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Steric Hindrance Underestimated: It´s a Long, Long Way to Tri-tert-alkylamines Klaus Banert, Manuel Heck, Andreas Ihle, Julia Kronawitt, Tom Pester, and Tharalla Shoker J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00496 • Publication Date (Web): 09 Apr 2018 Downloaded from http://pubs.acs.org on April 9, 2018

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The Journal of Organic Chemistry

Steric Hindrance Underestimated: It´s a Long, Long Way to Tri-tertalkylamines Klaus Banert,* Manuel Heck, Andreas Ihle, Julia Kronawitt, Tom Pester, and Tharallah Shoker Chemnitz University of Technology, Organic Chemistry, Strasse der Nationen 62, 09111 Chemnitz, Germany *S Supporting Information

KEYWORDS: amines; Hofmann elimination; molecular dynamics; steric hindrance; synthetic methods

ABSTRACT: Ten different processes (Methods A−J) were tested to prepare tertiary amines bearing bulky alkyl groups. Especially, SN1 alkylation of secondary amines with the help of 1-adamantyl triflate (Method D) and reaction of Nchlorodialkylamines with organometallic reagents (Method H), but also attack of the latter reagents at iminium salts, which were generated in situ by N-alkylation of imines (Method J), led to trialkylamines with unprecedented steric congestion. These products showed a restriction of the rotation about the C−N bond. Consequently, equilibration of rotamers was slow on NMR time scale resulting in distinguishable sets of NMR data at room temperature. Furthermore, tertiary amines with bulky alkyl substituents underwent Hofmann-like elimination on heating in toluene to form an olefin and a secondary amine. Since the tendency to take part in this decay reaction correlated with the degree of steric hindrance around the nitrogen atom, Hofmann elimination at ambient temperature, which made the isolation of the tertiary amine difficult, was observed in special cases.

1. INTRODUCTION The amino unit belongs to the most fundamental functional groups of organic chemistry.1 Consequently, several generations of chemists have designed a variety of synthetic methods over the years. The same holds true for sterically hindered amines,2 for which wide ranges of application were found, for example, as bases with low nucleophilicity, such as 13 and 2,4 or precursors of persistent nitroxyl radicals, like 3,5 utilized for spin labeling tools (Figure 1).6 Numerous 2,2,6,6tetramethylpiperidines of type 4 and free radicals derived from these heterocycles are polymerization inhibitors and thermoand photostabilizers, known as hindered amine light stabilizers (HALS).7 Furthermore, sterically hindered amines have recently come into industrial use in a variety of gas-treating processes.8 Finally, amines with bulky alkyl groups were investigated in view of their pharmacological activity.9 __________________________________________________

Figure 1. Sterically crowded amine derivatives with wide range of applications.

Owing to the method of synthesis, several tertiary amines with a high degree of steric congestion, such as 5,10a 6,10b and 7,11 include additional functional groups, which strongly influence the molecular structure around the amine nitrogen atom and the corresponding reactivity (Figure 2). Compound 8 has been presented as the most highly congested tertiary amine known to date.12 However, the cyclopropyl group of 8 features special electronic effects and a bulkiness similar to that of an ethyl group. Unfortunately, non-functionalized amines, such as 9−15 have not yet been reported, and triisopropylamine (16) seemed to define the achievable limit for steric distress in a simple trialkylamine.10b Consequently, studies of the molecular structure were focussed on 16, which should be very nearly planar about nitrogen based on the results of electron diffraction studies.13 This outcome was claimed to be confirmed by NMR investigations,14 whereas low-temperature single-crystal X-ray diffraction of 16 led to a height of the NC3 pyramid (nitrogen at the top) of 0.27−0.29 Å.15 This value is more than a half of the corresponding height in triethylamine (0.467 Å).15 Thus, the molecule of 16 adopts a somewhat flatter pyramid instead of a planar structure. In a famous textbook of organic chemistry,16 amine 11 was compared with the stable tertiary alcohol 17, which is known since 1945 and easily accessible via different routes.17 It was stated that 11 should have less steric strain than 17 and it should be possible to prepare 11 because crowding can be eased somewhat in the amine, but not in the alcohol, if the three bulky groups assume a planar instead of the pyramidal configuration.16 We believe that this argumentation is not convincing since simple trialkylamines generally avoid planar

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structures,15 and steric congestion in 11 is underestimated because different bond lengths were not taken into account.

Figure 2. Molecules with great steric crowding. __________________________________________________ The C−N bond in 11 should be significantly shorter than the corresponding C−C bond in 17,18 which will lead to a smaller distance between the bulky groups in the amine. Moreover, stability of 11 should be lower than that of 17 since amines with such steric distress may undergo β-elimination to form a secondary amine and an olefin (Hofmann-like elimination). The analogous direct β-elimination of water is not possible with 17, and its dehydration is always accompanied by Wagner−Meerwein rearrangement.19 Herein, we describe the syntheses of 9, 10, and 12−14, and the access to tertiary amines with even more bulky alkyl substituents such as 32−40 and 43. The steric stress in such products is indicated by a surprising tendency to undergo Hofmann elimination under mild conditions, and by slow rotation about the C−N bond leading to distinguishable conformers.

2. RESULTS AND DISCUSSION

by the reaction of iminium salt 23 with MeMgBr is a simple procedure to generate 9, and Method F is possible with chlorine, bromine, or iodine. But in all cases, one equivalent of hydrogen halide is formed, which blocks half of 16 as an ammonium salt. Thus, a mixture of 9 and 16 was observed after addition of MeMgBr, and separation of these amines is inconvenient. For example, oxidation of 16 with iodine and subsequent exposure to MeMgBr/Et2O furnished 9 with 21% yield after isolation by preparative GC. Transformation of 25, which was easily available by formylation of 18, into iminium salt 24 and succeeding treatment with MeMgBr produced 9 in 62% yield (Method G).24 This procedure facilitated purification of 9 by simple distillation on multi-gram scale. Activation of 25 by O-methylation followed by treatment of the resulting salt 26 with MeMgCl afforded 9 with 23% yield.25 The reaction of N-chlorodialkylamines with alkyl Grignard reagents has been long known; however, yields of tertiary amines are very low (4−7%), even without steric hindrance.26 Recently, it was demonstrated that arylation of the same substrates with the help of aryl Grignard reagents could be significantly improved if the reaction was performed in the presence of a major excess of TMEDA.27 Thus, we treated 2728 with iPrMgCl/TMEDA and obtained 9 in an acceptable yield of 46% (Method H). Without TMEDA, 9 was formed with 4% yield only. Tertiary organometallic reagents are generally less appropriate as shown by the reaction of 2828 with tBuMgCl/TMEDA, which gave 9 in 11% yield. Method H often led to the dechlorination products in a side reaction; however, these secondary amines could easily be separated from the desired tertiary amines. When N,N-dichloroamine 2928 was subjected to i-PrMgCl/TMEDA, 9 was generated besides other products; but the yield of 9 was disappointingly low (Method I). __________________________________________________ Scheme 1. Unsuccessful attempts to prepare 9

First, we looked for an efficient method to prepare the model compound 9 by using established methods. Whereas Bruylants reaction via 2-(diisopropylamino)propionitrile is wellknown13,20 to effectively transform 20 into 16, the analogous attempts with substrate 18 (Method A) were completely unsuccessful (Scheme 1). Treatment of 18 with diisopropyl sulfate (Method B) also did not lead to 9 although a similar SN2 alkylation of diisopropylamine was reported to produce 16 with 18% yield.20 When we reacted 2 with diisopropyl sulfate, we did not get the desired product 14 while 2,2,5,5tetramethylpyrrolidine gave 12 in very low yield (2−3%) with the same reagent. Our experiments to synthesize 9 from 19 via the corresponding N,N-diisopropyl(prop-2-ylidene)ammonium salt (Method C) were unfruitful.21 The same was true for our efforts to prepare 9 by SN1 alkylation of 20 (Method D).22 After this frustration, we tested also less established and new methods. Chlorination of the purchasable sulfur compound 21 and subsequent treatment of the resulting iminium salt 22 with an excess of MeMgCl led to the wanted product 9 (Scheme 2, Method E).23 However, the overall yield was low (ca. 5%), and the separation of 9 was laborious. Halogenation of 16 followed

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The Journal of Organic Chemistry Scheme 2. Successful methods to synthesize 9

Method F

Method E N S S

S

S

Cl2

3 MeMgCl

N Cl

N

MeMgBr

N 2 i-PrMgCl TMEDA ca. 4%

Method I

N

16

23

9 Cl (COCl) 2

2 MeMgBr

Cl

X = Cl, Br, I

X

22

N

HX

Cl Cl

21

X2

N

Cl

N

N

24

25

CHO

Cl

Method H Method G

29

t-BuMgCl TMEDA 11%

i-PrMgCl TMEDA 46% 2 MeMgCl

N Cl

N

28

27

CHCl 3 NaOH H2O 81%

OMe

Cl

MeOTf

N OTf

NH

26 18

_________________________________________________________________________________ Next, we transferred the promising methods, which opened up an access to 9, to the more ambitious synthesis of 10 (Scheme 3). After oxidation of 9 with X2 (X = Cl, Br, or I) followed by treatment with MeMgBr or MeLi (with or without TMEDA), however, 10 was not formed (Method F). Unfortunately, exposure of 3028 to (COCl)2 or MeOTf did not lead to a precipitate of an iminium salt, which could be reacted with MeMgBr. Consequently, the most likely variations of Method G could not be realized, and the direct reaction of 30 with MeMgBr produced 10, after separation by preparative GC, with 4% yield only. A better yield of 10 (32%) resulted when 3128 was treated with i-PrMgCl/TMEDA (Method H). As might have been expected, the reaction of 27 with tBuMgCl/TMEDA did not provide an efficient access to 10. Further trialkylamines with a high degree of steric congestion, such as 12−14 and 32−40 were prepared with quite __________________________________________________

Table 1. Synthesis of 12−14 and 32−40a

Scheme 3. Synthesis of 10 Method F N

X2 X = Cl, Br, I

MeMgBr or MeLi

9

N CHO

30

MeMgBr 4%

(Method G)

i-PrMgCl

N Cl

31

t-BuMgCl TMEDA

N

10

a

N

For the Methods D, F−I, see also Schemes 1−3 and 5. b(COCl)2 and then MeMgBr were used. cFrom 12 and I2, then MeMgBr was used. dt-BuMgCl was used. eFrom 45/AgOTf. f48% yield from 44b/Me3SiOTf. g51% yield from 44b/Me3SiOTf. h12% yield from 44b/Me3SiOTf. ii-PrMgCl was used. jEtMgBr was used. kFrom 44a/Me3SiOTf. l1-Adamantylmagnesium bromide was used. m n Cyclohexylmagnesium chloride was used. 2Norbornylmagnesium bromide was used.

Cl

ca. 1%

Method H

27

Method H

TMEDA 32%

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Scheme 4. Hofmann elimination of 38b Unwanted Hofmann elimination of trialkylamines led to the idea to introduce 1-adamantyl groups, which are even more bulky than t-butyl units, but nearly immune to β-elimination. Furthermore, 1-adamantyl-substituted amines can also be prepared by using Methods D and J. Thus, 43 was not only available from 4228 through Method H (Scheme 5). It was likewise synthesized by SN1 N-alkylation of 18 via 1adamantyl triflate,29 which was generated in situ from acetate 44a,22,28 mesylate 44b,28 or bromide 45 (Method D). The latter substrate was most convenient and provided the highest yield (63%), whereas somewhat lower yields of 43 resulted from 44a (46%) and 44b (54%). After exposure of imine 4628 to 45/AgOTf, treatment of the formed iminium salt 47 with MeLi produced 43 in 42% yield (Method J). Despite very serious efforts, all our experiments to generate tri-tert-alkylamines of type 11 or 15 were unsuccessful. For example, reactions of 31, 42, or 1-chloro-2,2,6,6tetramethylpiperidine28 with t-BuMgCl or t-BuLi led to products of dechlorination only, and attempts to N-alkylate 2, ditert-butylamine,28 1-adamantyl(tert-butyl)amine,28 or di-1adamantylamine28 with the help of 45/AgOTf were also in vain. Subjection of 4828 to 45/AgOTf followed by treatment with MeLi gave enamine 49 instead of the desired product with two t-butyl groups. Such unwanted deprotonation was similarly observed in the case of other iminium salts with great steric hindrance. Thus, simple tri-tert-alkylamines include a very high degree of steric congestion; consequently, they are sensitive to Hofmann elimination, and cannot be prepared easily. On the other hand, tri-tert-alkylamines 13 and 32−36, in which two groups at nitrogen are connected to form a fivemembered ring, are available (Table 1). In the cases of 33 and 34, ring opening to synthesize the corresponding open-chain tri-tert-alkylamines is perhaps possible by oxidation or ethenolysis (metathesis) at the C=C bond. The unprecedented steric congestion of the presented tertiary amines is demonstrated not only by Hofmann elimination, occurring under surprisingly mild conditions, but also by restriction of the rotation about the C−N bond, which is slow on NMR time scale in several cases. Hence, the tardy rotation of the secondary alkyl group led to two distinct t-butyl groups of 10, two distinguishable t-amyl groups of 37b, and two different 1-adamantyl groups of 40 in the NMR spectra at room temperature. A barrier of 79 kJ/mol with Tcoalescence = 80 °C was estimated for the rotation of the isopropyl group in 10 by utilizing dynamic 1H NMR spectroscopy (Figure 3). For amines with lower symmetry of substitution, such as 37a, 38b, and 43, two complete 1H and 13C NMR data sets of rotamers were detected at ambient temperature, and 37a, for example, showed two 15N NMR signals. Whereas the ratio of the rotamers was nearly 1:1 in the cases of 37a and 38b, a 5:1 mixture of conformers was observed for 43. Assignment of these conformers was performed with the aid of 1H NMR NOE experiments. The conformational dynamics of 10 and similar amines significantly differ from those of trialkylamines with less bulky substituents14b,30 but more flexible moieties and that of

__________________________________________________ different yields by using Methods D and F−I (Table 1). It turned out that some of these amines underwent Hofmann-like elimination on heating in toluene. In all cases, a tertiary alkyl group was split off to generate an olefin and a secondary amine. For example, 37a gave 18 and tertamyl(isopropyl)amine, but no tert-amyl(tert-butyl)amine after heating a toluene solution at 100 °C. The tendency to take part in Hofmann elimination correlates with the degree of steric hindrance around the amine nitrogen atom. Whereas 9 and also alcohol 17 are nearly stable at 100 °C (toluene-d8, 60−140 days), 37a and 38a possess, at the same temperature, a halflife t½ of ca. 9 days and 1−2 days, respectively. At 40 °C, the decay of 38b to produce 18 and exclusively regioisomer 41 led to t½ = 30 h (Scheme 4). The Hofmann elimination of 38a in (toluene-d8, at 100 °C was not enhanced in the presence of additional bases, such as TMEDA, and even decelerated by addition of DABCO, but strongly accelerated with one equivalent of trichloroacetic acid or in slightly protic solvents like toluene, which was previously saturated with water at 20 °C. Since it was very difficult to isolate unstable 38b, the question arises whether 11 could be handled at room temperature or not. __________________________________________________ Scheme 5. Synthesis of 1-adamantylamines

i-PrMgCl

N Cl

24%

42

5:1

Method H

N

N H

H

43 Me3SiOTf

OX

K2CO3

MeLi

AgOTf

44a X = Ac 44b X = Ms

HN

63%

18

K2CO3

N

HN

Method D

OTf

18

47 Method J N

Br

46

AgOTf K2CO3

45 AgOTf K2CO3

MeLi

N

N

48

49


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the hydrocarbon 3-isopropyl-2,2,4,4-tetramethylpentane,31 i.e. 10 with CH instead of the N atom. Shorter C−N bonds in comparison with C−C bonds, and underestimated steric congestion of tertiary amines16 may be relevant factors to provide an explanation.

cover new applications for amines with a high degree of steric congestion.

4. EXPERIMENTAL SECTION General. All the reactions dealing with air- or moisture-sensitive compounds were carried out in a dry reaction vessel under a positive pressure of nitrogen. Air- and moisture-sensitive liquids and solutions were transferred via a syringe. All reactions were carried out with freshly distilled, dry solvents. Anhydrous solvents were distilled immediately before use. AgOTf was obtained commercially from abcr (Germany). 1-Bromoadamantane (1-AdBr), t-BuMgCl, MeMgCl, MeMgBr, i-PrMgCl, LiCl, NCS, TMEDA, Me3SiOTf were obtained commercially from Acros Organics (Belgium). MeLi, i-PrMgBr, i-PrMgBr·LiCl, CyMgCl, 2-exo-bromonorbonane were obtained commercially from SigmaAldrich (Germany). Diisopropylamine (20) was purchased from Dr. Grüssing GmbH (Germany). Diisopropylamine hydrobromide (19) was obtained commercially from TCI (Germany). 2,2,6,6-Tetramethylpiperidine was obtained commercially from Merck KGaA (Germany).The Grignard-reagents 2-exonorbornylMgBr, 1-AdMgBr, EtMgBr, and t-BuMgBr were prepared from the corresponding alkyl bromide and magnesium turnings following a general literature procedure and used immediately after preparation.33,34 Compounds 16,20 18,35 21,36 44a,37 44b,38 46,39 48,40 di-tert-butylamine,42 2,2,5,5-tetramethylpyrrolidine,43 1,1,3,3-tetramethylisoindoline,45 1,1,3,3-tetraethylisoindoline,45 tert-amyl-tert-butylamine,46 di-tert-amyl-amine,47 tert-butyl-tert-octylamine,48 di-1-adamantylamine,49 1-adamantyltert-butylamine,50 30,51 and 1-formyl-2,2,6,6-tetramethylpiperidine,52 were analogously prepared according to reported literature. NMR spectra were recorded with a UNITY INOVA 400 FT spectrometer (Varian Inc., Palo Alto, CA, USA) operating at 400 MHz for 1H NMR, 100.6 MHz for 13C NMR, and 40.5 MHz for 15N NMR; ULTRASHIELD 500 FT spectrometer (Bruker Corp., Billerica, MA, USA) operating at 500 MHz for 1H NMR, 125.8 MHz for 13C NMR, and 50.6 MHz for 15N NMR; ASCEND 600 FT spectrometer (Bruker Corp., Billerica, MA, USA) operating at 600 MHz for 1H NMR, 150.9 MHz for 13C NMR, and 60.8 MHz for 15N NMR. 1H NMR and 13C NMR signals were referenced with the help of the solvent signals and recalculated relative to TMS. 15N NMR was referenced indirectly to external MeNO2 (δ = 0). Data are presented as follows: chemical shift, multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, quint = quintet, sext = sextet, sept = septet, m = multiplet, br = broad), coupling constant in Hertz (Hz) followed by the number of hydrogen atoms. In all cases of 13C NMR spectra, DEPT135 experiments were also performed. Assignments of NMR signals were further supported by COSY, HSQC, HMBC 2D-NMR methods and also by comparison of the data of homologous compounds in several cases. Signal assignment was omitted if it was unclear. IR-spectra were messured on a NicoletTM iSTM 5 spectrometer (Thermo Fisher Scientific Inc., Waltham, MA, USA) in KBr-matrix for solids or in KBr-cuvette for liquids. Mass spectra were obtained from micrOTOF QII spectrometer (Bruker Corp., Billerica, MA, USA) utilizing electrospray-ionization technique (source: Apollo II ESI). Quantitative elementary analyses were performed on a vario Micro cube (Elementar Analyensysteme GmbH, Langenselbold, HE, Germany). Melting points (m.p.) were measured by BOETIUS-method on a heating apparatus from VEB Analytik Dresden PHMK 74/0032. Reaction tracking was realized via analytical gas chromatography using a gas chromatograph 5890

Figure 3. 1H NMR spectra of 10 in toluene-d8 at different temperatures (400 MHz, upfield region).

_____________________________________________ 3. CONCLUSIONS In summary, we have shown that model compound 9 can be prepared by using different methods; but several procedures, which provided an access to triisopropylamine (16), failed in the case of 9. Di-tert-butyl(isopropyl)amine (10) and tertiary amines with an even higher degree of steric congestion were effectively available by three processes (methods D, H, J) only, and these methods were never previously utilized to prepare sterically hindered amines. The presented trialkylamines establish new records of steric distress and show surprising spectroscopic and chemical properties. However, the negative results in our attempts to prepare simple tri-tertalkylamines may indicate a limit of steric congestion. This impression is intensified by the dramatic drop of the yield when the synthesis of 43 (63%, Method D) is compared with the completely unsuccessful efforts to prepare 1-adamantyl-ditert-butylamine by the same method. Moreover, it is doubtful whether tri-tert-butylamine (11) can be isolated at room temperature, because even the less sterically hindered amine 38b undergoes a rapid Hofmann elimination under such conditions. Nevertheless, the potential existence and properties of 11 as well as the calculated structure and the stability of the corresponding Lewis pairs were discussed intensively.32 Currently, we are investigating conformational dynamics of trialkylamines with bulky substituents by using NMR methods, and we try to find correlations between 15N NMR chemical shifts and increasing steric hindrance around the N atom. Work on single crystals to perform analysis of the molecular structures by X-ray diffraction is also in progress. Finally, we would like to support all colleagues who will attempt to dis-



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adamantyl)amine49 as a pure white solid (84% yield). m.p. = 172– 173 °C. 1H NMR (400 MHz, C6D6): δ = 1.47–1.55 (m, 12H), 1.96 (bs, 6H), 2.21 (bs, 12H). 13C NMR (100.6 MHz, C6D6): δ = 30.7 (d, CH), 36.4 (t, CH2), 43.3 (t, CH2), 66.6 (s, C). Anal. Calcd. for C20H30ClN (319.21): C, 75.09; H, 9.45; N, 4.38; found: C, 75.20; H, 9.48; N, 4.34.

Series II (Hewlett Packard Inc., Palo Alto, CA, USA; column: HP-5 M.S. (crosslinked 5% Ph Me Silicone) 30 m x 0.25 mm x 0.25 µm). For the separation of complex mixtures, a preparative gas chromatograph GC-8A (Shimadzu Corp., Kyoto, Japan) was used with a Carbowax-column (KOH, 1 m or 3 m, Inj.-Temp.: 70 °C, Col.-Temp.: 60°C, Carrier Gas: Helium 5.0, 30 mL/min). N-tert-Butyl-N-isopropylformamide (25). The product was analogously synthesized according to a reported procedure51 for compound 30 and was obtained as a white crystalline solid in 81% yield. m.p. = 38–40 °C. 1H NMR (400 MHz, CDCl3): δ =1.34 (s, 9H, -C(CH3)3), 1.43 (d, 3JH,H = 6.8 Hz, 6H, -CH(CH3)2), 3.52 (sept,3JH,H = 6.8 Hz, 1H, -CH(CH3)2), 8.35 (s, 1H, -CHO). 13C NMR (100.6 MHz, CDCl3): δ = 20.0 (q, -CH(CH3)2), 29.1 (q,C(CH3)3), 47.1 (d, -CH(CH3)2), 56.3 (s, -C(CH3)3), 161.0 (d, CHO). IR [cm–1]: ῦ = 1659. HRMS: m/z calcd for C8H18NO (M + H+) 144.1383; found 144.1394. Compounds 27,54 28,55,56 29,57 31,55 42, N,Ndichloroadamantane-1-amine,58 1-chloro-2,2,5,5-tetramethylpyrrolidine, 1-chloro-2,2,5,5-tetramethylpyrroline, N-tert-butyl-Nchloro-tert-amylamine,55 N-chloro-di-tert-amylamine, and N-tertbutyl-N-chloro-tert-octylamine were analogously prepared according to reported literature.59 N-(tert-Butyl)-N-chloro-adamantan-1-amine (42). The product was prepared analogously to the general procedure59 from N(tert-butyl)adamantan-1-amine50 as a pure white solid (0.93 g, 80% yield); m.p. = 140–142 °C. 1H NMR (400 MHz, C6D6): δ = 1.35 (s, 9H, C(CH3)3), 1.47 (bs, 6H), 1.93 (bs, 3H), 2.08 (bs, 6H). 13 C NMR (100.6 MHz, C6D6): δ = 30.4 (d, CH), 31.5 (q, CH3), 36.3 (t, CH2), 42.4 (t, CH2), 64.7 (s, C), 66.1 (s, C). HRMS m/z calcd for C14H25ClN (M+H+) 242.1670; found 242.1660. N-Chloro-2,2,5,5-tetramethylpyrrolidine. The product (2.3 g) was isolated by removing solvents in vacuum and recondensed as yellowish liquid in 90% yield. 1H NMR (400 MHz, CDCl3): δ = 1.20 (s, 12H, CH3), 1.75 (s, 4H, CH2). 13C NMR (100.6 MHz, CDCl3): δ = 27.0 (q, CH3), 35.6 (t, CH2), 65.6 (s, C(CH3)2). HRMS m/z calcd for C8H18N (M–Cl+2H)+ 128.1434; found 128.1474. N-Chloro-2,2,5,5-tetramethylpyrroline. The product (1.01 g) was isolated by removing solvents with a 25 cm Vigreux column at 50 °C and recondensed in vacuum as yellowish liquid in 53% yield. 1H NMR (400 MHz, CDCl3): δ = 1.25 (s, 12H, -C(CH3)2), 5.68 (s, 2H, -CH). 13C NMR (100.6 MHz, CDCl3): δ = 26.2 (q, C(CH3)2), 71.4 (s, -C(CH3)2), 134.6 (d, =CH-). HRMS m/z calcd for C8H16N (M–Cl+2H)+ 126.1277; found 126.1289. N-Chloro-di-tert-amylamine. The product (5.3 g) was synthesized by general procedure59 by using di(tert-amyl)amine47 and was obtained as a colorless oil (83% yield). 1H NMR (400 MHz, toluene-d8): δ = 0.96 (t, 3JHH = 8 Hz, 6H, -CH2CH3), 1.15 (s, 12H, -C(CH3)2), 1.56 (q, 3JHH = 8 Hz, 4H, -CH2CH3). 13C NMR (100.6 MHz, C6D6): δ = 8.4 (q, -CH2CH3), 27.4 (q, -C(CH3)2), 38.4 (t, CH2CH3), 66.2 (s, CN). HRMS m/z calcd for C10H24N (M– Cl+2H)+ 158.1903; found 158.1887. N-tert-Butyl-N-chloro-tert-octylamine. The product was prepared analogously to the general procedure59 from N-tert-butyltert-octylamine48 as a yellow oil (1.88 g, 8.6 mmol, 70% yield). 1 H NMR (400 MHz, CDCl3): δ (ppm) = 1.03 (s, 9H, (CH3)3-CCH2), 1.37 (s, 9H, (CH3)3-C-N), 1.41 (s, 6H, (CH3)2-C-N), 1.66 (s, 2H, (CH2)-C-N). 13C NMR (100.6 MHz, CDCl3): δ (ppm) = 30.6 (q, (CH3)2-C-N), 31.4 (q, (CH3)3-C-N), 31.7 (q, (CH3)3-C-CH2), 31.8 (s, (CH3)3-C-CH2), 53.9 (t,-CH2-), 65.1 (s, (CH3)3-C-N), 69.3 (s, CH2-C-N). HRMS m/z calcd for C12H28N (M–Cl+2H)+ 186.2216; found 186.2212. N,N-Di(1-adamantyl)-N-chloro-amine. The product was prepared analogously to the general procedure59 from di(1-

Preparation of Tertiary Amines. Method D-1 (General SN1 protocol between secondary amines and 45): A two-neck-round bottom flask (50 mL) was equipped with a magnetic stirring bar and gas inlet valve. The whole system was flame-dried under vacuum followed by purging with nitrogen. Under nitrogen and dark, 1-bromoadamantane (45, 0.25 g, 1.16 mmol) and silver trifluoromethanesulfonate (0.30 g, 1.16 mmol) were dissolved in 20 mL dry methylene chloride at 0 °C. The reaction mixture was stirred at 0 °C for at least 4 h. Anhydrous potassium carbonate (0.60 g, 5.79 mmol) was added followed by the addition of amine (1.74 mmol). The mixture was stirred at 0 °C for 4 h under dark. After cooling to –10 °C, the reaction mixture was quenched with saturated solution of sodium bicarbonate (20 mL). The neutralized reaction mixture was extracted with more DCM (2 x 25 mL). The organic layers were collected, dried over potassium carbonate, and the solvent was removed under vacuum. Method D-2 (General SN1 protocol between secondary amines and 44b): A two-neck-round bottom flask (50 mL) was equipped with a magnetic stirring bar and gas inlet valve. The whole system was flame-dried under vacuum followed by purging with nitrogen. Under nitrogen, trimethylsilyl trifluoromethanesulfonate (TMSOTf, 0.26 g, 1.17 mmol) and anhydrous potassium carbonate (0.60 g, 5.79 mmol) were added to a solution of 1adamantyl mesylate38 (44b, 0.27 g, 1.16 mmol) in 20 mL dry methylene chloride. The reaction mixture was stirred at 0 °C for 30 minutes followed by the addition of amine (1.74 mmol). The reaction mixture was stirred at r.t. for 3 h. The neutralized reaction mixture was extracted, worked up, and purified as mentioned in Method D-1. Method D-3 (General SN1 protocol between secondary amines and 44a): A two-neck-round bottom flask (50 mL) was equipped with a magnetic stirring bar and gas inlet valve. The whole system was flame-dried under vacuum followed by purging with nitrogen. Under nitrogen, trimethylsilyl trifluoromethanesulfonate (TMSOTf, 0.26 g, 1.17 mmol) and anhydrous potassium carbonate (0.60 g, 5.79 mmol) were added to a solution of 1adamantyl acetate37 (44a, 0.23 g, 1.16 mmol) in 20 mL dry methylene chloride. The reaction mixture was stirred at 0 °C for 30 minutes followed by the addition of amine (1.74 mmol). The mixture was stirred at r.t. for 12 h. The neutralized reaction mixture was extracted, worked up, and purified as mentioned in Method D-1. Method E: Into a solution of 21 (3.0 g, 8.5 mmol) in anhydrous chloroform was bubbled Cl2 at –10 °C for 30 min. After the temperature was not rising, Cl2 was bubbled into the solution for another 10 min followed by purging with nitrogen gas. After removing the solvent, the white residue was filtered and washed well with dry hexane and suspended in 20 ml dry THF. To the mixture was added a solution of methylmagnesium chloride (11.5 mL, 3 M in THF, 34.5 mmol) at –10 °C. The reaction mixture was stirred for another 10 min and then quenched with ice-water followed by addition of conc. HCl to adjust pH 1. The acidic mixture was washed three times with diethyl ether, basified with NaOH to pH 14, and extracted four times with diethyl ether. The organic phases of the alkaline extraction were collected, dried over MgSO4, and the solvent was removed by distillation with a 25 cm


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Vigreux column. The residue was then recondensed at room temperature into a liquid nitrogen trap to afford the crude product. Method F: To a solution of a tertiary amine (2.48 mmol) in 2 mL Et2O was added Br2/Cl2/I2 (9.8 mmol) in 15 mL Et2O at 0 °C. After stirring for 1 h at 25 °C, the mixture was decanted and the black precipitate was washed ten times with Et2O. The black residue was suspended in dry THF (10 mL). To the mixture was added a solution of methylmagnesium bromide (10 mL, 3 M in Et2O, 30 mmol) at – 5 °C. The reaction mixture was stirred at room temperature for 30 min, and then quenched with ice-water followed by addition of conc. HCl to adjust pH 1. The acidic mixture was washed three times with diethyl ether, then conc. NaOH was added to get pH 14. The alkaline solution was extracted four times with diethyl ether. The organic phases were collected, dried over MgSO4, and the solvent was removed by distillation with a 25 cm column. The remaining part of solvent was removed under vacuum (250 mbar). The residue was recondensed at 0.05 mbar and then further purificated by preparative gas chromatography to afford the desired product. Method G: The formamide (6.9 mmol) was dissolved in toluene (20 mL) under nitrogen atmosphere. At −78 °C oxalyl chloride (10.5 mmol) or MeOTf (7 mmol) was added and the mixture was warmed to room temperature and stirred for two hours. All volatiles were removed in vacuo and the residue was washed with dry Et2O. THF or Et2O was added again, the suspension was cooled to −78 °C and MeMgBr (35 mmol, 11.6 mL, 3 M in Et2O) or MeMgCl (35 mmol, 11.6 mL, 3 M in Et2O) was added. The reaction mixture was stirred overnight at r.t. and quenched with icecold water, extracted with Et2O and dried over K2CO3. The solvent was distilled off and the product was purified by condensation at 4 mbar to gain the desired compound. Method H (electrophilic amination): A two-neck-round bottom flask (50 mL) was equipped with a magnetic stirring bar and gas inlet valve. The whole system was flame-dried under vacuum followed by purging with nitrogen. Under nitrogen, N-chloroamine (1.00 mmol) was added to a solution of isopropylmagnesium chloride (0.75 mL, 2 M in THF, 1.5 mmol) and TMEDA (3.00 g, 26.0 mmol) in diethyl ether (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water (10 mL) and extracted with n-pentane (3 x 25 mL). The organic layer was washed with water (2 x 20 mL), dried over potassium carbonate, and the solvent was evaporated. Method I: The reaction was carried out for the preparation of tertiary amines by using N,N-dichloro-amine (2.28 mmol), TMEDA (3.00 g, 26.20 mmol), and isopropylmagnesium chloride (2.85 mL, 2 M in THF, 5.70 mmol) in diethyl ether (10 mL) at 0 °C. The reaction mixture was stirred at room temperature for 3 h. The reaction was quenched with water (10 mL) and extracted with n-pentane (3 x 25 mL). The organic layer was washed with water (2 x 20 mL), dried over potassium carbonate, and the solvent was evaporated. Method J (General SN1 protocol between imines and 1-AdOTf): A two-neck-round bottom flask (50 mL) was equipped with a magnetic stirring bar and gas inlet valve. The whole system was flame-dried under vacuum followed by purging with nitrogen. Under nitrogen and dark, silver trifluoromethanesulfonate (AgOTf, 0.30 g, 1.16 mmol) and 1-bromoadamantane (45, 0.25 g, 1.16 mmol) were dissolved in dry methylene chloride (20 mL) at 0 °C. The reaction mixture was stirred at 0 °C for at least 4 h. Anhydrous potassium carbonate (0.60 g, 5.79 mmol) was added followed by the addition of imine (1.16 mmol), and the reaction mixture was stirred at 0 °C for 4 h under dark. The reaction mixture was cooled to –78 °C followed by the dropwise addition of methyllithium (0.75 mL, 3.10 M in diethoxymethane, 2.32 mmol).

The reaction mixture was stirred at –78 °C for 2 h. The reaction was quenched with saturated solution of ammonium chloride (20 mL). N,N-Diisopropyl-tert-butylamine (9). Method H: Using N-chloro-N-isopropyl-tert-butylamine54 (27, 0.50 g, 3.34 mmol) and isopropylmagnesium chloride (3.3 mL, 2.0 M in THF, 6.8 mmol). The crude product was recondensed at 25 °C and 0.05 mbar to yield a mixture of compound 9 (0.25 g, 46% yield) and the side product 18 (0.05 g, 14% yield) as colorless liquid. Method H: Using N-chloro-N,N-diisopropylamine55,56 (28, 0.5 g, 3.7 mmol), TMEDA (5.0 g, 43.1 mmol), and tert-butylmagnesium chloride (4.3 mL, 1.7 M in diethyl ether, 7.4 mmol). The crude product was recondensed at 25 °C and 0.05 mbar to yield a mixture of compound 9 (70.0 mg, 11% yield) and the side product 20 (30.0 mg, 9% yield) as a colorless liquid. Method E: The crude product contains a proportion of 9 (0.126 g, 4.7%, calculated by 1H NMR). Method F: Using iodine and then MeMgBr (3 M in Et2O), the product (978 mg) was isolated by preparative GC in 21% yield. Method G: From 25 using oxalyl chloride and MeMgBr (3 M in Et2O) and isolation of 9 (3.51 g) by distillation in 62% yield or with MeOTf and MeMgCl (3M in Et2O) in 23% yield (250 mg). Method I: From 29 using iPrMgCl (2 M in THF), the product 9 (250 mg) was isolated in 4% yield. 1 H NMR (400 MHz, toluene-d8): δ = 1.08 (d, 3J = 6 Hz, 12H, CH(CH3)2), 1.12 (s, 9H, C(CH3)3), 3.15 (sept, 3J = 6 Hz, 2H, CH(CH3)2). 1H NMR (400 MHz, CDCl3): δ = 1.11 (d, 3J =6.9 Hz, 12H, CH(CH3)2), 1.16 (s, 9H, C(CH3)3), 3.26 (sept, 3J = 6.9 Hz, 2H, CH(CH3)2). 13C NMR (100.6 MHz, CDCl3): δ = 24.6 (q, CH(CH3)2), 31.00 (q, C(CH3)3), 46.3 (d, CH(CH3)2), 55.9 (s, C(CH3)3). 13C NMR (100.6 MHz, C6D6): δ = 24.4 (q, CH(CH3)2), 30.8 (q, C(CH3)3), 46.2 (d, CH(CH3)2), 58.0 (s, C(CH3)3). HRMS: m/z calcd for C10H23N (M+H+) 158.1903; found 158.1894. N,N-Di(tert-butyl)isopropylamine (10). Method H: The product was prepared by using N-chloro-di(tert-butyl)amine55,59 (31, 0.50 g, 3.07 mmol), TMEDA (5.0 g, 43.11 mmol), and isopropylmagnesium chloride (3.1 mL, 2.0 M in THF, 6.1 mmol). The crude product was recondensed at 25 °C and 0.05 mbar to yield a mixture of 10 (0.17 g, 32% yield) and di-tert-butylamine as side product (0.06 g, 16% yield) as colorless liquid. Product 10 was also synthesized via Method H using N-chloro-Nisopropyl-tert-butylamine (27) and t-BuMgCl with 1% yield and from 30 and MeMgBr through Method G (without forming an iminium salt) with 4% yield. 1 H NMR (400 MHz, toluene-d8): δ = 1.20 (s, 9H, -C(CH3)3), 1.24 (d, 3JH,H = 7.0 Hz, 6H, -CH(CH3)2), 1.31 (s, 9H, -C(CH3)3), 3.37 (sept, 3JH,H = 7.0 Hz, -CH(CH3)2. 13C NMR (100.6 MHz, toluened8): δ = 26.2 (q, -CH(CH3)2), 32.6 (q, -C(CH3)3), 34.6 (q, C(CH3)3), 48.7 (d, -CH(CH3)2), 57.2 (s, -C(CH3)3), 58.8 (s, C(CH3)3). HRMS: m/z calcd for C11H26N (M + H+) 172.2060; found 172.2068. N-Isopropyl-2,2,5,5-tetramethylpyrrolidine (12). Method G: The product was synthesised using 1-formyl-2,2,5,5tetramethylpyrrolidine53, (COCl)2, and then MeMgBr (3 M in Et2O), and isolated by removing of solvents as yellowish oil in 38% yield. 1 H NMR (400 MHz, CDCl3): δ = 1.12 (s, 12H, C-CH3), 1.15 (d, 3 J = 7.0 Hz, 6H, CH-CH3), 1.58 (s, 4H, CH2), 3.20 (sept, 3J = 7.0 Hz, CH-CH3). 13C NMR (100.6 MHz, CDCl3): δ = 26.0 (q, CHCH3), 30.2 (q, C-CH3), 40.1 (t, CH2), 44.7 (d, CH), 61.6 (s, C-CH3). HRMS: m/z calcd for C11H24N 170.1903; found 170.1903. N-tert-Butyl-2,2,5,5-tetramethylpyrrolidine (13).



Method F: From 12 and I2, then MeMgBr, preparative gas chromatography afforded 13 (31 mg, 0.17 mmol, 6.9 %) as a white solid; m.p. = 86 °C. Method H: Synthesized from 1-chloro-2,2,5,5tetramethylpyrrolidine using t-BuMgBr (3 M in Et2O) and isolated as white solid in 4% yield. 1 H NMR (400 MHz, toluene-d8): δ = 1.26 (s, 12H, CH3), 1.28 (s, 9H, CH3), 1.54 (s, 4H, CH2). 13C NMR (100.6 MHz, toluene-d8): δ = 32.6 (q, CH3), 34.0 (q, CH3), 42.7 (t, CH2), 54.7 (s), 63.7 (s). HRMS m/z calcd for C12H26N (M+H+) 184.2060; found 184.2058. N-Isopropyl-2,2,6,6-tetramethylpiperidine (14). Method G: The product (3.66 g) was synthesized using 1-formyl-2,2,6,6tetramethylpiperidine,52 (COCl)2, and then MeMgBr (3 M in Et2O), and isolated by recondensation as colorless oil in 36% yield. 1 H NMR (400 MHz, CDCl3): δ = 1.17 (s, 12H, C–CH3), 1.21 (d, 3 J = 7.2 Hz, 6H, CH–CH3), 1.37 (m, 4H, 3–H and 5–H), 1.5 (m, 2H, 4–H), 3.46 (sept, 3J = 7.2 Hz, 1H, N–CH). 13C NMR (100.6 MHz, CDCl3): δ = 18.0 (t, C–4), 26.5 (q, CH–CH3), 30.0 (q, C– CH3), 44.4 (br. d, N–CH), 47.1 (t, C–3 and C–5), 55.1 (s, C–2 and C–6). HRMS: m/z calcd for C12H25N (M+H+) 184.2060; found 184.2074. 1-(1-Adamantyl)-2,2,5,5-tetramethylpyrrolidine (32). Method D-1: The reaction was carried out using 2,2,5,5tetramethylpyrrolidine43 (0.08 g, 0.65 mmol), AgOTf (0.17 g, 0.65 mmol), and 1-bromoadamantane (0.14 g, 0.65 mmol). Further purification was achieved by washing with MeOH. The desired product (32) was collected as white solid (0.11 g, 65% yield); m.p. = 92–93 °C. Method D-2: The reaction was carried out using 2,2,5,5tetramethylpyrrolidine (0.20 g, 1.57 mmol), TMSOTf (0.23 g, 1.05 mmol), and 1-adamantyl mesylate38 (44b, 0.24 g, 1.05 mmol). After acid base/extraction, further purification was done by washing with MeOH. The desired product (32) was collected as white solid (0.13 g, 48% yield). 1 H NMR (400 MHz, C6D6): δ = 1.29 (s, 12H, CH3), 1.51 (s, 4H, CH2CH2), 1.52–1.58 (m, 6H), 1.93–2.01 (m, 9H). 13C NMR (100.6 MHz, C6D6): δ = 30.5 (q, CH3), 33.2 (d, CH), 36.8 (t, CH2), 42.7 (t, CH2), 44.9 (t, CH2), 56.6 (s, C), 63.3 (s, C). HRMS m/z calcd for C18H32N (M+H+) 262.2529; found 262.2531. N-(tert-Butyl)-2,2,5,5-tetramethylpyrroline (33). Method H: The product was synthesised using t-BuMgCl (3 M in Et2O) and 1-chloro-2,2,5,5-tetramethylpyrroline, and isolated by removing the solvents in vacuum followed by purification by preparative gas chromatography to get a colorless oil in 8% yield. 1 H NMR (400 MHz, toluene-d8): δ = 1.31 (s, 9H, CH3), 1.34 (s, 12H, CH3), 5.11 (s, 2H, CH). 13C NMR (100.6 MHz, toluene-d8): δ = 32.1 (q, CH3), 33.7 (q, CH3), 54.7 (s), 69.5 (s), 135.9 (d, CH). HRMS m/z calcd. for C12H24N (M+H+) m/z 182.1903; found 182.1903. 1-(1-Adamantyl)-2,2,5,5-tetramethyl-2,5-dihydro-1H-pyrrole (34). Method D-1: The reaction was carried out using 2,2,5,5tetramethyl-2,5-dihydro-1H-pyrrole44 (0.08 g, 0.65 mmol), AgOTf (0.17 g, 0.65 mmol), and 1-bromoadamantane (0.14 g, 0.65 mmol). After acid/base extraction, the desired product 34 was obtained as thick oil (25.3 mg, 15% yield). 1 H NMR (400 MHz, C6D6): δ = 1.42 (s, 12H, CH3), 1.60–1.63 (m, 6H), 1.99–2.03 (m, 3H), 2.07–2.10 (m, 6H), 5.14 (s, 2H). 13C NMR (100.6 MHz, C6D6): δ = 30.2 (q, CH3), 32.5 (d, CH), 36.9 (t, CH2), 44.8 (t, CH2), 57.0 (s, C), 69.0 (s, C), 135.7 (d, CH). HRMS m/z calcd for C18H30N (M+H+) 260.2373; found 260.2373. 2-(1-Adamantyl)-1,1,3,3-tetramethylisoindoline (35). Method D-1: The reaction was carried out using 1,1,3,3tetramethylisoindoline45 (0.11 g, 0.65 mmol), AgOTf (0.17 g,

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0.65 mmol), and 1-bromoadamantane (0.14 g, 0.65 mmol). After acid/base extraction, the crude product was subjected to column chromatography (or thick layer chromatography) by using basic aluminum oxide and n-hexane as solvent. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 35 as white solid (0.14 g, 68% yield); m.p. = 117–118 °C (soften at 110°C). Method D-2: The reaction was carried out using 1,1,3,3tetramethylisoindoline (0.20 g, 1.14 mmol), TMSOTf (0.17 g, 0.76 mmol), and 1-adamantyl mesylate38 (44b, 0.18 g, 0.76 mmol). After acid/base extraction, the crude product was subjected to column chromatography (or thick layer chromatography) by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 35 as white solid (0.12 g, 51% yield). 1 H NMR (400 MHz, C6D6): δ = 1.58–1.68 (m, 18H), 1.98–2.05 (m, 3H), 2.15–2.21 (m, 6H), 6.92–6.97 (m, 2H), 7.11–7.15 (m, 2H). 13C NMR (100 MHz, C6D6): δ = 30.6 (d, CH), 34.8 (q, CH3), 36.7 (t, CH2), 44.8 (t, CH2), 57.3 (s, C), 67.0 (s, C), 120.9 (d, CH), 126.5 (d, CH), 148.7 (s, C). HRMS m/z calcd for C22H32N (M+H+) 310.2529; found 310.2529. 2-(1-Adamantyl)-1,1,3,3-tetraethylisoindoline (36). Method D-1: The reaction was carried using 1,1,3,3tetraethylisoindoline45 (0.15 g, 0.65 mmol), AgOTf (0.17 g, 0.65 mmol), and 1-bromoadamantane (0.14 g, 0.65 mmol). After acid/base extraction, the crude product was subjected to column chromatography (or thick layer chromatography) by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 36 as white solid (42.7 mg, 18% yield); m.p. = 126–128 °C. Method D-2: The reaction was carried out using 1,1,3,3tetraethylisoindoline (0.20 g, 0.86 mmol), TMSOTf (0.13 g, 0.57 mmol), and 1-adamantyl mesylate38 (44b, 0.13 g, 0.57 mmol). After acid/base extraction, the crude product was subjected to column chromatography (or thick layer chromatography) by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The least polar fraction was collected, and the solvent was removed under vacuum to yield the desired product 36 as white solid (25.3 mg, 12% yield). 1 H NMR (400 MHz, C6D6): δ = 0.89 (t, 3J = 7.6 Hz, 12H, CH2CH3), 1.56–1.69 (m, 6H), 1.99–2.16 (m, 11H), 2.25–2.30 (m, 6H), 6.86–6.91 (m, 2H), 7.09–7.13 (m, 2H). 13C NMR (100.6 MHz, C6D6): δ = 10.9 (q, CH2CH3), 30.6 (d, CH), 36.2 (t, CH2), 36.7 (t, CH2), 43.8 (t, CH2), 58.6 (s, C), 74.6 (s, C), 121.9 (d, CH), 125.7 (d, CH), 145.1 (s, C). Anal. Calcd for C26H39N (365.30): C, 85.42; H, 10.75; N, 3.83; found: C, 85.02; H, 10.66; N, 3.80. N-(tert-Butyl)-N-isopropyl-tert-amylamine (37a). Method H: The product was prepared using N-(tert-butyl)-Nchloro-tert-amylamine55 (0.50 g, 2.82 mmol), TMEDA (5.0 g, 43.11 mmol), and isopropylmagnesium chloride (2.82 mL, 2.0 M in THF, 5.6 mmol). The crude product was recondensed at 25 °C and 0.05 mbar to yield a mixture of 37a (0.14 g, 26% yield) and N-(tert-butyl)-tert-amylamine as side product (0.16 g, 41% yield) as colorless liquid. 1 H NMR (400 MHz, toluene-d8): δ = 0.94 (t, 3J = 7.3 Hz, 3H, CH3-CH2 ), 1.15 (s (3H, C(CH3)2), 1.18 (s, 4.5H, C(CH3)3,), 1.23 (d, 3J = 7.1 Hz, 3H, CH3-CH), 1.24 (d (overlapped, 3H, CH3-CH), 1.24 (s, C(CH3)2, overlapped), 1.30 (s, , 4.5H, C(CH3)3, overlapped), 1.32 (q, 3J = 7.3 Hz, 1H, CH2, overlapped), 1.50 (q , 3 J = 7.3 Hz, 1H, CH2), 3.27 (sept, 3J = 7.1 Hz, CH3-CH, 0.5H), 3.37 (sept, 3J = 7.1 Hz, CH3-CH, 0.5H). 13C-NMR (100.6 MHz, toluene-d8): δ = 9.5 (q, CH2CH3), 9.6 (q, CH2CH3), 26.2 (q), 26.3


Page 9 of 13 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60


(q), 29.6 (q), 30.9 (q), 32.1 (q), 34.7 (q), 36.9 (t), 38.4 (t), 47.9 (d), 48.3 (d), 56.9 (s), 58.5 (s), 60.1 (s), 61.2 (s). HRMS m/z calcd for C12H28N (M+H+) 186.2216; found 186.2217. N-Isopropyl-di(tert-amyl)amine (37b). Method H: The reaction was carried out using N-chloro-di(tert-amyl)amine (0.5 g, 2.6 mmol), TMEDA (5.0 g, 43.1 mmol), and isopropylmagnesium chloride (2.5 mL, 2.0 M in THF, 5.0 mmol). The crude product was subjected to recondensation method via liquid nitrogen trap. The side product di-tert-pentylamine was collected first at 60 °C and 10 mbar for a period of 4 h, and the desired product 37b was collected at 60 °C and 1 mbar as pure colorless oil (0.1 g, 19% yield); m.p. = 6–7 °C. 1 H NMR (400 MHz, toluene-d8): δ = 0.90 (t, 3J = 8 Hz, 3H, CH2CH3), 0.92 (t, 3J = 8 Hz, 3H, CH2CH3), 1.13 (s, 6H, C(CH3)2), 1.22 (d, 3J = 8 Hz, 6H, CH(CH3)2), 1.24 (s, 6H, C(CH3)2), 1.40 (q, 3 J = 8 Hz, 2H, CH2CH3), 1.57 (q, 3J = 8 Hz, 2H, CH2CH3), 3.29 (sept, 3J = 8 Hz, 1H, CH(CH3)2). 13C NMR (100.6 MHz, CDCl3): δ = 9.6 (q, CH2CH3), 10.0 (q, CH2CH3), 26.6 (q, CH(CH3)2), 29.0 (q, C(CH3)2), 31.6 (q, C(CH3)2), 37.2 (t, CH2), 37.7 (t, CH2), 47.6 (d, CH(CH3)2), 60.2 (s, C(CH3)2), 61.4 (s, C(CH3)2). HRMS: m/z calcd for C13H30N (M+H+) 200.2373; found 200.2385. N-tert-Butyl-N-ethyl-tert-octylamine (38a). Method H: The product was synthesised using N-tert-butyl-N-chloro-tertoctylamine and EtMgBr (3 M in Et2O), and isolated by column chromatography (basic Al2O3, hexane:Et2O = 1:1) as a colorless liquid (43% yield). 1 H-NMR (400 MHz, CDCl3): δ = 0.99 (s, 9H, (CH3)3-C-CH2), 1.04 (t, 3J = 7.0 Hz, 3H, CH3-CH2-N) , 1.20 (s, 9H, (CH3)3-C-N), 1.29 (s, 6H, (CH3)2- C-N), 1.55 (s, 2H, CH2-C-N), 2.60 (q, 3J = 7.0 Hz, 2H, CH3-CH2-N). 13C-NMR (100.6 MHz, CDCl3): δ = 21.6 (q, N-CH2-CH3), 31.6 (s, (CH3)3-C-CH2), 32.1 (q, tBu), 32.2 (q, tBu), 32.6 (q, (CH3)2-C-N), 40.9 (t, N-CH2-CH3), 52.8 (t, CH2C-N), 57.8 (s, (CH3)3-C-N), 62.5 (s, (CH3)2-C-N). HRMS: m/z calcd for C14H32N (M+H+) 214.2529; found: 214.2513. N-tert-Butyl-N-isopropyl-tert-octylamine (38b). Method H: The product was prepared using i-PrMgCl (2 M in THF) and Ntert-butyl-N-chloro-tert-octylamine, and then removing all volatiles at 0 °C and 10−2 mbar to get a colorless liquid (15% NMRyield). The product is highly unstable and cannot be isolated. 1 H-NMR (400 MHz, toluene-d8, syn-rotamer): δ = 1.00 (s, 9H, Ct-Bu), 1.24 (s, 9H, N-t-Bu), 1.28 (d, 3J = 7.1 Hz, 6H, iPr), 1.40 (s, 6H, CH2CMe2), 1.83 (s, 2H, CH2), 3.39 (sept, 1H, 3J = 7.1 Hz, NCH). 1H-NMR (400 MHz, toluene-d8, anti rotamer): δ = 1.01 (s, 9H, C-t-Bu), 1.27 (d, 3J = 7.1 Hz, 6H, iPr), 1.31 (s, 6H, CH2CMe2), 1.32 (s, 9H, N-t-Bu), 1.59 (s, 2H, CH2), 3.42 (sept, 1H, 3J = 7.1 Hz, N-CH). 13C-NMR (100.6 MHz, toluene-d8, syn/anti-rotamer): δ = 26.6 (q, iPr), 26.7 (q, iPr), 31.8 (s, CH2CMe2), 31.9 (q, CH2CMe2), 32.1 (s, C-t-Bu), 32.4 (q, C-t-Bu), 32.5 (q, C-t-Bu), 32.9 (q, N-t-Bu), 34.9 (q, N-t-Bu), 35.0 (q, CH2CMe2), 48.6 (d, N-CH), 48.9 (d, N-CH), 54.5 (t, CH2), 55.9 (t, CH2), 57.6 (s, N-t-Bu), 59.0 (s, N-t-Bu), 62.4 (s, CH2CMe2), 63.7 (s, CH2CMe2). 15N-NMR (40.6MHz, toluene-d8, syn rotamer): δ = _ 299.1. 15N-NMR (40.6MHz, toluene-d8, anti rotamer): δ = _ 302.4. N,N-Diisopropyladamantan-1-amine (39). Method I: Using N,N-dichloro-adamantan-1-amine58 (0.50 g, 2.28 mmol), TMEDA (3.00 g, 26.20 mmol), and isopropylmagnesium chloride (2.85 mL, 2 M in THF, 5.70 mmol), the crude product was added to MeOH (15 mL) and stirred for 5 min at 40 °C. The side product 1,2-di(adamantan-1-yl)diazene was removed as white solid by filtration (35% yield). The mother liquor was collected, concentrated under vacuum, and purified over column chromatography using basic aluminum oxide as the stationary phase and nhexane as the mobile phase. The least polar fraction was collect-

ed, and the solvent was removed under vacuum to yield the desired product 39 as yellowish oil (64 mg, 12% yield). Method H: N-chloro-diisopropylamine55,56 (28, 0.50 g, 3.70 mmol), TMEDA (3.00 g, 26.20 mmol), and 1adamantylmagnesium bromide (11.11 mL, 0.5 M in diethyl ether, 5.55 mmol) were used for the preparation. The crude product was dissolved in ether, and HCl(g) was bubbled inside the solution for 20 seconds. The formed amine hydrochloride salts were filtered and washed well with ether. The salt was dissolved in dichloromethane, and a cold saturated solution of sodium bicarbonate, or NaOH (5%), was added slowly. The neutralized mixture was transferred to a separatory funnel and extracted using dichloromethane and water. The organic phase was collected, dried over K2CO3, and the solvent was removed under vacuum to yield the desired product 39 as yellowish oil (60.9 mg, 7% yield). Method D-3: Using diisopropylamine (20, 0.20 g, 1.98 mmol), TMSOTf (0.29 g, 1.32 mmol), and 1-adamantyl acetate37 (44a) (0.26 g, 1.32 mmol). After the acid/base extraction, the desired product 39 was collected as yellowish oil (0.20 g, 66% yield). 1 H NMR (400 MHz, C6D6): δ = 1.17 (d, 3J = 8 Hz, 12H, CH(CH3)2), 1.59 (bs, 6H, CH2), 1.82 (bs, 6H, CH2), 1.99 (bs, 3H, CH), 3.27 (sept, 3J = 8 Hz, 2H, CH(CH3)2). 13C NMR (100.6 MHz, C6D6): δ = 25.5 (q, CH(CH3)2), 30.5 (d, CH), 37.2 (t, CH2), 43.4 (t, CH2), 45.4 (d, CH(CH3)2), 56.9 (s, C). HRMS m/z calcd for C16H30N (M+H+) 236.2373; found 236.2378. N,N-Di(1-adamantyl)isopropylamine (40a). Method H: The reaction was carried using N-chloro-di(1-adamantyl)amine (0.3 g, 1.0 mmol), TMEDA (3.0 g, 26.2 mmol), and isopropylmagnesium chloride (1 mL, 2 M in THF, 2.0 mmol). The crude product was dissolved in MeOH (20 mL), heated at 50 °C, and the product filtered off while hot. The desired product 40a was collected as pure white solid (92.0 mg, 30% yield). m.p. = 160–162 °C. 1 H NMR (400 MHz, C6D6): δ = 1.42 (d, 3J = 6 Hz, 6H, CH(CH3)2), 1.56–1.69 (m, 12H), 2.02 (bs, 6H), 2.07 (bs, 6H), 2.22 (bs, 6H), 3.61 (sept, 3J = 6 Hz, 1H, CH(CH3)2). 13C NMR (100.6 MHz, C6D6): δ = 28.2 (q, CH(CH3)2), 31.2 (d, CH), 31.3 (d, CH), 37.2 (t, CH2), 37.3 (t, CH2), 45.3 (t, CH2), 45.4 (t, CH2), 46.4 (d, CH(CH3)2), 60.3 (s, C), 62.0 (s, C). Anal. Calcd. for C23H37N (327.29): C, 84.34; H, 11.39; N, 4.28; found: C, 84.02; H, 11.31; N, 4.30. N,N-Di(1-adamantyl)cyclohexanamine (40b). Method H: The reaction was carried out using N-chloro-di(1-adamantyl)amine (0.32 g, 1.00 mmol), TMEDA (3.00 g, 26.20 mmol), and cyclohexylmagnesium chloride (0.75 mL, 2 M in diethyl ether, 1.50 mmol). The crude product was added to MeOH (30 mL), heated at 50 °C, and the product filtered off while hot. The desired product 40b was collected as pure white solid (0.09 g, 25% yield); m.p. = 201–202 °C. 1 H NMR (400 MHz, C6D6): δ = 1.00–1.13 (m, 1H), 1.25–1.38 (m, 2H), 1.55–1.81 (m, 15H), 1.85–2.08 (m, 10H), 2.10 (bs, 6H), 2.21 (bs, 6H), 3.02 (tt, 3J1 = 11.6 Hz, 3J2 = 2.8 Hz, 1H, CH). 13C NMR (100.6 MHz, C6D6): δ = 26.6 (t, CH2), 28.6 (t, CH2), 30.7 (d, CH), 30.9 (d, CH), 36.8 (t, CH2), 36.9 (t, CH2), 38.8 (t, CH2), 45.1 (t, CH2), 45.6 (t, CH2), 58.0 (d, CH), 59.5 (s, C), 61.7 (s, C). HRMS: m/z calcd for C26H42N (M+H+) 368.3312; found 368.3306. N,N-Di(1-adamantyl)-exo-2-norbornylamine (40c). Method H: The reaction was carried out using N-chloro-di(1adamantyl)amine (0.32 g, 1.00 mmol), TMEDA (3.00 g, 26.20 mmol), and 2-norbornylmagnesium bromide33 (1.50 mL, 1 M in diethyl ether, 1.50 mmol). The crude product was added to MeOH (30 mL), heated at 50 °C, and the product filtered off while hot. The desired product 40c was collected as pure white solid (60.8 mg, 16% yield); m.p. = 225–226 °C.



1 H NMR (400 MHz, C6D6): δ = 1.12 (d, 3J = 9.5 Hz, 1H), 1.17– 1.24 (m, 1H), 1.40–1.48 (m, 1H), 1.53–1.68 (m, 15H), 1.97–2.27 (m, 22H), 3.26 (t, 3J = 9.5 Hz, 1H, CHN). 13C NMR (100.6 MHz, C6D6): δ = 27.5, 30.1, 30.8, 33.5, 36.7, 36.8, 38.3, 44.9, 45.4, 45.6, 45.7, 46.7, 58.7 (s, C), 59.7 (d, CH), 61.2 (s, C). Anal. Calcd. for C27H41N (379.32): C, 85.42; H, 10.89; N, 3.69; found: C, 85.35; H, 10.81; N, 3.62. N-(tert-Butyl)-N-isopropyladamantan-1-amine (43). Method H: Using N-(tert-butyl)-N-chloroadamantan-1-amine (42, 0.24 g, 1.00 mmol), isopropylmagnesium chloride (0.75 mL, 2 M in THF, 1.5 mmol) and TMEDA (3.00 g, 26.0 mmol) in diethyl ether (10 mL, the crude product, which contains the secondary amine N-tert-butyladamantan-1-amine (37% yield), was added to cold MeOH (5 mL) and stirred for 5 min. The desired product 43 was collected by filtration as pure white solid (59.5 mg, 24% yield). Further purification can be achieved by dissolving in minimum quantity of methanol at 50 °C, and left to crystalize at –20 °C; m.p. = 55–56 °C. Method D-1: 1-Bromoadamantane (0.25 g, 1.16 mmol), silver trifluoromethanesulfonate (AgOTf, 0.30 g, 1.16 mmol) and Ntert-butyl-N-isopropylamine (18, 0.20 g, 1.74 mmol) were used. After the reaction, the residue was dissolved in ether, and the formed solid, if any, was filtered off. The clear ether solution was cooled down to –10 °C, and HCl(g) was bubbled inside the solution for 20 seconds. The formed amine hydrochloride salt was filtered and washed well with diethyl ether. The salt was dissolved in dichloromethane, cooled to –10 °C, and a cold saturated solution of sodium bicarbonate, or NaOH (5%), was added slowly. The neutralized mixture was transferred to a separatory funnel and extracted using dichloromethane and water. The organic phase was collected, dried over K2CO3, and the solvent was removed under vacuum. Further purification was achieved by washing with methanol to yield compound 43 as pure white solid (0.18 g, 63% yield). Method D-2: Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 0.26 g, 1.17 mmol), 1-adamantyl mesylate (44b, 0.27 g, 1.16 mmol), N-tert-butyl-N-isopropylamine (18, 0.20 g, 1.74 mmol) were used in the reaction. The neutralized reaction mixture was extracted, worked up, and purified as mentioned in method D-1 to yield compound 43 as pure white solid (0.16 g, 54% yield). Method D-3: Trimethylsilyl trifluoromethanesulfonate (TMSOTf, 0.26 g, 1.17 mmol), 1-adamantyl acetate (44a, 0.23 g, 1.16 mmol) and N-tert-butyl-N-isopropylamine (18, 0.20 g, 1.74 mmol) were used in the preperation. The neutralized reaction mixture was extracted, worked up, and purified as mentioned in method D-1 to yield compound 43 as pure white solid (0.13 g, 46% yield). Method J: Silver trifluoromethanesulfonate (AgOTf, 0.30 g, 1.16 mmol), 1-bromoadamantane (45, 0.25 g, 1.16 mmol), Nethylidene-tert-butylamine39 (46, 0.11 g, 1.16 mmol), and methyllithium (0.75 mL, 3.10 M in diethoxymethane, 2.32 mmol) were used to prepare the title compound. The reaction mixture was extracted, worked up, and purified as mentioned in method D-1 to yield compound 43 as pure white solid (0.12 g, 42% yield). 1 H NMR (400 MHz, C6D6): (signals for the major rotamer where distinguishable are marked as “*”; signals for the minor rotamer where distinguishable are marked as “**”) δ = 1.24** (s, 1.8H, C(CH3)3), 1.26* (d, 3J = 7.2 Hz, 6H, CH(CH3)2), 1.31** (d, 3J = 7.2 Hz, 1.2H, CH(CH3)2), 1.33* (s, 9H, C(CH3)3), 1.50–1.57 (m, 7.2H), 1.87–2.07 (m, 10.8H), 3.41** (sept, 3J = 7.2 Hz, 0.2H, CH(CH3)2), 3.47* (sept, 3J = 7.2 Hz, 1H, CH(CH3)2). 13C NMR (100.6 MHz, C6D6): δ = 26.5* (q, CH3), 27.0** (q, CH3), 30.4* (d, CH), 30.7** (d, CH), 33.4** (q, CH3), 35.0* (q, CH3), 36.7* (t, CH2), 36.8** (t, CH2), 43.8* (t, CH2), 44.4** (t, CH2), 45.8* (d, CH), 48.3** (d, CH), 57.0* (s, C), 59.0** (s, C), 59.4** (s, C), 60.0*

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(s, C). HRMS m/z calcd for C17H32N (M+H+) 250.2529; found 250.2506. N-(tert-Butyl)-N-(prop-1-en-2-yl)adamantan-1-amine (49). Method J: The reaction was carried out using N-(tertbutyl)propan-2-imine40 (48, 0.74 g, 6.53 mmol), 1bromoadamantane (45, 1.41 g, 6.53 mmol), AgOTf (1.67 g, 6.53 mmol), and methyllithium (4.21 mL, 3.10 M in diethoxymethane, 13.06 mmol). Further purification was achieved via thick layer chromatography by using basic aluminum oxide as the stationary phase and n-hexane as the mobile phase. The compound 49 was collected as thick oil (0.37 g, 23% yield). 1 H NMR (400 MHz, C6D6): δ = 1.36 (s, 9H, CH3), 1.55–1.58 (m, 6H), 1.82 (s, 3H, CH3), 1.99–2.02 (m, 9H), 4.71 (d, 2J = 2 Hz, 1H), 5.07 (m, 1H). 13C NMR (100.6 MHz, C6D6): δ = 29.9 (q, CH3), 30.6 (d, CH), 33.5 (q, CH3), 36.6 (t, CH2), 44.4 (t, CH2), 55.3 (s, C), 56.6 (s, C), 115.6 (d, CH2), 150.2 (s, C). HRMS m/z calcd for C17H30N (M+H+) 248.2373; found 248.2373.

5. ASSOCIATED CONTENT *S Supporting Information The Supporting Information is available free of charge on the ACS Publications website at DOI: Spectroscopic data of known compounds, course of the reaction of 38a to form 41, and IR and NMR spectra (PDF)

6. AUTHOR INFORMATION Corresponding Author *[email protected]

ORCID Klaus Banert: 0000-0003-2335-7523

Notes The authors declare no competing financial interest.

7. ACKNOWLEDGMENTS Generous support by the Deutsche Forschungsgemeinschaft (BA903/17-1) is gratefully acknowledged. We thank Julia Hänchen, Niels Klein, Pankaj Lathiya, Ioana Müller, Daniel Schmidtke, and Alexander Voigt for performing some of the syntheses, and Dr. Manfred Hagedorn for his assistance with NMR measurements.

8. DEDICATION This work is dedicated to Prof. Ernst-Ulrich Würthwein on the occasion of his 70th birthday.

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