylic amines with 2-butynedioates: Direct access to the pyrrolo-b-cyclobutene and dihydro-1Hazepines Xinhong Li,1 Songmeng Wang,1 Shengli Li,1 Kangming Li,1 Xin Mo,1 Lingyan Liu,*1 Weixing Chang,1 Jing Li*1,2 1

the State Key Laboratory and Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai

University, Tianjin 300071, P. R. China 2

Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Weijin Road 94#,

Nankai District, Tianjin 300071, P. R. China

E-mail: [email protected]; [email protected]

Dedicated to 100th anniversary of Nankai University

KEYWORDS: homopropargylic amines, hydroamination cyclization cascade reaction, ring-opening rearrangement, pyrrolo-b-cyclobutene, dihydro-1H-azepines

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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

ABSTRACT

The diversified temperature-controlled hydroamination cyclization cascade reactions of homopropargylic amines and 2-butynedioates were developed for the construction of various pyrrolo-b-cyclobutenes and dihydro-1H-azepines, respectively. This reaction actually involved an intramolecular hydroamination cyclization of homopropargylic amines to give the active dihydropyrroles intermediates, which subsequently underwent [2+2]-cycloaddition with 2-butynedioates to generate the pyrrolo-b-cyclobutenes at no more than 120 oC. Alternatively, the dihydro-1H-azepines were directly produced at 150 o

C in the reactions of homopropargylic amines and 2-butynedioates. The application of

substrates scope was wide and the corresponding products were obtained in high to excellent yields.

INTRODUCTION

The cycloaddition of unsaturated olefins or alkynes is a very important organic reaction and has always gained popularity in the synthesis of cyclic compounds due to its high


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efficiency and good atom economy. However, the [2+2]-cycloaddition reaction remains great challenging because of the limitation of orbital symmetry and the possible unstability of corresponding four-membered cycles. And this reaction generally requires the photochemical reaction conditions1 or Lewis acids2 or transition metals catalysis at high temperature.3 More importantly, this reaction pathway is often inefficient and has poor specificity. Therefore, designing appropriate reactants and developing new effective methodologies are highly desirable for the construction of the four-membered cyclic compounds.

Figure 1. Biologically active natural products containing azepine skeletons.

On the other hand, heterocycles such as azepine derivatives are frequently observed possessing diverse biological and medicinal activities (Figure 1).4 Thus, the development of highly efficient synthetic methods to access this type of skeleton has attracted increasing attention. But to our knowledge, only very limited methods have been developed to date. Among them, the intermolecular [5+2]-cycloaddition reactions are commonly used.5 For example, Mascarenas’s group reported a palladium-catalyzed formal [5+2]-annulation between ortho-alkenylanilides and allenes to prepare



2,3-dihydro-1H-benzo[b]azepines (Scheme 1a).6 Zhang and co-workers developed a Rhodium(I)-catalyzed intermolecular [5+2]-cycloaddition of vinyl aziridines and alkynes to access nitrogen heterocycles (Scheme 1b).7 The research group of Luo reported an iron /BF3.OEt2 co-catalyzed intermolecular [5+2]-cycloaddition of 2-(2-aminoethyl)oxiranes with alkynes for producing 2,3-dihydro-1H-azepines (Scheme 1c).8 Despite the obvious synthetic utility, these approaches remain limited substrate scope with regard to both the five-atom units and the alkynes. Especially, the five-atom units are limited to the protected amines with electron-withdrawing substituents such as Tf, Ts, Ms or Ns, the common arylamines substrates are very sparse. In view of these cases and combining with our previous work on the homopropargylic amines,9 we herein reported a novel temperature-controlled cascade cyclization reaction of homopropargylic amines for the construction of pyrrolo-b-cyclobutenes and dihydro-1H-azepines, respectively (Scheme 1d).


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Scheme 1. Cycloaddition reactions for the synthesis of nitrogen heterocycles

RESULTS AND DISCUSSION

In our initial study, the homopropargylic amine 1a and diethyl but-2-ynedioate 2a were selected as model substrates. As shown in Table 1, it was found that no reaction was occurred at 60 oC in 1,2-dichloroethane (DCE) in the presence of CuCl2/Ph3P (entry 1). Using CuOTf/Ph3P, the reaction could afford the expected pyrrolo-b-cyclobutene product 3aa in 31% yield (Table 2, entry 2). Intrigued by this result, other Cu(I) salts, CuI, CuBr and CuCl, were finely screened. But unfortunately, no obvious improved results were obtained (entries 3-5). Changing the Ph3P to other phosphine reagents, such as (2-MeC6H4)3P, 1,2-bis(diphenylphosphanyl)ethane (dppe), tricyclohexylphosphane (Cy3P) and tributylphosphane (nBu3P) or 2,2’-bipyridine, the reactions of homopropargylic amine 1a and diethyl but-2-ynedioate 2a still resulted in the target molecule in low yields (Table 1, entries 6-12) even at increased temperature of 80 oC (entry 12). In view of these results, we attempted to employ the noble metal gold catalyst, a “privileged” candidate for the activation of alkynes, although it was incompetent in our previous work on the



cascade

reactions

of

homopropargylic

amines.

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Consequently,

the

yield

of

pyrrolo-b-cyclobutene 3aa was also low with 37% in the presence of 20 mol% Ph3PAuCl at 60 oC in DCE (entry 13). To our delight, an improved yield of 3aa was obtained in 63% yield at 80 oC with 5 mol% Ph3PAuCl as a catalyst (entry 14). Further increasing the reaction temperature to 105 oC, the reaction of 1a and 2a could smoothly proceed and afford the 3aa in high up to 90% yield in DMF in a short time of 3 h (entry 15). Attempting to use other gold catalysts (IPrAuCl, (PhO)3AuCl, JohnphosAuCl, Me2SAuCl and Ph3PAuNTf2) (Table 1, entries 16-20) or Au/Ag combining system (entries 21-24), no obvious improved results were obtained and the great amount of starting material was recovered in the cases of low yields. Furthermore, using AuCl3 as a catalyst, a low yield of target molecule 3aa was produced (entry 25). Summarily, the optimal reaction conditions were determined as follows: 5 mol% Ph3PAuCl, 1a/2a = 1/2 ratio, in DMF (0.1M) at the heating temperature under argon atmosphere. Table 1. Optimization studies of the hydroamination cyclization-[2+2]-cycloaddition cascade reaction of homopropargylic amine 1a and diethyl but-2-ynedioate 2aa

Entry

Catalyst (mol%)

Additive (equiv.)

Solv.


T (C)

Yield (%)b

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1

CuCl2 (10)

Ph3P (1.2)

DCE

60

NR

2

CuOTf (10)

Ph3P (1.2)

DCE

60

31

3

CuI (10)

Ph3P (1.2)

DCE

60

15

4

CuBr (10)

Ph3P (1.2)

DCE

60

21

5

CuCl (10)

Ph3P (1.2)

DCE

60

34

6

CuCl (10)

(2-MeC6H4)3P (1.2)

DCE

60

30

7

CuCl (10)

Dppe (0.6)

DCE

60

34

8

CuCl (10)

Cy3P (1.2)

DCE

60

2ó(I)], R1 = 0.0854, wR2 = 0.2588, R indices (all data) R1 = 0.1080, wR2 = 0.2358, a = 8.9323 (18) Å, b = 5.4480 (11) Å, c = 38.734 (8) Å, V) 1878.1 (7) A^3, T) 113 K, Z) 4. Reflections collected / unique: 3245/ 2523 [R(int) = 0.078], number of observations [>2ó(I)] 3245, parameters) 247, Goodness-of-fit on F^2) 1.060. Supplementary crystallographic data have been deposited at the Cambridge Crystallographic Data Center. CCDC 1834348. (11) Crystal data for the compound 4ja: C24H31NO4, MW) 397.50, Orthorhombic, Pbca, Final R indices [I> 2ó(I)], R1 = 0.0621, wR2 = 0.1764, R indices (all data) R1 = 0.0740, wR2 = 0.1876, a = 11.923 (2) Å, b = 18.737 (4) Å, c = 19.416 (4) Å, V) 4337.5 (15) A^3, T) 113 K, Z) 8. Reflections collected / unique: 5167/ 4429 [R(int) = 0.057], number of observations [>2ó(I)] 3312, parameters) 265, Goodness-of-fit on F^2) 1.046. Supplementary crystallographic data have been deposited at the Cambridge Crystallographic Data Center. CCDC 1834347. (12) Psutka, K. M.; Bozek, K. J. A.; Maly, K. E. Synthesis and Mesomorphic Properties of Novel Dibenz[a,c]anthracenedicarboximides. Org. Lett. 2014, 16, 5442−5445.



(13) Crystal data for the compound 8: C28H29NO5, MW) 459.54, Triclinic, P1, Final R indices [I> 2ó(I)], R1 = 0.0573, wR2 = 0.1529, R indices (all data) R1 = 0.0639, wR2 =0.1398, a = 7.9305 (16) Å, b = 8.0260 (16) Å, c = 10.9367 (14) Å, V) 588.8 (2) A^3, T) 113 K, Z) 22. Reflections collected / unique: 2066/ 1955 [R(int) = 0.030], number of observations [>2ó(I)] 2066, parameters) 309, Goodness-of-fit on F^2) 0.9614. Supplementary crystallographic data have been deposited at the Cambridge Crystallographic Data Center. CCDC 1844006. (14) Ma, C. L.; Yu, X. L.; Zhu, X. L.; Hu, Y. Z.; Dong, X. W.; Tan, B.; Liu, X. Y. Platinum-Catalyzed Tandem Cyclization Reaction to Multiply Substituted Indolines under Microwave-Assisted Conditions. Adv. Synth. Catal. 2015, 357, 569-575.


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Cycloaddition Cascade Reactions of ... - ACS Publications

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