Chemoselective Synthesis of δ‑Amino Alcohols from Chiral 1,4-Diols Catalyzed by an NHC–Ir(III) Complex

Abstract

The synthesis of δ-amino alcohols from 1,4-diols via the hydrogen borrowing strategy by an NHC–Ir­(III) catalyst is described. The amination occurs on the primary alcohol selectively. The mild, base-free conditions effectively suppress the common second intramolecular amination to pyrrolidines. sec-Alcohols, even benzylic ones, remain inert toward amination and even without racemization, enabling the synthesis of chiral δ-amino alcohols from readily available chiral 1,4-diols. Late-stage functionalization (LSF) of Lenalidomide and other complex drugs is demonstrated.

Efficient and selective formation of carbon–nitrogen (C–N) bonds is a fundamental transformation in synthetic organic chemistry. C–N bonds can be constructed through various methods, including Hofmann alkylations, Ullmann condensations, reductive aminations, Chan-Lam aminations, and Buchwald–Hartwig aminations. In recent years, amination via C–H activation has advanced remarkably, enabling challenging C–N bond construction in complex, highly functionalized, pharmaceuticals and drug intermediates via late-stage functionalization (LSF).

Alcohols can serve as benign and safe alternatives to alkyl halides for the alkylation of amines via the borrowing hydrogen methodology (BHM). In this instance, water is the only byproduct, making it a reaction with high atom economy. Further, selective monoalkylation of amines, over consecutive alkylations, can be achieved under catalyst control. Various transition metal complexesincluding those based on iridium, ruthenium, and first row transition metals have been explored for this transformation. ,

The BHM has been used primarily to introduce alkyl or benzylic substituents onto anilines and other relatively electron-poor amines, and even, though under harsher conditions, onto aliphatic amines. A few exceptions on complex functionalized amines, such as chiral amino acids, , small peptides, and amino sugars, have been reported. On the other hand, BHM applied to functionalized alcohols has lagged behind. A few examples have been reported dealing with vicinal diols by the Beller, Zhang and Zhao, Oe, and Madsen groups. An alternative approach that involves BHM and hydroamination to yield γ-amino alcohols was reported by the Wang and Xiao groups.

When 1,4-diols are used (Scheme ), the vast majority of examples report double N-alkylations, providing the cyclized products, namely, pyrrolidines (Scheme a). The second alkylation proceeds readily under the required catalytic conditions. The Zhao group has reported an enantioconvergent synthesis of chiral pyrrolidines combining a chiral Ir catalyst and a chiral phosphoric acid (Scheme a). Restricting the reaction to monoalkylation, thus preventing the cyclization, gives access to valuable δ-amino alcohols, which are also scaffolds and precursors for biologically active compounds. A few rare examples have been reported; Zhao and co-workers achieved the synthesis of 4-(phenylamino)­butan-1-ol from 1,4-butanediol and aniline by [Cp*IrCl₂]₂ in moderate yields (Scheme b); Banerjee, Hao, and Shi reported amination of the same diol using Ni, Ru, or a CuNiAlO _x catalyst, respectively. Takacs and co-workers disclosed the single example reported using a nonsymmetrical 1,4-diol, pentane-1,4-diol, with aniline using a Ru catalyst (Scheme b).

1. Syntheses of Pyrrolidine and δ-Amino Alcohols from 1,4-Diols .

^a (a) From 1,4-diols to pyrrolidine via BHM. (b) Current examples on mono N-alkylation of aniline with symmetric and non-symmetric 1,4-diols. (c) This work.

Accessing δ-amino alcohols from 1,4-diols remains challenging due to the prevalent annulation to pyrrolidines. Stereoconservative cases in which chiral secondary alcohols are preserved under BHM catalytic conditions are unknown. Here, we address these limitations by demonstrating the versatility of complex Ir-1 , for the direct monoalkylation of anilines by chiral 1,4-diols (Scheme c). Only the primary alcohol is selectively aminated in the presence of enantioenriched benzylic sec-alcohols. A particular focus on the late-stage functionalization of Lenalidomide offers a series of valuable intermediates for the synthesis of molecular glue or PROTAC compounds.

(rac)-1-Phenyl-1,4-butanol (1a) and aniline (2a) were selected for optimization (Table and Table S2) using the NHC–Ir­(III) catalyst Ir-1. We specifically aimed at obtaining high selectivity toward the primary alcohol, targeting δ-amino alcohol 3aa. Intra- or intermolecular multiple alkylations may also occur, with the former leading to pyrrolidine formation. We identified that 1,2-diphenylpyrrolidine 4aa and amino ketone 5aa were the major byproducts. 1,1,1,3,3,3-Hexafluoro-2-propanol (HFIP) was the optimal solvent (see Table S1). Catalyst loadings of 3 mol% gave good yields of 3aa (Table , entry 1). Higher temperatures than 75 °C led to significantly larger amounts of 4aa and 5aa (Table , entry 2). Varying the 1a/2a ratio from 2:1 to 1:1 (entry 3) or 0.5:1 (entry 4) led to lower yields of 3aa. The best conditions were found with 2 equiv of 1a, Ir-1 (4 mol%) at 75 °C, affording 3aa in 84% yield (Table , entry 5). These conditions served as the basis for exploring the substrate scope (Schemes and ). For certain substrates, the catalyst loading or reaction temperature could be further reduced (vide infra).

1. Optimization of the N-Alkylation 2a with 1a .

entry	Ir-1 (X mol%)	t (h)	1a (equiv)	3aa (%)	4aa (%)	5aa (%)
1	3	24	2	73	3	2
2	3	24	2	55	22	4
3	3	24	1	52	2	5
4	3	24	0.5	55	3	5
5	4	24	2	84	4	4

^aUnless otherwise noted: 2a (0.2 mmol), 1a (2 equiv), and Ir-1 (mol% with respect to limiting reagent) in HFIP (0.4 M) under an inert atmosphere.

^bYield determined by ¹H NMR spectroscopy using 1,1,2,2-tetrachloroethane (TCE) as internal standard.

^c100 °C.

^d 1a (0.2 mmol) and 2a (0.4 mmol).

2. Scope of 1,4-Diols (1)­ .

^a 2a (0.2 mmol), 1a–1u (2 equiv), and Ir-1 (4 mol%) in HFIP (0.4 M) under an inert atmosphere. Yields are isolated. In parentheses, yields determined by ¹H NMR spectroscopy using TCE as internal standard are shown.

^b 1 mmol 2a.

^c Ir-1: 3 mol %.

^d 65 °C.

^e 0.1 mmol of 2a.

^f r.c. = [ee of 3/ee of 1] × 100.

3. Scope of Anilines 2 .

^a Unless otherwise noted: 2b–2l (0.2 mmol), 1a (2 equiv), and Ir-1 (4 mol%) in HFIP (0.4 M) under an inert atmosphere. Yields are isolated. In parentheses, yields determined by ¹H NMR spectroscopy using TCE as internal standard are shown.

^b Ir-1: 3 mol%.

1,4-Diols with ortho-substituted phenyl groups gave excellent yields in general regardless of their electronic properties, selectively providing δ-amino alcohols 3aa–3ea at 75 °C or lower temperatures (3ea), even with 3 mol% of catalyst (3ba and 3da). meta-Substituted diols 1f and 1g provided 3fa (R = m-OMe) and 3ga (R = m-Me) in yields of 61% and 74%, respectively. Similarly, 3ha was obtained in 63% isolated yield from naphthyl 1,4-diol 1h with 3 mol% of Ir-1. A series of 1,4-diols with para-substituted phenyl rings provided δ-amino alcohols 3ia–3na in good yields. Pyridine groups were tolerated (3oa, 73%) as well as a diol with a tert-benzylic alcohol (3pa, 61%). Aliphatic neopentyl and adamantly aliphatic diols gave good yields of 3qa and 3ra, respectively. Other aliphatic 1,4-diols bearing shorter (1t) or longer (1u) aliphatic chains gave the corresponding δ-amino alcohols 3ta and 3ua in excellent yields. 1-Phenyl-1,5-pentanediol also reacts selectively at the primary alcohol (3sa, 68% yield). Building on this chemoselectivity, we explored whether the reaction could proceed without erosion of the chiral center presented using enantioeriched 1,4 diols. Indeed, δ-amino alcohols (S)-3aa, (S)-3ba, (S)-3ga, (S)-3ia, (S)-3ja, (S)-3ka, and (S)-3na were obtained from the corresponding chiral diols (S)-1 in good yields and with excellent retention of chirality (r.c.) levels in all instances above 96%, with the exception of ortho-substituted (S)-3ba for which racemization was observed to a larger extent (r.c. 85%).

The scope of the anilines was then investigated (Scheme ). ortho-Substituted anilines gave moderate to low yields, giving 3ab (o-OMe) and 3ac (o-Cl) in 65% and 38%, respectively. meta-Substituted anilines, such as m-pinacolborane ester- and m-bromoaniline, afforded 3ad and 3ae in 58% and 66%, respectively, with 3 mol% of Ir-1. Good yields were obtained with para-substituted anilines 3af–3aj, including those with phosphonate and sulfonamide substituents (3ak and 3al). Aliphatic amines can be alkylated by benzylic and aliphatic alcohols by Ir-1. However, the higher temperature required for alkylating aliphatic amines results in competitive cyclization to pyrrolidines when they are applied to 1,4-diols.

The method was then applied to the late-stage functionalization (LSF) of marketed drugs , containing primary amines. This gave access to novel conjugation platforms taking advantage of the possible multifunctional properties of 1,4-diols also carrying a functionalized aromatic motif. Darunavir (6a), an antiretroviral drug for the treatment of HIV/AIDS with a very complex chemical architecture carrying three differentiated nitrogen functionalities, a sec-alcohol, a chiral acetal, and 5 stereogenic centers, was selected. To our delight, 7aa was obtained in a very respectable 47% yield and with complete selectivity (Scheme ). Aminoglutethimide (6b), a drug for the treatment of hormone related diseases and cancers, also afforded an excellent yield with complete selectivity toward the aniline functionality in the drug and the primary alcohol on the diol (7ab, 58% yield, Scheme ). Next, LSF of the FDA-approved Lenalidomide (6c) and its C5 derivative 6d, which are Cereblon (CRBN) analogues widely exploited for targeted protein degradation strategies, was explored. Currently, N-alkylated Lenalidomides are prepared via reductive aminations and nucleophilic substitutions; however, alkylation at the imide nitrogen also occurs under the reaction conditions. The method reported herein has a rather high efficiency and good functional group tolerance. The reaction between 6c with 1a gave 7ac in 41% yield (Scheme ). To extend the scope, two bromine-containing diols (1c and 1k) were chosen as they provide a handle for conjugation with small molecule drugs, peptides, oligonucleotides, or lipids. Lenalidomide (6c) afforded 7cc and 7kc in 77% and 54% yield, respectively. The C5 Lenalidomide analogue (6d) provided similar results, giving 7ad, 7cd, and 7kd in 56%, 70%, and 65% yields, respectively. On the other hand, pyrrolidine derivative 7dd was obtained in 80% yield from ortho-methyl diol 1d.

4. LSF of Biologically Relevant Molecules .

^a Unless otherwise noted: 6 (0.2 mmol), 1 (2 equiv), and Ir-1 (4 mol%) in HFIP (0.4 M) at 65 °C. Yields are isolated. In parentheses, yields determined by ¹H NMR spectroscopy using TCE as internal standard are shown. CRBN binding was determined in a time-resolved-FRET competition assay using a Cy5-labeled CRBN ligand.

^b 0.1 mmol of 6a or 6b.

^c 75 °C.

All of the derivatives synthesized (7ac–7dd) retained nanomolar binding to CRBN (Scheme ). Further, none of them affect cell viability in concentrations up to 100 μM in THP1 cells at a 48 h time point (Table S3), indicating that they are excellent candidates for further synthesis of molecular glue libraries or PROTAC compounds.

To understand the observed selectivity, we conducted control experiments. The reaction in the absence of the amine substrate results in full conversion of 1a into cyclodehydration product 8a (Scheme a and Figures S2–S4). Hammett studies (Figure S3) indicate intermediacy of benzylic carbocations in the formation of tetrahydrofurans 8 under these reaction conditions, i.e., in the absence of aniline (Scheme a). This unwanted reactivity is effectively inhibited when the reaction is performed in the presence of aniline 2a. The excellent outcome obtained from enantioenriched/enantiopure diols (Scheme ) further supports the absence of carbocation intermediates. From (S)-1a, (S)-3aa was formed in 75% yield with excellent chirality retention (Scheme b), even upon extended reaction times, highlighting the remarkable selectivity of Ir-1 toward primary alcohols over secondary ones. In HFIP-d ₂, from 1a (Scheme c), D was found on the aniline fragment, as well as at Cα and Cβ (20% and 48% D, respectively, Figure S7). D was not detected in recovered 1a (Figure S9). From 1a– d ₂ (98% D) in HFIP (Scheme c), the deuterium content diminished at Cα (52% D), and D was not incorporated at Cβ (see SI, Figure S8). From these control experiments, it can be concluded that (i) H/D scrambling occurs at the Ir–H/D stage, explaining D loss or incorporation at Cα, and that (ii) imine/enamine tautomerizations are involved, as D is incorporated at Cβ in the reactions run in HFIP-d ₂. The remaining 1a– d ₂ in Scheme c, bottom maintained the original 98% D content (Figure S10).

5. Control Experiments .

^a Deuterium content determined on isolated product by ¹H NMR spectroscopy.

A BHM mechanism, involving alcohol oxidation, imine formation, and imine reduction, with concomitant formation of Ir–H species is proposed (Scheme ). As the reaction is run in HFIP, iminium species are likely intermediates. Iminium/enamine tautomerizations are involved for these aliphatic alcohol substrates, as confirmed by the deuterium-labeling studies shown in Scheme .

6. Proposed Mechanism.

In conclusion, a method to access δ-amino alcohols from readily available nonsymmetrical 1,4-diols has been developed. The reaction proceeds via a hydrogen borrowing pathway mediated by Ir-1, where the dehydrative amination takes place selectively at the primary alcohol, in the presence of a sec-alcohol and without affecting the stereochemistry of the latter. The effectiveness and selectivity of the reaction was demonstrated with a large variety of substrates, including the LSF of Darunavir, aminoglutethimide, and C5 and C6 Lenalidomides. It is also shown that the obtained compounds bind to CRBN without affecting the THP1 cell viability up to 100 μM. Thus, they are potential candidates to afford new molecular glue libraries or PROTAC compounds, opening new opportunities in the late-stage diversification of aniline-based drugs.

The data underlying this study are available in the published article and in its Supporting Information and openly available in Zenodo at 10.5281/zenodo.17828442.

The Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.5c04592.

• General information; experimental procedures; supplementary tables and schemes; mechanism research; product derivation; characterization data of products; references (PDF)

E.S., A.B.-L., M.J.J., and B.M.-M. conceived the project and designed the experiments. M.J.J. and B.M-M. directed the project. E.S., A.B.-L., and S.J. performed and analyzed the experiments. M.P. designed the biological test on Lenalidomide products and related data evaluation. All the authors reviewed and edited the manuscript.

The authors declare no competing financial interest.