Communication pubs.acs.org/JACS
Transition Metal-Free trans-Selective Alkynylboration of Alkynes Marina Nogami,† Keiichi Hirano,*,† Misae Kanai,‡ Chao Wang,† Tatsuo Saito,† Kazunori Miyamoto,† Atsuya Muranaka,‡ and Masanobu Uchiyama*,†,‡ †
Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan Advanced Elements Chemistry Research Team, RIKEN Center for Sustainable Resource Science, and Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan
‡
S Supporting Information *
which enables concurrent formations of a C−B bond and a C− Csp3 or C−Csp2 bond. To our knowledge, however, there has been no C−Csp-forming carboboration in the absence of external catalyst. Here, we report a TM-free alkynylboration of alkynes. We have been working on TM-free nucleophilic boration reactions15,16 based on alkoxide-activated diboron reagents,17,18 as well as TM-free cross-coupling.19 In the course of our studies, we have found that the “pseudo-intramolecular activation”20 of diborons enables trans-selective diboration of alkynes by virtue of entropic stabilization of the transition state of C−B bond formation.16a On the basis of this finding, we focused here on propargylic alcohol as a substrate (Scheme 1).
ABSTRACT: We report the first transition metal-free and trans-selective alkynylboration reaction of alkynes. This unprecedented carboboration reaction is enabled by pseudo-intramolecular activation of alkynylboronates using propargylic alcohols. The carboboration affords 4alkynyl-1,2-oxaborol-2(5H)-ols, which are not only versatile building blocks but also exhibit strong violetblue fluorescence emission.
O
rganoboron compounds are undoubtedly one of the most important classes of organic compounds due to their facile C−C bond formation,1 as well as C−heteroelement bond formation.2 Recently, the physicochemical properties of organoborons, such as relatively high bond dissociation energy of the C−B bond and highly electron-withdrawing nature of the vacant p-orbital of the boron atom have been applied in the design of novel functional materials.3 Moreover, the misconception that boron is toxic is being overcome, and the use of organoboron compounds in medicinal chemistry is becoming more widespread.4 The triple bond is a versatile functionality, which can undergo various element-metalation reactions5 thanks to its low bond dissociation energy (acetylene: 55.4 kcal/mol vs ethylene: 83.9 kcal/mol).6 This synthetic flexibility of alkynes has been extensively exploited in work on complex natural products, as exemplified by Trost’s “alkyne linchpin strategy”.7 Moreover, conjugated π-systems can be readily fine-tuned by installing triple bonds to extend the wavelength of light absorption.3d From the viewpoints of materials science and medicinal chemistry, it is highly desirable to install boron and alkyne moieties concurrently onto a double bond in a regio- and stereoselective fashion. Suginome pioneered carboboration of alkynes,8,9 including alkynylboration,9,10 with the aid of transition metal (TM) catalysts. Nickel-catalyzed direct-type alkynylboration reaction gives vinylboronates with cis-selectivity,9 and the transmetalative approach using homo- and bishomopropargylic alcohols enables trans-selectivity.10 Copper-catalyzed element-boration of alkynes has been extensively investigated by Yoshida et al.11 On the other hand, TM-free carboboration of alkynes still remains elusive and has been limited to alkylboration with the use of highly Lewis-acidic trialkylboranes12 and vinylboration of alkynes bearing an azole at the acetylenic terminus.13 Recently, Sawamura and Ohmiya developed a phosphine-catalyzed carboboration of alkynoates,14 © 2017 American Chemical Society
Scheme 1. Our Strategy
Our study commenced with optimization of the reaction conditions; deprotonation of the propargylic alcohol 1a with n BuLi, and subsequent reaction with alkynylboronate 2a at 90 °C, led to the formation of the desired product 3a in 70% isolated yield (Table 1, entry 1). The structure of 3a was determined unequivocally by single-crystal X-ray diffraction analysis, and the boron atom and the triple bond were found to be positioned in a trans-fashion.21 Examination of several solvents showed THF to be much superior to diglyme, nonpolar solvent, or aromatic solvent (entries 2−4). No alkynylboration reaction occurred in the absence of base (entry 5). The use of NaH as a base gave 3a in 28% yield (entry 6), whereas Grignard reagent was totally unproductive (entry 7). DBU did not promote the reaction either (entry 8). These results indicate that the basicity of alkoxide plays a pivotal role in activation of alkynylboronate. Lower temperature (70 °C) resulted in lower conversion of 1a (entry 9), whereas a complex mixture was obtained at 120 °C (entry 10). Lower or higher loading of alkynylboronate 2a decreased the yield to 10% and 34%, respectively (entries 11 and 12). As a result, the set of Received: June 15, 2017 Published: August 14, 2017 12358
DOI: 10.1021/jacs.7b06212 J. Am. Chem. Soc. 2017, 139, 12358−12361
Communication
Journal of the American Chemical Society
-neutral substrates (3n and 3o). Heteroarenes can be installed in the oxaborole structure (3p and 3q). Tetra-substituted olefin equipped with perfluoroalkyl, alkyl, alkynyl, and boryl groups was obtained with perfect regiocontrol (3r) in 55% yield using perfluoroalkylated alcohol. The propiolate derivative was converted to 3s in 82% yield at 70 °C. The oxaborole 3d could also be obtained from a terminal alkyne by in situ preparation of lithium alkoxide in one pot. Intriguingly, oxaboroles other than 3m and 3r emit violet-blue fluorescence (e.g., 3d: ΦF = 67%, CHCl3), and thus might find novel applications in materials science. As shown in Table 3, the substrate with ethyl groups gave the desired product in 55% yield (4a). On the other hand,
Table 1. Optimization of Reaction Conditions
entry 1 2 3 4 5 6 7 8 9 10 11 12 a1
base
temp. (°C)
X
yield (%)a
BuLi BuLi n BuLi n BuLi none NaH MeMgBr DBU n BuLi n BuLi n BuLi n BuLi
90 90 90 90 90 90 90 90 70 110 90 90
1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.5 1.1 2.0
68 (70) 48 trace trace 0 28 0 0 21 40 10 34
solvent THF diglyme hexane toluene THF THF THF THF THF THF THF THF
n n
Table 3. Scope of Propargylic Substituentsa
H NMR yields. Isolated yield is given in parentheses.
conditions of entry 1 was found to be optimal, and the scope of this methodology was next investigated. A wide range of fluorine-containing aromatics is compatible with an acetylenic terminus (Table 2). CF3-substituted Table 2. Scope of Acetylenic Terminusa
a
Isolated yields. bSmall amount of inseparable pinacol. c4 mmol scale, 44 h.
isopropyl groups shut down the reaction (4b) indicating clearly that steric congestion around alkoxy group interferes with efficient pseudo-intramolecular activation (4a and 4b vs 3d, Table 2). Contrary to our expectation, diphenyl-substituted alcohol gave 4c in 60% yield, though its A-value is large (Ph: 3.0 vs iPr: 2.15).24 This could be attributed to the free rotation and flat structural character of the phenyl group, which circumvents repulsive interaction with alkynylboronate 2a. Aryl(methyl)alkynols are particularly reactive, harnessing this type of steric advantage (4d−4f). When the phenyl ring was locked, the yield was slightly decreased (4g). Alcohols with cyclic structure are excellent substrates, minimizing unfavorable steric interactions. Oxaboroles containing four-, five-, and six-membered rings and even adamantane were obtained in high yields (4h−4k). Heteroelements in the ring are not deleterious (4l−4p). An endocyclic double bond had no detrimental effect, and this transformation could be operated on a 4 mmol scale, giving 4q in 60% yield (945 mg). In the presence of a styryl double bond, the triple bond was transformed chemoselectively (4r). It is worth emphasizing that the dialkynyl alcohol was converted to highly unsaturated product 4s in 93% yield. Secondary alcohols were less reactive than the tertiary counterparts and oxaborole
a
Isolated yields. bSubsequent addition of lithium phenylacetylide (5 equiv), followed by stirring for another 24 h. c40 h. dSmall amount of inseparable impurity. e70 °C.
(hetero)aryl groups are of great interest in the discovery of biologically active substances,22 and this methodology offers singly or multiply CF3-containing oxaboroles (3b−3e). The more electronegative SF5, so-called “super CF3” group,23 was installed in the same manner (3f). Polyfluorinated arenes reacted smoothly (3g−3i). The diyne substrate afforded the enediyne product 3j in 68% yield. Mesomerically electronwithdrawing groups are applicable (3k−3m). On the other hand, further optimization is needed for electron-rich and 12359
DOI: 10.1021/jacs.7b06212 J. Am. Chem. Soc. 2017, 139, 12358−12361
Communication
Journal of the American Chemical Society Scheme 4. Transformation of Oxaborolesa
4t was obtained in a significantly lower yield, probably due to the absence of the Thorpe−Ingold effect. Alkynylboronates with a 4-methoxyphenyl, 1-chloropropyl, or TBS group underwent the desired alkynylboration reactions in 78% yield (5a), 38% yield (5b), and 20% yield (5c), respectively. To gain mechanistic insights, we performed DFT calculations using model compounds (Scheme 2). The alkynylation step is Scheme 2. DFT Calculations (M062X/6-31+G*)
a
(a) 4-Iodotoluene (1.1 equiv), Pd(PtBu3)2 (5 mol %), 5 N NaOH aq (2 equiv), dioxane, 90 °C, 48 h. (b) AgNO3 (6 mol %), EtOH/H2O, 80 °C, 20 min. (c) sat. KHF2 aq (ca. 5.4 equiv), MeOH, rt, 4.5 h. (d) MesMgBr (3 equiv), THF, 75 °C, 24 h. (e) NaBO3·4H2O (5 equiv), THF/H2O, rt, 90 min.
protodeboration (11 and 12).26 These compounds are no longer fluorescent (vide supra), showing the importance of the rigid molecular architecture27 and the resonance effect of the boron atom for fluorescence. Highly substituted trifluoroborate 13 was prepared in 68% yield. The hydroxyl group was easily replaced by a mesityl group (14).28 Oxidation with NaBO3 generates α-alkynyl-β-hydroxyketone 15, which can be regarded as the cross-aldol product derived from α-alkynylketone and acetone. In conclusion, we present the first TM-free trans-selective alkynylboration of alkynes. Synthetic utility of this methodology was confirmed by transformations of the oxaborole products. Oxaborole is becoming established as one of the pharmacophores of choice in drug discovery, and further investigations on applications of oxaboroles in medicinal chemistry and utilization of their strong blue fluorescence emission are ongoing.
computed to be a concerted process of C−B bond cleavage and C−C bond formation assisted by the lithium cation, with an activation barrier of 26.9 kcal/mol leading to CP2intra. The compact five-membered transition state (TS1intra) and the sp3hybridized borate structure provide efficient overlap of σB−C of alkynylboronate with the π* orbital of the triple bond of the alcohol compared with the intermolecular reaction (36.3 kcal/ mol).25 Unstable vinyllithium intermediate CP2intra undergoes intramolecular capture of the boron atom, and this barrierless process gives CP3intra with release of a large amount of energy (25.0 kcal/mol). DFT calculations indicated that formation of CP1-like borate is the key to achieving efficient C−C bond formation. This type of borate could be obtained by the reaction of trialkoxyborane with alkynyllithium reagent. Our reaction design utilizes pinacolborane as a boron source, and its catalytic activation by alkoxide 6 generated by 10 mol % nBuLi, results in the formation of trialkoxyborane 8 via dehydrogenative coupling between borate 7 and alcohol 1 (Scheme 3). Subsequent addition of the lithium acetylide gives the corresponding alkynylboration product 9 in 69% yield. Oxaborole is a versatile platform for further chemical elaborations (Scheme 4). Suzuki−Miyaura cross-coupling gives tetra-substituted olefin 10 in 82% yield. Trisubstituted olefins were obtained quantitatively via AgNO3-catalyzed
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ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/jacs.7b06212. Experimental details, NMR spectra (PDF) Chemical data (CIF)
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AUTHOR INFORMATION
Corresponding Authors
*
[email protected] *
[email protected] Scheme 3. Another Approach to Alkynylboration
ORCID
Keiichi Hirano: 0000-0002-2702-9183 Tatsuo Saito: 0000-0001-7477-1674 Kazunori Miyamoto: 0000-0003-1423-6287 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS This work was partly supported by JSPS KAKENHI (S) (No. 17H06173), The Asahi Glass Foundation, Foundation NAGASE Science Technology Development, and Sumitomo Foundation (to M.U.), JSPS Grant-in-Aid for Young Scientists 12360
DOI: 10.1021/jacs.7b06212 J. Am. Chem. Soc. 2017, 139, 12358−12361
Communication
Journal of the American Chemical Society
Kurauchi, D.; Kato, H.; Miyamoto, K.; Saito, T.; Uchiyama, M. Org. Chem. Front. 2016, 3, 565. (17) For a comprehensive review on diboron reagents, see: Neeve, E. C.; Geier, S. J.; Mkhalid, I. A. I.; Westcott, S. A.; Marder, T. B. Chem. Rev. 2016, 116, 9091 and references therein.. (18) Diboration of nonactivated olefin with alkoxide-activated diborons was pioneered by Fernández, see: (a) Bonet, A.; PubillUlldemolins, C.; Bo, C.; Gulyás, H.; Fernández, E. Angew. Chem., Int. Ed. 2011, 50, 7158. (b) Miralles, N.; Alam, R.; Szabó, K. J.; Fernández, E. Angew. Chem., Int. Ed. 2016, 55, 4303. (19) (a) Minami, H.; Saito, T.; Wang, C.; Uchiyama, M. Angew. Chem., Int. Ed. 2015, 54, 4665. (b) Minami, H.; Wang, X.; Wang, C.; Uchiyama, M. Eur. J. Org. Chem. 2013, 2013, 7891. (20) (a) Yamamoto, Y.; Ishii, J.; Nishiyama, H.; Itoh, K. J. Am. Chem. Soc. 2005, 127, 9625. (b) Blaisdell, T. P.; Caya, T. C.; Zhang, L.; SanzMarco, A.; Morken, J. P. J. Am. Chem. Soc. 2014, 136, 9264. (c) Verma, A.; Snead, R. F.; Dai, Y.; Slebodnick, C.; Yang, Y.; Yu, H.; Yao, F.; Santos, W. L. Angew. Chem., Int. Ed. 2017, 56, 5111. (21) Structural data can be retrieved from CSD (CCDC 1553760). (22) (a) Meanwell, N. A. J. Med. Chem. 2011, 54, 2529. (b) Müller, K.; Faeh, C.; Diederich, F. Science 2007, 317, 1881. (c) Purser, S.; Moore, P. R.; Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320. (23) For a review of chemistry of SF5 group, see: Savoie, P. R.; Welch, J. T. Chem. Rev. 2015, 115, 1130. (24) Basic Organic Stereochemistry; Eliel, E. L.; Wilen, S. H.; Doyle, M. P., Eds.; Wiley-Interscience: New York, 2001. (25) Intermolecular reaction did not afford the desired product. For computational analyses, see Supporting Information.
(A) (No. 16H06214), and (B) (No. 26860010) (to K.H.). We thank RIKEN Integrated Cluster of Clusters (RICC) for providing resources for the DFT calculations.
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