Letter Cite This: Org. Lett. 2018, 20, 4081−4085
pubs.acs.org/OrgLett
Chemoselective Photoredox Synthesis of Unprotected Primary Amines Using Ammonia Jiawei Rong,† Peter H. Seeberger,†,‡ and Kerry Gilmore*,† †
Max Planck Institute for Colloids and Interfaces, Am Mühlenberg 1, 14476 Potsdam, Germany Freie Universität Berlin, Institute for Chemistry and Biochemistry, Arnimallee 22, 14195 Berlin, Germany
‡
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S Supporting Information *
ABSTRACT: Unprotected α-amino carbon radicals are produced as novel intermediates via a transformation that merges acidpromoted N−H imine generation and chemoselective photocatalytic single-electron reduction. Coupling ammonia and aldehydes/ketones allows the generation of primary amines under mild conditions without the need for protecting groups. The key intermediate can be efficiently transformed into primary (di)amines by a formal dimerization, reductive amination via hydrogen atom transfer, and arylation through radical−radical coupling.
P
Unlike primary amines, which form imines rapidly, ammonia is less nucleophilic, resulting in a slow equilibrating condensation (see the Supporting Information (SI)). This equilibrium presents a significant challenge for the process due to the differences in the reduction potentials. For example, the N−H ketamine 1-(4-fluorophenyl)ethan-1-imine (Scheme 1 and SI) has a significantly lower potential (E1/2red = −2.384 vs Ag/AgCl in MeCN) than the corresponding 4-fluoroacetophenone (E1/2red = −2.088 vs Ag/AgCl in MeCN), meaning that the carbonyl should be selectively reduced instead of the imine.
rimary amines play an essential role in natural and synthetic compounds, including pharmaceuticals, agrochemicals, dyes, and materials.1 Although numerous catalytic methods have been developed to access primary amines,1−3 typically, protected amino groups are used that necessitate a subsequent−sometimes challenging−deprotection step. One common method for the synthesis of primary amines is via the protected imine, which is further functionalized via nucleophilic addition,2b,c imine reduction,2d or single-electron reduction to the α-amino carbon radical.2e,f This latter approach offers the greatest synthetic potential, with a range of efficient coupling methods available including aminopinacol couplings,4a−d Michael additions,4e−g aryl/ alkylations,4h−l and reductive aminations.4m−o A powerful method to generate these α-amino carbon radicals is photoredox chemistry, where a photocatalyst and sacrificial electron donor, typically a Hantzsch ester or Hünig’s base, are used to reduce a preformed imine. Select multicomponent examples exist, which circumvent the necessity of a two-step approach, efficiently forming an imine in situ from aldehydes and electron-rich primary amines.4e,f,m However, there are two main challenges in this multicomponent reaction; the slow, reversible formation of the imine and the chemoselective reduction of an imine in the presence of a carbonyl, which typically exhibit competitive reduction potentials.5 To date, no unprotected imines have been generated and utilized to generate functionalized primary amines directly. However, reductive amination reactions illustrate that it is possible to selectively react N−H imines formed in situ by ammonia condensation.3,6 Herein, we present a method for the chemoselective formation and utilization of primary amine αamino radicals by the photocatalytic reduction of N−H imines generated in situ from ammonia and an aldehyde/ketone. © 2018 American Chemical Society
Scheme 1. Reduction Potential of an N−H Imine Is More Strongly Affected by Acid Activation than the Respective Ketonea
a
R1 = 4-fluorophenyl, R2 = CH3.
Received: May 24, 2018 Published: June 27, 2018 4081
DOI: 10.1021/acs.orglett.8b01637 Org. Lett. 2018, 20, 4081−4085
Letter
Organic Letters
fluorobenzaldehyde, Hünig’s base (2 equiv), ammonia (7 N in MeOH, 10 equiv), and Ru(bpy)3Cl2·6H2O (PC1) (1 mol %) in acetonitrile was irradiated with blue light in a sealed vial for 15 h at room temperature (for the full experimental procedure, see the SI). Stronger reducing Ir photocatalysts such as Ir(dtbbpy)ppy2PF6 (PC2) and Ir(dF(CF3)ppy)2dtbbpy PF6 (PC3) resulted in high yields of the diol product (entries 2 and 3). The selectivity of the reaction drastically changes when 20 mol % of Sc(OTf)3 is used. Complete conversion is observed with the Ru catalyst, chemoselectively giving the desired diamine product in 79% yield as a ∼1:1 mixture of diastereomers (Table 1, entry 4). The chemoselectivity diminishes with the stronger reducing photocatalysts, with PC3 providing only 3:2 selectivity for the diamine (entries 5 and 6). A range of Lewis and Brønsted acids were screened next; they exhibited either poor-to-moderate yields of diamine or were unable to promote the reaction at all (entries 7−9 and Table S2). Lower loadings of Sc(OTf)3 saw diminished yields (SI). Methanol was the only solvent examined where no reductive dimerization occurred, with most solvents giving poor-to-moderate yields (entries 10−12 and Table S3). Finally, ammonia sources were screened. Solvated ammonia gave better results than ammonium salts, and the equivalents of NH3 in MeOH can be dropped to three without any loss in yield (entries 13−16 and Table S4). The requisite control studies demonstrated that both light and photocatalyst were essential to the reaction, and the transformation proved sensitive to oxygen (Table S1). With the optimized conditions in hand (Table 1, entry 4), a series of (hetero)aromatic aldehydes were examined to determine the versatility of the transformation (Scheme 2). The unsubstituted benzyl aldehyde gave 2b in 81% isolated yield. Halogen substituents (F, Cl, Br) were well tolerated in the ortho, meta, and para positions (2a, 2c−h, 55−82%), with fluorinated and chlorinated derivatives giving higher yields. The reaction also works well with electron-rich benzaldehydes. Alkyl substituents in the para-, meta-, and ortho-positions gave similar yields to the halogenated derivatives (2i−l, 54−78%). Excellent yields of the diamine were obtained with stronger electron donating groups such as OMe and SMe (2m: 62%, 2n: 82%, 2o: 82%). Other aryl aldehydes, such as 2naphthalene aldehyde (2p, 62%) and 5-methylfuran-2carbaldehyde (2q, 73%), can also be used. No diastereoselectivity was observed for all substrates, with dr values around 1:1. Unfortunately, when aliphatic aldehydes were employed in the reaction, the photocatalytic reduction did not occur and only trimerized imine was obtained (SI). This result is presumably caused by the lack of stabilization of the corresponding α-amino carbon radical, allowing for the slower side reaction of the activated imine to occur. Initial attempts to extend these conditions to monoaryl ketones were unsuccessful, despite the favorable differences in reduction potentials of activated ketones vs ketimines (Scheme 1). Switching to gaseous NH3 as an alternate ammonia source, as well as raising the reaction temperature to 60 °C, was found to be necessary to effect the transformation, due to the slower rate of N−H ketimine formation (Tables S5 and S6). Moreover, while at room temperature a small amount of N− H imine was detected, no product formed, suggesting that the higher temperature is also required for the dimerization reaction. Reexamination of reductants and activators revealed favorable conversions with 1.2 equiv of Hanstzch ester and 1
The reduction potential of carbonyls is raised in the presence of Lewis7 or Brønsted acids.8 Circumstantial evidence suggests that a similar effect is observed with imines activated by the oxidized sacrificial electron donor.4a,c However, direct evidence of this effect, as well as its degree of influence as compared to the analogous carbonyl, was lacking. When we measured the reduction potential of 4-fluoroacetophenone in the presence of 1 equiv of trifluoroacetic acid (TFA), a significant increase in the potential was observed compared to the nonacidic conditions (E1/2red = −1.586 vs −2.088, Ag/ AgCl in MeCN). However, an even more dramatic change is observed for the corresponding N−H imine, increasing more than 1.3 V (E1/2 red = −1.052 vs Ag/AgCl in MeCN), making the N−H imine more energetically favorable to reduce than the respective ketone (Scheme 1). To test whether this difference in reduction potentials of activated carbonyls/imines is sufficient for a chemoselective reduction, we first examined the reductive formal dimerization of a 4-fluorobenzaldehyde and methanolic ammonia to generate the useful 1,2-diamine motif.1,9 The aryl aldehyde was chosen to develop the reaction because it exhibits a higher rate of imine formation compared to the respective ketone (see Table S6) and the conjugative stabilization of the intermediate α-amino benzylic radical. As anticipated based on the reduction potentials, no reaction occurred (Table 1, entry 1) when a degassed solution of 4Table 1. Optimization of the Selective Aminopinacol Coupling of in Situ Formed Aldiminea,b
entry
PC
additive
solvent
1 2 3 4 5 6 7 8 9 10 11 12 13
PC1 PC2 PC3 PC1 PC2 PC3 PC1 PC1 PC1 PC1 PC1 PC1 PC1
Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 In(OTf)3 LiBF4 (PhO)2PO2H Sc(OTf)3 Sc(OTf)3 Sc(OTf)3 Sc(OTf)3
MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN MeCN DMF MTBE MeOH MeCN
14 15 16
PC1 PC1 PC1
Sc(OTf)3 Sc(OTf)3 Sc(OTf)3
MeCN MeCN MeCN
ammonia source
2c (%)
3d (%)
NH3/MeOH NH3/MeOH NH3/MeOH NH3/MeOH NH3/MeOH NH3/MeOH NH3/MeOH NH3/MeOH NH3/MeOH NH3/MeOH NH3/MeOH NH3/MeOH NH3/ MeOHe NH3/H2O NH4Cle NH4CO2He
0 0 0 79 24 33 55 0 0 57 67 0 78
0 97 92 0 8 22 0 0 0 0 0 0 0
63 12 8
0 0 0
a
For a full list of additives, solvents, and ammonia sources examined, see the Supporting Information. bReactions were carried out with 1a (0.2 mmol); for full experimental details, see the SI. cYields were determined after workup by 1H NMR spectra using 1,3,5trimethoxybenzene as the internal standard. Product was obtained as a ∼1:1 mixture of diastereomers dYields were determined by 19F NMR spectra using trifluorotoluene as an internal standard. e3.0 equiv. PC1: Ru(bpy)3Cl2·6H2O. PC2: Ir(dtbbpy)ppy2PF6. PC3: Ir(dF(CF3)ppy)2dtbbpyPF6. 4082
DOI: 10.1021/acs.orglett.8b01637 Org. Lett. 2018, 20, 4081−4085
Letter
Organic Letters Scheme 3. Scope of Ketones Examineda
Scheme 2. Scope of Aryl Aldehydes Examined*
a
For full experimental details and a description of aryl and aliphatic ketones examined, see the Supporting Information.
observed with the protected derivatives due to steric constraints, as has been noted in SmI2 mediated iminopinacol coupling reactions.10 However; conditions were found where the dimerization can be out-competed. The one electron reduction of N−H imines can be merged with hydrogen atom transfer catalysis to produce the reductive amination product.4m−o Adapting the conditions developed for ketones, catalytic amounts of thiophenol (20 mol %), with the Hantzch ester already present in the solution, yielded primary alkyl amines efficiently in 71−96% yields (Scheme 4a). The Brønsted acid catalyzed reduction of premade N−H ketimines, employing Hantzch ester as reductant, had been reported to fail due to the rapid condensation of the primary amine products and the N−H ketimines.6,11 Under our conditions,
*
For full experimental details and a description of aryl and aliphatic aldehydes examined, see the Supporting Information. aHanstzch ester used instead of Hünig’s base.
equiv of TFA, respectively. When 4a was reacted with PC1, Hanstzch ester, and TFA in MeCN under an atmosphere of ammonia gas at 60 °C, quantitative conversion to the desired vicinal diamine (5a, Scheme 3) was observed. In general, the reductive dimerization proceeded cleaner and with higher yields for the ketones than with the respective aldehydes, presumably due to the enhanced stability of both the N−H ketimines and the corresponding radical anions. Aryl alkyl ketones exhibited excellent functional group tolerance, and good-to-quantitative yields were observed in the presence of electron-deficient and electron-rich substituents at various positions (5a−h, 53%-quant). 1-(Naphthalen-2-yl)ethan-1-one and α-tetralone gave products 5i and 5j in 95% and 74% yields, respectively. Heteroaryl alkyl ketones, such as 1-furyl (5k), 1thienyl (5l), and 2-thienyl (5m) also exhibited good-toexcellent yields (73−91%). At lower temperatures (40 °C), ethyl pyruvate can also be reacted, generating the corresponding amino ester dimer in 44% isolated yield (5n). However, efforts to extend this method further to dialkyl ketones without adjacent stabilizing groups were unsuccessful (SI). The potential for α-amino carbon radicals to access functionalized, unprotected primary amines beyond reductive dimerizations directly was subsequently investigated. Common transformations of protected α-amino radicals such as vinylation4e,f and alkylation4g by reaction with various Michael acceptors were not successful, as only vicinal diamine was obtained. Addition of the unprotected α-amino carbon radical to the activated imine intermediate is likely faster than what is
Scheme 4. Additional Reactions Pathways Involving Unprotected α-Amino Carbon Radicals: (a) Photoredox Reductive Amination of Alkyl Ketones; (b) Reductive Arylations of Aryl Ketones to Generate Primary Amines on Quaternary Centersa
a
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For full experimental conditions, see the Supporting Information. DOI: 10.1021/acs.orglett.8b01637 Org. Lett. 2018, 20, 4081−4085
Organic Letters
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with the in situ generation of N−H aldimines and ketimines, this condensation was never observed. Finally, radical−radical coupling was achieved with 4cyanopyridine.4l,12 In the presence of an increased amount of Hantzch ester, 2 equiv of the cyanopyridine were found to be sufficient to give unprotected 1° amines on quaternary centers (α-diarylalkylamines) in high to near-quantitative yields (Scheme 4b). The first step of our method is a Lewis acid/Brønsted acid promoted N−H imine formation between ammonia and the carbonyl group (Scheme 5). Simultaneously, visible-light
Letter
ASSOCIATED CONTENT
S Supporting Information *
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.orglett.8b01637. Experimental details, full and additional optimization tables, characterization data, and associated NMR (PDF)
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AUTHOR INFORMATION
Corresponding Author
Scheme 5. Proposed Mechanism for the Formation and Trapping of Unprotected Primary α-Amino Radicals
*E-mail:
[email protected]. ORCID
Peter H. Seeberger: 0000-0003-3394-8466 Kerry Gilmore: 0000-0001-9897-6017 Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS We gratefully acknowledge the Max-Planck Society and DARPA (Contract No. W911NF-16-1-0557) for generous financial support. We thank Ms. Sooyeon Moon (MPIKG) for analytical support, Ms. Mara Guidi (MPIKG) for the scale-up reaction, as well as Dr. Bart Pieber (MPIKG) and Dr. Matthew Plutschack (MPIKG) for fruitful discussions.
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REFERENCES
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irradiation produces an exited PC1* that can be reductively quenched by the sacrificial donor (iPr2NEt or Hantzsch ester) to afford a Ru(bpy)31+ species. The activated imine, either by the Lewis or Brønsted acid, is then selectively reduced to form an unprotected α-amino alkyl radical. In the absence of an added trapping agent, the radical adds to the activated starting material to generate the formally dimerized aminopinacol product. Introducing thiophenol as a hydrogen atom transfer catalyst4m enables the α-amino alkyl radical to obtain an H atom from the Hanztch ester to form unprotected primary amines. When 4-cyanopyridine was added to the system instead of thiophenol, a second photoredox cycle reduces the cyanopyridine to a radical anion that reacts with the α-amino alkyl radical to form the unprotected tertiary amine following elimination of a cyanide anion.4l,12 In conclusion, a photocatalytic method has been developed to synthesize primary amines directly from ammonia and aldehydes/ketones. N−H imines are formed as intermediates, promoted, and further activated by a Lewis/Brønsted acid and are subsequently reduced to generate an unprotected α-amino carbon radical. This radical can dimerize to produce unprotected vicinal diamines and can engage in other transformations to construct primary amines, such as thiophenol-catalyzed hydrogen atom abstraction and radical− radical coupling with 4-cyanopyridine. The chemoselective reduction is only possible due to the larger change in the reduction potential of activated imines as compared to the respective carbonyls. The expansion of this strategy in additional transformations is currently underway. 4084
DOI: 10.1021/acs.orglett.8b01637 Org. Lett. 2018, 20, 4081−4085
Letter
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DOI: 10.1021/acs.orglett.8b01637 Org. Lett. 2018, 20, 4081−4085
