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Radical Multicomponent Carboamination of [1.1.1]Propellane Junichiro Kanazawa, Katsuya Maeda, and Masanobu Uchiyama J. Am. Chem. Soc., Just Accepted Manuscript • DOI: 10.1021/jacs.7b11865 • Publication Date (Web): 13 Nov 2017 Downloaded from http://pubs.acs.org on November 13, 2017
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Radical Multicomponent Carboamination of [1.1.1]Propellane Junichiro Kanazawa,*,†,‡ Katsuya Maeda,† and Masanobu Uchiyama*,‡,# †
Central Pharmaceutical Research Institute, Japan Tobacco Inc., 1-1 Murasaki-cho, Takatsuki, Osaka 569-1125, Japan. Elements Chemistry Laboratory, RIKEN, 2-1 Hirosawa, Wako-shi, Saitama 351-0198, Japan. # Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan. Supporting Information Placeholder ‡
ABSTRACT: Three-dimensional, small-ring scaffolds
are very important in modern drug discovery to expand the available drug-like chemical space and to optimize drug candidates. Among them, bicyclo[1.1.1]pentane (BCP) is regarded as a high-value bioisostere for a phenyl ring or tert-butyl group; it provides an option to generate drug-like molecules with good passive permeability, high aqueous solubility, and improved metabolic stability, though the lack of methodology to functionalize BCP remains a significant challenge. Here we present an efficient method, developed with the aid of density functional theory (DFT) calculations, for the synthesis of multi-functionalized BCP derivatives by means of a radical multicomponent carboamination of [1.1.1]propellane. This reaction features mild conditions, one-pot operation, and gram-scale synthetic capability, and opens up a unique and highly efficient route for the synthesis of muli-functionalized BCP derivatives, including synthetically useful 3-substituted BCP-amines.
In modern drug discovery, three-dimensional smallring scaffolds are increasingly being employed to expand the available drug-like chemical space and to optimize drug candidates.1 A representative example is bicyclo[1.1.1]pentane (BCP, 1), which was first utilized in the MGluR1 antagonists developed by Novo Nordisk in 1996.2 BCP is considered as a bioisostere of the phenyl ring3 and tert-butyl group,4 and its introduction can significantly improve passive permeability, aqueous solubility, metabolic stability, and other properties (Chart 1). Chart 1. Bicyclo[1.1.1]pentane
1-Aminobicyclo[1.1.1]pentane (BCP-amine) derivatives are already a pharmaceutically important scaffold,1c,1d but they remain synthetically challenging. The use of [1.1.1]propellane (2) has opened up new avenues
A ~ C: Pioneering Synthetic Work of Bicyclo[1.1.1]pentane (BCP) Derivatives H2 N
C [1.1.1]Propellane (2)
1-Amino-BCP (BCP-amine)
Symmetric Disubstitution
A, B
X
H2N
X
X
Unsymmetrization
A Michl et al. (1988)7
O
Cl
O
3 steps
MeCOCOMe hv
2 steps H3N
HO O
B Adsool et al. (2015)9 I
Unsymmetric Disubstituted BCPs
Multi-step Transformation
Disubstituted BCPs
I2
Lack of Methodology
This Work
NaN3
N3
I
C Baran et al. (2016)1c,1d Bn2NMgClLiCl
OMe
OMe O
Cl
1. TBACB, AIBN, Benzene, Air Flow H3N I 2. TTMSS, AIBN, HCl Cl
Pd(OH)2/C, H2 H3N
D This Work
Boc
N N
O
Boc H2N
H N
Fe(Pc) / TBHP / Cs2CO3 X
HN N Boc
Boc
Radical Multicomponent X Carboamination X = COOMe, Ar, HetAr, Alkyl
Figure 1. (A), (B), (C) Synthesis of BCP-amine and 3substituted BCP-amines. (D) One-pot radical multicomponent strategy. for synthesis of BCP derivatives,5 but access to 3substituted BCP-amines is still difficult. For example, 3aminobicyclo[1.1.1]pentane-1-carboxylic acid has considerable potential as an unnatural amino acid in the pharmaceutical sciences,6 but is extremely costly (methyl ester: ~$300,000/kg) due to the complex multi-step synthetic procedure, including photoreaction as the first step (Figure 1A).7 3-Aryl BCP-amines are also synthetically inaccessible, though they are of interest in drug discovery as a bioisostere of biarylamine to escape the “flatland” of multiple aryl systems.8 So far, there is the only one example of the synthesis of 3-phenyl BCPamine (Figure 1B)9 and there has been no report on the introduction of substituted aryl groups into BCP-amine. Bunker et al. demonstrated that Carreira’s hydroamination10 could be applied to [1.1.1]propellane to give BCPamine.11 Baran has reported a strain-release-type transformation of [1.1.1]propellane by turbo-amido-Grignard reagents to give BCP-amine (Figure 1C).1c,1d Also, Knochel developed an elegant practical method to syn-
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thesize bis-arylated BCPs by combining Grignard reagent-mediated ring-opening of [1.1.1]propellane and Negishi coupling after transmetalation with ZnCl2.12 However, the applicability of these protocols to synthesize 3-functionalized BCP-amines remains unclear.13 Taking account of the facts that [1.1.1]propellane contains a characteristic fragile central bond14 and bicyclo[1.1.1]pent-1-yl radical (BCP-radical) is kinetically stable (energy barrier to ring opening: ~26 kcal/mol),15 we hypothesized that a one-pot radical multicomponent carboamination (radical addition / central bond cleavage / radical trapping) protocol (Figure 1D) might provide direct methodology to form C–C and C–N bonds simultaneously on a BCP scaffold and generate 3functionalized BCP-amines. In radical reactions involving [1.1.1]propellane, it is usually difficult to control polymerization as a side reaction.16 However, our model calculations indicated that di-tert-butyl azodicarboxylate (3) can act as a radical acceptor of the intermediary 3substituted BCP-radical (INT1) to give a more stable radical intermediate (INT2a).10,11a The C–N bond formation (∆G‡ = 6.6 kcal/mol) is kinetically preferred by 3.6 kcal/mol over radical oligomerization of [1.1.1]propellane (∆G‡ = 10.2 kcal/mol) to give [n]staffanes (Figure 2). INT2a contains an intrinsically stable amidyl radical, resulting in a highly exothermic process. Therefore, if we can find an appropriate precursor that generates radical species by hydrogen abstraction with INT2a, an efficient radical chain reaction might be possible.
unsuccessful. Thus, we focused on screening of other catalysts/oxidants/additives and on optimization of the reaction conditions for the radical multicomponent carboamination of [1.1.1]propellane (2), as summarized in Table 1. We found that the combination of tert-butyl hydroperoxide (TBHP) and iron(II) phthalocyanine (Fe(Pc)) (cat.) was most effective; on the other hand, FeCl2, Fe(OAc)2, CuBr, or CuCl did not catalyze this transformation. Other terminal oxidants, such as di-tertbutyl peroxide (TBP), benzoyl peroxide (BPO), and cumene hydroperoxide (CHP), gave the desired product in moderate yield. Addition of inorganic base to the reaction mixture was effective, and Cs2CO3 gave the best result (Entry 7). Use of K2CO3 or K3PO4 gave comparable results, but organic bases and NaHCO3 decreased the yield of 5. The reaction temperature/time, solvent, and ratio of substrates also influenced the yield of this radical multicomponent carboamination. Examination of several solvents showed acetonitrile to be greatly superior to etheric solvents, non-polar solvents, or aromatic solvents.20 Finally, the set of conditions shown in Entry 19 was found to be optimal. Table 1. Optimization of Reaction Conditionsa
Boc
2
∆G (Kcal/mol) TS1b
+10.2
–35.2 TS1a
+6.6 OMe O
INT1
Boc
N N
Boc Boc
N N
Boc OMe
INT2b OMe –52.2
O
INT2b [n]Staffanes
O
INT2a Target Molecule
INT2a
Figure 2. Our model calculation at the UM062X/631G* level (∆G in kcal/mol). Based on this working hypothesis, we initially selected methyl carbazate (4) as a methoxycarbonyl radical precursor.17 The initial hydrogen abstraction step from 4 proceeds in the presence of oxidant and transition metal catalyst, and the use of toxic tin reagents or photoirradiation equipment is not necessary.18 We then investigated the radical multicomponent carboamination of [1.1.1]propellane (2) freshly prepared in pentane solution19 in the presence of 3 and 4 to determine the best reaction conditions (Table 1). Gratifyingly, an initial attempt under typical Fenton reaction conditions (H2O2/FeCl2 (cat.) system; MeCN, 0 °C, 12 h) afforded the desired product 5 in 28% yield (Entry 1). However, attempts improve the yield of 5 in the FeCl2/H2O2 system under various conditions were
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N N
H N
Boc H2N
OMe O
3
4
Catalyst Oxidant Additive MeCN, Temp., Time
Entry
Catalyst (mol%)
Oxidant (equiv.)
Additive (equiv.)
Temp. (°C)
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
FeCl2 (20) Fe(Pc) (20) Fe(Pc) (20) Fe(Pc) (20) Fe(Pc) (20) Fe(Pc) (20) Fe(Pc) (20) Fe(Pc) (20) Fe(Pc) (20) Fe(Pc) (20) Fe(Pc) (20) Fe(Pc) (20) Fe(Pc) (20) FeCl2 (20) Fe(OAc)2 (20) CuBr (20) CuCl (20) Fe(Pc) (5) Fe(Pc) (5) Fe(Pc) (5)
H2O2 (4.0) H2O2 (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBP (2.0) BPO (2.0) CHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (2.0) TBHP (1.5) TBHP (1.0)
none none none K2CO3 (1.0) K3PO4 (1.0) NaHCO3 (1.0) Cs2CO3 (1.0) DMAP (1.0) Pyridine (1.0) Et3N (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0) Cs2CO3 (1.0)
0 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. 0 to r.t. –20 –20 –20
HN N Boc
Boc OMe
5 O Time Yieldb (h) (%) 12 28 12 18 12 40 12 47 12 47 12 29 12 52 12 42 12 30 12 39 12 33 12 37 12 44 12 8 12 7 12 6 12 5 1 58 c 1 61(57) 1 39
a
Reaction conditions: 2 in pentane (1.0 mmol), 2.0 equiv. of 3 and 4, catalyst, oxidant, additive in acetonitrile (6.0 mL). bDetermined by 1H NMR using benzyl benzoate as an internal standard. cIsolated yield.
Scheme 1. Gram-scale Synthesis and Transformation to Amine Fe(Pc) (5 mol%) Boc
2 (6.4 mmol)
N N
Boc H2N
OMe TBHP (1.5 equiv.)
Cs2CO3 (1.0 equiv.)
O
3 (2.0 equiv.)
HCl
H N
MeCN, –20 °C, 1 h
4 (2.0 equiv.)
Cl H N
H3N
OMe
AcOEt, r.t., 36 h O
6
[X-ray] 5 1.6 g (71%) PtO2 (10 mol%) H2 (1 atm) MeOH, r.t., 12 h
Cl H3N OMe O
7 92% (2 steps)
Notably, the reaction could be conducted on gram scale to provide 5 in 71% yield. The structure of 5 was deter-
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mined unequivocally by single-crystal X-ray diffraction analysis, and the methoxycarbonyl group and the hydrazine moiety were found to be installed at the 1- and 3positions of the BCP skeleton, respectively, as expected. The hydrazine moiety is a versatile platform for further chemical elaborations. Treatment of 5 with 4 N HCl in AcOEt gave the hydrazine hydrochloride salt (6). Reduction of the N–N bond under hydrogenation conditions in the presence of PtO2 gave methyl 3aminobicyclo[1.1.1]pentane-1-carboxylate hydrochloride salt (7) in 92% yield (over 2 steps) (Scheme 1).21 Table 2. Radical Multicomponent Carboamination of [1.1.1]Propellanea
Boc
2 (1 mmol) HN N Boc
N N
Boc
Fe(Pc) (5 mol%) nCl H TBHP (1.5 equiv.) N X Cs2CO3 (n + 1.0 equiv.) nH+H2N
HN N Boc
MeCN, –20 °C, 1 ~ 3 h
9
3 (2.0 equiv.)
Boc
HN N Boc
8 (2.0 equiv.) Boc
Boc
HN N Boc
HN N Boc
Boc
HN N Boc
Boc
HN N F Boc
Boc
9i:
41%d Boc
HN N Boc
9m: 64%d HN N Boc
Boc
9k:
HN N Boc OCF3
57%d
Boc
Cl
Me
9p: 46%e
N
9q: 56%b
HN N Boc
Radical Trapping
Boc
N
HN N Boc
N
OMe
43%c
HN N Boc
OMe
∆G‡ =
+7.0 INT3 ∆G = –33.6 ‡ ∆G = +5.9
OMe
Fe(Pc) TBHP N
OMe ref. 18
4
O
10 Fe(Pc)/TBHP 12
Boc OMe
5 O
Boc
INT3 O
HN N
N
Boc
INT2a O
N2
OMe
O
N N
OMe
5 Not Detected by LC-MS Analysis
∆G‡ = +6.6 ∆G = –52.2
OMe
Boc
O
3
OMe
11
Hydrogen Abstraction
Figure 3. (A) Radical trapping experiment with TEMPO. (B) DFT calculation on radical chain cylcle at the UM062X/6-31G* level (∆G in kcal/mol).
Boc
Boc CF3
N
9r: 60%f
Boc
O
Regeneration of Methoxycarbonyl Radical
HN N Boc
Cl
N N
Boc
∆G‡ = +9.1 ∆G = –28.3
Boc
9o: 42%d
Boc
MeCN, –20 °C, 1 h
4 (2.0 equiv.)
Radical Addition and Central Bond Cleavage
∆G‡ = +1.5 ∆G = –27.8
N N N
3 (2.0 equiv.)
Fe(Pc) (5 mol%) TBHP (1.5 equiv.) Cs2CO3 (1.0 equiv.) TEMPO (2.0 equiv.)
12
9l:
HN N Boc
HN N Boc
OMe O
NO2
OMe
CN
HN N Boc
H2 N
H N
O
9n: 72%b Boc
B
Boc
O
O
9j: 71%b F
2 (1 mmol)
2
9h: 42%d
HN N Boc
Br
Boc
N N
INT1
Boc
F
9e (ortho): 49%b 9f (meta): 57%b 9g (para): 53%b
9b (ortho): 66%b 9c (meta): 38%c 9d (para): 44%c
A
X
HN N Boc
CF3
9a: 53%b
Boc
amined alkyl hydrazine substrates. When 2,2,2trifluoroethyl)hydrazine was used, 9s was obtained in moderate yield. This result suggests that the present radical multicomponent carboamination is applicable to C(sp3)–substrates on the BCP scaffold. To our knowledge, this is the first example of one-pot radical multicomponent carboamination of [1.1.1]propellane (2) to afford highly multi-functionalized BCPs.
9s: 56%b
a
Reaction conditions: 2 in pentane (1.0 mmol), 2.0 equiv. of 3 and 8, Fe(Pc), TBHP, Cs2CO3 in acetonitrile (6.0 mL) at –20 °C. Yields were determined by 1H NMR using benzyl benzoate as an internal standard. b hydrazine monohydrochloride (n = 1), time (1 h). chydrazine (n = 0), time (3 h). dhydrazine monohydrochloride (n = 1), time (3 h). ehydrazine dihydrochloride (n = 2), time (1 h). fhydrazine (n = 0), time (1 h).
We next applied this radical multicomponent carboamination to the synthesis of 3-aryl BCP-amine equivalents (Table 2). A wide range of arylhydrazines could be employed: both electron-donating and -withdrawing substituents at the ortho-, meta-, and para-positions of the aryl ring were well tolerated (9b–g, o). Halogens on the aryl ring (F, Cl, and Br) were not deleterious to the reaction; the desired products were obtained (9e–j), and radical-mediated dehalogenation reactions were not observed. Various functional groups were also compatible, including trifluoromethyl (9b–d), methyl ester (9k), nitro (9l), trifluoromethyl ether (9m), nitrile (9n), and tertbutyl (9o). The reaction also allowed introduction of heterocyclic groups, such as pyrazolyl (9p), pyridinyl (9q), and pyrazyl (9r). To access further synthetically useful radical multicomponent carboamination, we ex-
To reach a better understanding of the present radical multicomponent carboamination, a mechanistic investigation was performed. When 2.0 equiv. of TEMPO was added to the reaction mixture as a radical inhibitor, the desired product (5) was not obtained at all and the TEMPO-COOMe, and TEMPO-BCP-COOMe adducts were detected by LC-MS analysis (Figure 3A), supporting the free radical mechanism. Density functional theory (DFT) calculations (UM062X/6-31G*) were then employed to corroborate the experimental results and to comprehensively unveil the radical chain cycle (Figure 3B). Firstly, addition of methoxycarbonyl radical (12) (generated in situ by oxidative denitrogenation of methyl carbazate (4)) to [1.1.1]propellane (2) with a small activation energy of 9.1 kcal/mol, led to cleavage of the central bond to give BCP-radical intermediate (INT1) with a high stabilization energy of 28.3 kcal/mol. Di-tertbutyl azodicarboxylate (3) acts as an excellent radical acceptor of INT1 to give a stable amidyl radical (INT2a) (∆G‡ = 6.6 kcal/mol) with a very large stabilization energy of 52.2 kcal/mol. INT2a undergoes hydrogen abstraction from 10 (∆G‡ = 7.0 kcal/mol) with a large exothermicity to provide the unsymmetrically disubstituted BCP product (5) and diazenyl radical (11), which smoothly produces 12 with the release of molecular nitrogen (∆G‡ = 1.5 kcal/mol). In this hydrogen abstraction step, there are multiple candidates for hydrogen
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sources in the reaction mixture, such as H2O, tBuOH, TBHP, and CH3CN. Based on the activation energies, 10 appears to be the most energetically favorable substrate.22 This means that the hydrazine moiety is an ideal precursor to prevent generation of highly reactive oxygen free radicals.18,23 The whole of this catalytic cycle turned out to be kinetically and thermodynamically favorable, in good accordance with the experimental observation (the reaction proceeds under very mild conditions, and is generally completed within 1 h at –20 °C). We have developed the first radical multicomponent carboamination of [1.1.1]propellane with hydrazyl reagents as a radical precursor and di-tert-butyl azodicarboxylate as a radical acceptor. This multicomponent carboamination features mild reaction conditions, a tinfree/photoirradiation-free system, one-pot operation, and gram-scale synthetic capability, and thus provides a highly efficient method for synthesizing a wide range of novel multi-functionalized bicyclo[1.1.1]pentane derivatives. These products can be easily transformed into a variety of synthetically useful 3-substituted BCPamines, which have many potential applications in pharmaceutical chemistry, agricultural chemistry, and materials sciences. We also obtained a comprehensive reaction profile of the present radical multicomponent carboamination, by employing a combination of experimental and computational methods. Further studies to expand the scope of this radical multicomponent methodology to activated/inactivated olefins, benzyne, and other types of propellanes are ongoing in our laboratory. ASSOCIATED CONTENT Supporting Information. The Supporting Information is available free of charge on the ACS Publications website at DOI: Experimental details and characterization data (PDF) X-ray data for compound 5 (CCDC 1570594) (CIF)
AUTHOR INFORMATION Corresponding Author
*
[email protected] *
[email protected] Notes The authors declare no competing financial interest.
ACKNOWLEDGMENT Financial support for experimental work was provided by Japan Tobacco Inc. (JT). This work was also supported by JSPS Grant-in-Aid for Scientific Research on Innovative Areas (No. 17H05430), JSPS KAKENHI (S) (No. 17H06173), and grants from Asahi Glass Foundation and Kobayashi International Scholarship Foundation (to M.U.). The DFT calculations were performed on the RIKEN HOKUSAI GreatWave (GW). We gratefully acknowledge the Advanced Center for Computing and Communication (RIKEN) for providing computational resources. We also thank Dr. Hiromasa Hashimoto, Dr. Motohide Sato, Dr.
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Makoto Shiozaki, and Mr. Kazuyuki Hirata (JT) for their support, Mr. Ryuhei Okura (JT) for assistance with X-ray crystallographic analysis of 5, Mr. Mitsumasa Takahashi and Ms. Toshimi Yamada (JT) for the NMR measurements, and Mr. Eita Nagao (JT) for the ESI-MS measurements.
REFERENCES (1) (a) Burkhard, J. A.; Guérot, C.; Knust, H.; Carreira, E. M. Org. Lett. 2012, 14, 66. (b) Carreira, E. M.; Fessard, T. C. Chem. Rev. 2014, 114, 8257. (c) Gianatassio, R.; Lopchuk, J. M.; Wang, J.; Pan, C.-M.; Malins, L. R.; Prieto, L.; Brandt, T. A.; Collins, M. R.; Gallego, G. M.; Sach, N. W.; Spangler, J. E.; Zhu, H.; Zhu, J.; Baran, P. S. Science 2016, 351, 241. (d) Lopchuk, J. M.; Fjelbye, K.; Kawamata, Y.; Malins, L. R.; Pan, C.-M.; Gianatassio, R.; Wang, J.; Prieto, L.; Bradow, J.; Brandt, T. A.; Collins, M. R.; Elleraas, J.; Ewanicki, J.; Farrell, W.; Fadeyi, O. O.; Gallego, G. M.; Mousseau, J. J.; Oliver, R.; Sach, N. W.; Smith, J. K.; Spangler, J. E.; Zhu, H.; Zhu, J.; Baran, P. S. J. Am. Chem. Soc. 2017, 139, 3209. (2) Pellicciari, R.; Raimondo, M.; Marinozzi, M.; Natalini, B.; Costantino, G.; Thomsen, C. J. Med. Chem. 1996, 39, 2874. (3) Stepan, A. F.; Subramanyam, C.; Efremov, I. V.; Dutra, J. K.; O’Sullivan, T. J.; Dirico, K. J.; McDonald, W. S.; Won, A.; Dorff, P. H.; Nolan, C. E.; Becker, S. L.; Pustilnik, L. R.; Riddell, D. R.; Kauffman, G. W.; Kormos, B. L.; Zhang, L.; Lu, Y.; Capetta, S. H.; Green, M. E.; Karki, K.; Sibley, E.; Atchison, K. P.; Hallgren, A. J.; Oborski, C. E.; Robshaw, A. E.; Sneed, B.; O’Donnell, C. J. J. Med. Chem. 2012, 55, 3414. (4) Westphal, M. V.; Wolfstädter, B. T.; Plancher, J.-M.; Gatfield, J.; Carreira, E. M. ChemMedChem 2015, 10, 461. (5) For reviews of [1.1.1]propellane, see: (a) Levin, M. D.; Kaszynski, P.; Michl, J. Chem. Rev. 2000, 100, 169. (b) Dilmaç, A. M.; Spuling, E.; de Meijere, A.; Bräse, S. Angew. Chem. Int. Ed. 2017, 56, 5684. (6) Pätzel, M.; Sanktjohanser, M.; Doss, A.; Henklein, P.; Szeimies, G. Eur. J. Org. Chem. 2004, 493. (7) Kaszynski, P.; Michl, J. J. Org. Chem. 1988, 53, 4593. (8) Lovering, F.; Bikker, J.; Humblet, C. J. Med. Chem. 2009, 52, 6752. (9) Thirumoorthi, N. T.; Shen, C. J.; Adsool, V. A. Chem. Commun. 2015, 51, 3139. (10) Waser, J.; Gaspar, B.; Nambu, H.; Carreira, E. M. J. Am. Chem. Soc. 2006, 128, 11693. (11) (a) Bunker, K. D.; Sach, N. W.; Huang, Q.; Richardson, P. F. Org. Lett. 2011, 13, 4746. (b) For syntheses of BCP-amine other than ref 1c, 1d, and 11a, see: Bunker, K. D. Patent WO 2015/089170 A1 (12) Makarov, I. S.; Brocklehurst, C. E.; Karaghiosoff, K.; Koch, G.; Knochel, P. Angew. Chem. Int. Ed. 2017, 56, 12774. (13) For synthesis of 3-alkyl BCP-amines, see: Bunker, K. D.; Guo, C.; Grier, M. C.; Hopkins, C. D.; Pinchman, J. R.; Slee, D. H.; Huang, Q.; Kahraman, M. Patent WO 2016/044331 A1 (14) Wu, W.; Gu, J.; Song, J.; Shaik, S.; Hiberty, P. C. Angew. Chem. Int. Ed. 2009, 48, 1407. (15) Della, E. W.; Schiesser, C. H.; Taylor, D. K.; Walton, J. C. J. Chem. Soc., Perkin Trans. 2 1991, 0, 1329. (16) Wiberg, K. B.; Waddell, S. T. J. Am. Chem. Soc. 1990, 112, 2194. (17) We examined other methods for the generation of C-radicals, but these were not applicable the present multicomponent reaction, and did not afford the target molecule; see Supporting Information. (18) Taniguchi, T.; Sugiura, Y.; Zaimoku, H.; Ishibashi, H. Angew. Chem. Int. Ed. 2010, 49, 10154. (19) We synthesized 2 in pentane by slightly modified relevant experiments reported in ref 1c and 1d, see Supporting Information. (20) For details of optimizations, see Supporting Information. (21) We confirmed the conversion of some of the aryl-substituted hydrazines to the corresponding amines; see Supporting Information. For reaction conditions, refer to ref. 11a. (22) For details of DFT calculation, see Supporting Information. (23) (a) Liu, W.; Li, Y.; Liu, K.; Li, Z. J. Am. Chem. Soc. 2011, 133, 10756. (b) Cheng, J.-K.; Loh, T.-P. J. Am. Chem. Soc. 2015, 137, 42.
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