Letter Cite This: Org. Lett. 2018, 20, 3601−3604
pubs.acs.org/OrgLett
Catalyst-Free Aminomethylamination of o‑Hydroxystyrenes with Aminals to 1,3-Diamines Peipei Liu,†,∇ Suchen Zou,‡,∇ Bangkui Yu,‡ Lin Li,*,† and Hanmin Huang*,‡ †
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Key Laboratory of Catalysis and Materials Science of the State Ethnic Affairs Commission and Ministry of Education, College of Chemistry and Materials Science, South-Central University for Nationalities, Wuhan 430074, People’s Republic of China ‡ Hefei National Laboratory for Physical Sciences at the Microscale and Department of Chemistry, CAS Center for Excellence in Molecular Synthesis, University of Science and Technology of China, Chinese Academy of Sciences, Hefei, 230026, People’s Republic of China S Supporting Information *
ABSTRACT: A new catalyst-free protocol for aminomethylamination of ohydroxystyrenes with simple aminals is described. This direct and operationally simple method provides a fundamentally novel and rapid approach for the synthesis of 1,3-diamines. This novel reaction occurs under mild reaction conditions and provides a fundamentally unique and efficient strategy for the synthesis of 1,3-diamines with good to excellent yields.
development of efficient methods toward 1,3-diamines via difunctionalization of simple alkenes is still a great challenge. As an electron-rich aromatic alkene, o-hydroxystyrenes have long been recognized as a type of versatile reactant in both metal- and organocatalyst-mediated reactions.7 In these transformations, the hydroxyl moiety serves as an activating group and plays a key role in facilitating the double bond to be attacked by either an electrophile or nucleophile in the presence of suitable catalysts. On the other hand, the facile [1,5]-H-shifts existing in these types of molecules enabled the formation of quinone methide,8 which might be captured by a suitable nucleophile to furnish a difunctionalization reaction. In this context, Sigman and co-workers described an elegant palladium-catalyzed oxidative dialkoxylation of o-hydroxyaromatic alkenes with alcohols under aerobic reaction conditions,9 in which the quinone methide intermediate was postulated as a key intermediate for incorporating the second nucleophile into the alkene to furnish the difunctionalization reaction. These results, together with our chemistry on the Pdcatalyzed C−N bond activation of aminals,4−6,10 inspired us to envision that the quinone methide would be likewise generated after insertion of the double bond into the C−Pd bond of the palladated complex. The generated quinone methide might be captured by aminal to furnish the desired 1,3-diamine. (See Scheme 1.) Herein, we report a new reaction between ohydroxystyrene and aminal, which provides a new and rapid approach to 1,3-diamines from simple starting materials. To investigate the possibility of the aminomethylamination reaction between an o-hydroxystyrene and an aminal, we initially tested the reaction of o-hydroxystyrene (1a) and N,N,N′,N′-tetrabenzylmethanediamine (2a) in the presence of Pd(TFA)2/dppe catalyst. To our delight, the desired product
1,3-Diamines are found in a wide range of pharmaceuticals, agrochemicals, nature products, and organic materials. In addition, chiral 1,3-diamines have not only been utilized as important chiral building blocks for the synthesis of bioactive molecules, but also could be employed as ligands and catalysts in catalytic asymmetric reactions.1 As a result, much effort has been devoted to the development of effective methods to access these compounds.2 At present, the most common approaches to these types of compounds are based on multistep reactions. However, these methods suffer from some disadvantages, such as the use of stoichiometric amounts of organometallic compounds, toxic reagents, and harsh reaction conditions. An alternative strategy to 1,3-diamines would be the direct difunctionalization of alkene with simultaneous incorporation of an amine and aminomethyl group into the double bond of the alkene.3 In this context, in our efforts to construct 1,3diamines, we have recently reported a palladium-catalyzed difunctionalization of allenes with aminals via C−N bond activation, in which the challenging β-hydride elimination was suppressed by the formation of a π-allylpalladium intermediate.4 In addition, an enantioselective aminomethylamination of conjugated 1,3-dienes with aminals was also realized with chiral palladium complex as a catalyst with the same strategy.5 These reactions are particularly effective for the synthesis of allylic 1,3diamines, which have proven to be valuable building blocks for the efficient synthesis of functionalized complex organic compounds. In order to investigate the capability of our newly developed cyclopalladated complex,6 our research interest focused on exploring the potential difunctionalization reaction between simple alkenes and aminals with the cyclopalladated complex as a leading complex. Unexpectedly, attempts to construct simple 1,3-diamines with common simple alkenes as starting materials via the analogous aminomethylamination reaction strategy have not been successful, because of the facile β-hydride elimination step. Thus, the © 2018 American Chemical Society
Received: May 1, 2018 Published: June 7, 2018 3601
DOI: 10.1021/acs.orglett.8b01383 Org. Lett. 2018, 20, 3601−3604
Letter
Organic Letters
Having identified the effective reaction conditions, we next investigated the scope and generality of this catalyst-free difunctionalization reaction. As shown in Scheme 2, a series of
Scheme 1. New Strategy for the Synthesis of 1,3-Diamines
Scheme 2. Substrate Scopea
was obtained in 84% isolated yield when the reaction was conducted in CH2Cl2 at room temperature for 12 h. Further examination of different Pd-catalysts demonstrated that many types of palladium catalysts could promote this reaction (see the Supporting Information), which led us to doubt whether the desired reaction could proceed in the absence of palladium catalyst. Unexpectedly, the reaction of 1a with 2a in CH2Cl2 indeed produced 88% aminomethylamination product 3aa without a palladium catalyst (Table 1, entry 3). A solvent effect Table 1. Screening of Reaction Conditionsa
entry
cat
solvent
temperature (°C)
time (h)
yieldb (%)
1c 2d 3 4 5 6 7 8 9 10 11 12 13 14 15
Pd(TFA)2/dppe Pd(TFA)2
CH2Cl2 CH2Cl2 CH2Cl2 THF DMF toluene DCE CH3CN n-PrOH CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2 CH2Cl2
25 25 25 25 25 25 25 25 25 25 25 25 0 40 60
12 12 12 12 12 12 12 12 12 6 9 18 12 12 12
84 86 88 41 48 55 60 69 70 77 85 83 39 77 58
a Reaction conditions: 1 (0.48 mmol), 2 (0.4 mmol), CH2Cl2 (1.0 mL), room temperature, 12 h, isolated yield.
o-hydroxystyrenes bearing a variety of substituents were examined. This difunctionalization reaction appears to be insensitive to the electronic and steric effects of the substituents. Substrates bearing electron-donating and electron-withdrawing groups in the para positions of the −OH group on the phenyl ring provided the corresponding 1,3diamines in good to excellent yields (49%−93% yields). In addition, substrates with substitutions at various positions are useful in delivering the desired products. Moreover, this reaction exhibited excellent compatibility for a broad range of functional groups, such as ether (3ba and 3ca), chloride (3fa), bromide (3ga), hydroxyl (3ha), and nitro (3ia). To our delight, the highly electron-deficient substrates with a nitro group gave the desired product in 93% isolated yields. The sterically hindered substrate 1d with two t-Bu groups on the arene showed higher reactivity. As expected, no reaction occurred when o-methoxystyrene was utilized as a coupling partner. This result indicates that the hydroxy group is essential for the present reaction by forming the quinone methide intermediate (see the Supporting Information). Moreover, only monofunctionalized product was observed when 2-propenylphenol (internal alkene) was subjected to the standard reaction conditions.11 Combinations of different aminals with ohydroxystyrene were then explored in an effort to access
a
Reaction conditions: 1a (0.48 mmol), 2a (0.4 mmol), solvent (1.0 mL), room temperature, 12 h. bIsolated yield. cPd(TFA)2 (0.02 mmol), dppe (0.022 mmol), 12 h. dPd(TFA)2 (0.02 mmol), 12 h.
investigation demonstrated that the desired reaction could proceed in many solvents, which included tetrahydrofuran (THF), dimethyl formamide (DMF), toluene, dichloroethane, CH3CN, and n-PrOH (Table 1, entries 4−9). It was found that the reaction could be completed in 9 h to give the desired product in excellent yield (Table 1, entry 11). Finally, variation of the reaction temperatures resulted in diminished yields, as lower temperature led to lower conversion, but higher temperature may cause polymerization of the alkenes. 3602
DOI: 10.1021/acs.orglett.8b01383 Org. Lett. 2018, 20, 3601−3604
Letter
Organic Letters
this is an intermolecular reaction (see the Supporting Information). Based on the above results and precedent reports,7 a plausible reaction mechanism was proposed for this catalystfree reaction. As illustrated in Scheme 4, o-hydroxystyrene 1a
unprecedented structural motifs. A range of benzyl and simple amines derived aminals were found to be compatible with this system. The benzyl aminals with both electron-withdrawing and electron-donating group underwent the reaction smoothly at room temperature to give the desired products 3ab−3ah in moderate to good yields (48%−95% yields). Typical functional groups, such as chlorine, bromine, and fluorine, were welltolerated to afford the corresponding products in good yields. Substrate 2h with two steric demanded tert-butyl groups on the meta-position of phenyl ring gave the desired product in 95% yield. Aminals derived from simple aliphatic amines, such as diethylamine, dipropylamine, and dibutylamine, could react smoothly with o-hydroxylstyrene to give the corresponding products 3ai−3ak in 57%−74% yields. To demonstrate the synthetic potential of this transformation, a gram-scale reaction was carried out (see Scheme 3). Under the standard reaction conditions, the product 3aa
Scheme 4. Reaction Pathway for the Aminomethylamination of o-Hydroxystyrene
Scheme 3. Synthetic Applications serves as a Brønsted acid via hydrogen bond to activate the aminal, which is subsequently attacked by the C−C double bond of electron-rich o-hydroxystyrene to generate the quinone methide intermediate A and release one molecular of R2NH simultaneously. Finally, the intermediate A undergoes an intermolecular aza-Michael addition by R2NH and proton transfer to afford the desired 1,3-diamine 3. In summary, we have successfully developed a catalyst-free and operational simple protocol for the synthesis of 1,3diamines from readily available o-hydroxystyrenes and aminals, which allows for the rapid synthesis of a wide range of 1,3diamines under mild conditions. Some notable hallmarks of our protocol include high yields, operational simplicity, mild reaction conditions, and catalyst-free. In addition to demonstrating a wide substrate scope with a range of ohydroxystyrenes and aminals, we also report a high degree of scalability. This novel strategy provides practical access to 1,3diamines and shows great potential in synthetic chemistry. Further investigations aimed at the application of this new reaction in synthetic organic chemistry are currently underway.
was facilely prepared in 10.0 g-scale with 87% isolated yield. The pendent hydroxyl group in 3aa was easily converted to −OTf to produce compound 4.12 The alkyne functionality could be incorporated into the molecule via Pd-catalyzed Sonogashira coupling reaction, affording the corresponding amine alkynes 5a and 5b in good yields,13 which might be utilized as building blocks for further transformations. Moreover, through the Pd-catalyzed Suzuki coupling reaction, the arylated product 6 was obtained in good yield.14 To gain insights into the possible mechanism of this process, some control experiments were performed, as presented in Table 2. The controlling reactions of 1e and 2a with different amount of Bn2NH as an additive were conducted under standard conditions. The results showed that the yield of product 3ea was reduced with the increasing amount of Bn2NH, which suggested that o-hydroxystyrene may serve as a Brønsted acid to activate aminal to promote the reaction. Furthermore, the result of crossover experiment suggested that
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ASSOCIATED CONTENT
* Supporting Information S
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01383. Experimental details and full spectroscopic data for all new compounds (PDF)
Table 2. Control Experimentsa
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AUTHOR INFORMATION
Corresponding Authors entry
1e (mmol)
2a (mmol)
Bn2NH (mmol)
yieldb (%)
1 2 3 4 5
0.48 0.48 0.48 0.48 0.48
0.4 0.4 0.4 0.4 0.4
0.04 0.08 0.2 0.4
42 37 33 24 86
*E-mail:
[email protected] (L. Li). *E-mail:
[email protected] (H. Huang). ORCID
Hanmin Huang: 0000-0002-0108-6542 Author Contributions ∇
These authors contributed equally to this work.
Notes
a
Reaction conditions: 1e (0.48 mmol), 2a (0.4 mmol), CH2Cl2 (1.0 mL), room temperature, 12 h, bIsolated yield.
The authors declare no competing financial interest. 3603
DOI: 10.1021/acs.orglett.8b01383 Org. Lett. 2018, 20, 3601−3604
Letter
Organic Letters
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2016, 18, 5736. (d) Li, L.; Zhou, X.; Yu, B.; Huang, H. Org. Lett. 2017, 19, 4600. (11) The internal alkene 2-propenylphenol was investigated under standard reaction conditions. The result showed that no desired product was obtained and only monofunctionalized product could be isolated in 45% yield (see the Supporting Information). (12) Huang, Z.; Liu, Z.; Zhou, J. S. J. Am. Chem. Soc. 2011, 133, 15882. (13) Kers, I.; Csjernyik, G.; Macsari, I.; Nylof, M.; Sandberg, L.; Skogholm, K.; Bueters, T.; Eriksson, A. B.; Oerther, S.; Lund, P. E.; Venyike, E.; Nystrom, J. E.; Besidski, Y. Bioorg. Med. Chem. Lett. 2012, 22, 5618. (14) Jiang, X.; Gyu Park, B.; Riddle, J. A.; June Zhang, B.; Pink, M.; Lee, D. Chem. Commun. 2008, 45, 6028.
ACKNOWLEDGMENTS This research was supported by the National Natural Science Foundation of China (Nos. 21672199, 21702197, and 21790333) the CAS Interdisciplinary Innovation Team, the Fundamental Research Funds for the Central Universities and the Anhui Provincial Natural Science Foundation (No. 1708085MB28).
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REFERENCES
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DOI: 10.1021/acs.orglett.8b01383 Org. Lett. 2018, 20, 3601−3604
