Stereoselective Synthesis of Nitrogen-Containing Compounds from

Article Cite This: J. Org. Chem. 2017, 82, 10968-10979

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Stereoselective Synthesis of Nitrogen-Containing Compounds from Enamines Masaharu Sugiura,*,† Takeru Kashiwagi,† Mai Ito,† Shunsuke Kotani,‡,† and Makoto Nakajima† †

Graduate School of Pharmaceutical Sciences and ‡Priority Organization for Innovation and Excellence, Kumamoto University, 5-1 Oe-honmachi, Chuo-ku, Kumamoto 862-0973, Japan S Supporting Information *

ABSTRACT: The domino reaction of enamines, electrophiles (N-sulfonylimines, N-tosylisocyanate, or diethyl azodicarboxylate), and trichlorosilane provided trans-amines (trans/cis = > 99:1 to 96:4). Meanwhile, the sequential imino ene-type reaction of enamines and electrophiles/NaBH3CN reduction afforded cis-amines (trans/cis = 1:>99 to 15:85). The reversal of selectivity is discussed on the basis of diastereofacial selection of the plausible iminium ion intermediates. For the domino reaction of cyclic enamines and cyclic imines, high enantioselectivity (er = 95.7:4.3 to 99.9:0.1) was achieved by utilizing chiral Lewis base catalysts.

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INTRODUCTION Enamines are versatile nucleophiles in organic synthesis.1 Electrophiles like alkyl halides, acyl halides, and Michael acceptors react with enamines to form new C−C bonds. In these transformations, the amine moiety of the enamine is generally removed during the hydrolytic workup to obtain the corresponding ketone or aldehyde. On the other hand, trapping of the reaction intermediates with a reductant or other reagent may keep the amine moiety in the product (Scheme 1). Control of the diastereoselectivity becomes an issue because two or more stereogenic centers are generally constructed. Scheme 1. Synthesis of Nitrogen-Containing Compounds from Enamines

β-Amino amides are obtained by the reaction of enamines and N-aryl isocyanates followed by PtO2-catalyzed hydrogenation (eq 1)2a or NaBH4 reduction.2b The radical reaction of enamines and chloromethyl p-tolyl sulfone with tributyltin hydride generates 3-aminoalkyl sulfones with high cis diastereoselectivity (eq 2).3 Aminoalkylation of enamines with iminium salts followed by NaBH4 reduction affords 1,2-anti-2,3-syn-1,3-diamines with high diastereoselectivity (eq 3).4 A propargyl cation substituted with an arene chromium complex reacts with an enamine and subsequently with NaBH4 to give a bishomopropargylamine (eq 4).5 The reaction of trifluoroacetaldehyde hemiacetal with enamines © 2017 American Chemical Society

followed by Pd/C-catalyzed hydrogenation affords α-(trifluoromethyl)-γ-amino alcohols in moderate yields (eq 5; TFE: 2,2,2-trifluoroethanol).6 More recently, the stereodivergent Received: July 31, 2017 Published: September 15, 2017 10968

DOI: 10.1021/acs.joc.7b01923 J. Org. Chem. 2017, 82, 10968−10979

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The Journal of Organic Chemistry

absence of Lewis base (eq 7).14 Use of N-aryl, Boc, or ptoluenesulfinyl imines instead of N-sulfonylimine 1a or use of

synthesis of 1,3-diamines from enamides and N-acyl-N,Oacetals has been reported (eq 6).7 Despite the effective methods described above, stereochemical control remains elusive. We have recently found a domino reaction8 of Nsulfonylimines 1, cyclic ketone-derived enamines 2, and trichlorosilane that furnishes 1,2-anti-2,3-anti-1,3-diamines 3 with high diastereoselectivity (Scheme 2, the first equation).9a Scheme 2. Synthesis of Both trans- and cis-Amines from Various Electrophiles and Enamines

N-(1-cyclohexenyl)acetamide instead of enamine 2a did not provide the desired 1,3-diamines. The relative configuration of 3aa was assigned as 1,2-anti2,3-anti because the NMR analysis indicated the presence of the tosylamide proton bound to the piperidino nitrogen atom and a diaxial relationship of the 1-, 2-, and 3-hydogen atoms (from the coupling constants between them and the NOESY correlations of the 1-, 3-, and 7-hydrogen atoms), as shown in Figure 1.

Figure 1. Relative configuration of 3aa.

Screening of monodentate Lewis base catalysts (20 mol %) under otherwise identical conditions identified HMPA as the optimal catalyst (83% yield, dr = 99:1). Ph3PO, DMPU, NMP, and DMF resulted in lower yields (67, 70, 74, and 77% yield, respectively), although high diastereoselectivities were observed in all cases (dr = 98:2, 97:3, 99:1, and 99:1, respectively). Despite extensive efforts, asymmetric catalysis utilizing various chiral Lewis base catalysts was unsuccessful. On the other hand, an attempt to monitor the reaction by 1 H NMR spectroscopy revealed the instant generation of imino ene-type product 4aa (anti/syn = 88:12) upon mixing of imine 1a and enamine 2a in CD2Cl2 at 0 °C (eq 8). The

Imines 1 and enamines 2 also readily undergo an imino enetype reaction. Subsequent reduction of the resulting enamine intermediate by NaBH3CN affords 1,2-anti-2,3-syn-1,3-diamines 3 (Scheme 2, the second equation).9b Therefore, both 2,3-anti- and 2,3-syn-products (the trans- and cis-amines, in other words) can be obtained by choosing between the two methods (Scheme 2, general equation). This paper gives a full account of these methods including the reaction with cyclic imines or electrophiles other than N-sulfonylimines. High enantioselectivity has been achieved for the reaction with cyclic imines by utilizing chiral Lewis base catalysts.

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RESULTS AND DISCUSSION Reaction of Acyclic N-Sulfonylimines and Enamines.9 Our investigation started with a test of our hypothesis that iminium ion intermediate IM would be generated from imine 1, enamine 2, and trichlorosilane10−12 and reduced intramolecularly by the hydrosilyl group in the presence of an appropriate Lewis base13 (Scheme 3). It was soon discovered that the desired 1,3-diamine 3aa was obtained with high diastereoselectivity when 1-piperidinylcyclohexene (2a) was added to a dichloromethane solution of N-tosylimine 1a and trichlorosilane at 0 °C, even in the

second-order kinetic constant (k20°C) between 1a and 2a was estimated as 32.1 L mol−1 s−1 (>99% conversion within 10 s at 20 °C) according to Mayr’s reactivity scale.15 Thus, a question arose: did the domino reaction of 1a and 2a with trichlorosilane (eq 7) proceed via enamine 4aa? It is unlikely, because treatment of 4aa with trichlorosilane (addition of trichlorosilane to a solution of 1a and 2a at 0 °C) resulted in a low yield of 1,2-anti-2,3-anti-3aa (26%). Therefore, addition of the enamine to a solution of the imine and trichlorosilane is important for the domino reaction. The imino ene-type reaction proceeded even at −78 °C, and treatment with aqueous acetic acid after 21 h afforded βtosylamide cyclohexanone 5aa in 82% yield with high anti diastereoselectivity (eq 9). Addition of acetic acid (1 equiv)

Scheme 3. Working Hypothesis for the Domino 1,3Diamine Synthesis

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The Journal of Organic Chemistry was found to accelerate the imino ene-type reaction at −78 °C to give 5aa in 89% yield after 3 h.16

Scheme 4. Mechanistic Rationale for the Reversal of 2,3Anti/Syn Diastereoselectivity

In place of the hydrolytic workup, reduction of intermediate 4aa should keep the amine moiety in the product to afford 1,3-diamine 3aa. This idea was found to be feasible; treatment of the imino ene-type reaction mixture with acetic acid (9 equiv) and NaBH3CN (2 equiv)17 at −45 °C for 1 h provided 1,2-anti-2,3-syn-3aa in high yield with high diastereoselectivity (eq 10). The relative configurations of the two obtained Scheme 5. Substrate Scope of Enamines

diastereomers were unambiguously determined by X-ray crystallography (Figure 2).18 Both products have the 2,3-syn configuration, and the diastereomeric ratio with regard to the 1,2-positions was retained during the reduction step.

a

dr = 1,2-anti-2,3-anti/other isomers. bdr = 1,2-syn-2,3-syn/1,2-anti2,3-syn (no other isomers were observed). cThe reaction time was extended to 20 h. dThe imino ene-type reaction was conducted at −78 °C for 24 h.

The reactions of N-tosylimine 1a with other enamines 2b−d were investigated (Scheme 5). In all cases, reversal of the 2,3-anti/syn diastereoselectivity between the domino reaction (method A) and the sequential imino ene-type reaction/reduction (method B) was observed. Various N-sulfonylimines 1b−g were also subjected to these reactions (Table 1). The domino reactions were performed at −40 °C because lowering the reaction temperature improved the chemical yields for the reaction of several imines. The methods tolerated naphthyl, heteroaryl, and alkyl imines as well as both electron-rich and -poor aromatic imines. Reversal and high levels of diastereoselectivity were observed in all cases. Reaction of Cyclic N-Sulfonylimines and Enamines. We then turned our attention to the reaction of cyclic imines 619 because the stereochemical outcomes may differ from those with acyclic N-sulfonylimines 1 as a result of the orientation of the SO2 group and imino nitrogen lone pair (Figure 3).

Figure 2. X-ray crystallographic structures of 1,2-anti-2,3-syn- and 1,2-syn-2,3-syn-3aa.

It should be noted that the domino reaction with trichlorosilane (eq 7) afforded 2,3-anti-3aa, whereas 2,3-syn3aa was obtained with the sequential imino ene-type reaction/ NaBH 3 CN reduction (eq 10). This reversal can be rationalized by assuming the occurrence of two different transition states TS-1 and TS-2 (Scheme 4). In TS-1, hydride is delivered from the hydrosilyl group bound to the axial sulfonamide side chain to give the 2,3-anti product. The sulfonamide side chain locates in the axial position because of the allylic strain against the piperidine ring. However, in TS-2, the cyanoborohydride intermolecularly attacks the iminium ion intermediate, avoiding the axial sulfonamide side chain, to afford the 2,3-syn product. 10970


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The Journal of Organic Chemistry Table 1. Substrate Scope of N-Sulfonylimines

method A a

Table 2. Domino Reaction of Cyclic Imine 6a

method B b

entry

imine 1

yield (%)

dr

1 2 3 4 5 6 7

1a 1b 1c 1d 1e 1f 1g

78 80 75 70 95 81 41d

99:1 99:1 99:1 97:3 99:1 99:1 99:1

entry

Lewis base

T (°C)

yielda (%)

drb

erc

1 2 3 4 5d,e 6d,e,f

HMPA (20 mol %)

0 −40 −40 −40 −40 −40

59 41 68 60 79 60

50:50 80:20 84:16 75:25 78:22 78:22

86.6:13.4 93.9:6.1 95.8:4.2 97.9:2.1

(S)-BINAPO (S)-SEGPHOSO (S)-SEGPHOSO (S)-SEGPHOSO

a

a

yield (%)

dr

93 92 87 90 97 84 80e

5:95 4:96 4:96 4:96 3:97 6:94 7:93

Combined yields of the diastereomers. bdr = 1,2-syn-2,3-anti/1,2-anti2,3-anti. Determined by 1H NMR spectroscopic analysis. cThe enantiomer ratio of the 1,2-syn-2,3-anti-7aa. Determined by HPLC analysis. dIn dichloromethane (6 mL). eEnamine 2a (1.2 equiv) in dichloromethane (0.5 mL) solution was added over 5 min. fFor 1 h.

c

The reaction proceeded even in the absence of HMPA at −40 °C to afford 1,2-syn-2,3-anti-7aa as the major diastereomer with 80:20 dr (entry 2). Importantly, when (S)-BINAP dioxide (BINAPO, Figure 4)21 was used as the

a Combined yields of the diastereomers. bdr = 1,2-anti-2,3-anti/other isomers. cdr = 1,2-syn-2,3-syn/1,2-anti-2,3-syn (no other isomers were observed). dAt 0 °C. eThe imino ene-type reaction was conducted without acetic acid.

Figure 4. Chiral Lewis base catalysts.

Lewis base catalyst13 at −40 °C, 1,2-syn-2,3-anti-7aa was obtained with good enantioselectivity, whereas the 1,3-anti2,3-anti-isomer was racemic (entry 3). Screening of chiral Lewis bases identified (S)-SEGPHOS dioxide (SEGPHOSO, Figure 4) as the optimal catalyst (entry 4). After optimization of reaction parameters (temperature, solvent, concentration, reaction time, procedure, etc.), a lower concentration and slow addition of enamine 2a (over 5 min) effectively improved both the chemical yield and enantioselectivity (entry 5). This optimal procedure was presumably effective because the uncatalyzed pathway was prevented. A reduction in the reaction time to 1 h decreased the chemical yield but increased the enantioselectivity (entry 6). The Mannich-type product (β-amido cyclohexanone) and reduced enamine (Ncyclohexylpiperidine) were obtained as byproducts in the

Figure 3. Cyclic imine 6 versus acyclic imine 1.

Indeed, the reaction of cyclic imine 6a and enamine 2a with trichlorosilane in the presence of HMPA at 0 °C for 24 h gave 1,3-diamine 7aa with low diastereoselectivity (Table 2, entry 1). Among the four possible diastereomers, the 1,2-syn2,3-anti and 1,2-anti-2,3-anti isomers were obtained. The relative configurations of these isomers were determined by transforming 7aa into 3aa, as shown in Scheme 6, i.e., by removal of the sulfate group by LAH reduction,19c tosylation of both the hydroxy and amino groups, and reductive removal of the tosyloxy group by a low-valence nickel species.20 The less polar diastereomer 7aa was transformed into 1,2-syn-2,3anti-3aa, whereas more the polar isomer gave 1,2-anti-2,3-anti3aa. Scheme 6. Determination of Relative Configuration

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eoselectivities (entries 1−6). For the reaction of 6d, a reduction in the reaction temperature was effective (entries 4 versus 5). A shorter reaction time (1 h) improved the enantioselectivities (entries 7−11), although the chemical yields were about 20% lower. In the absence of catalyst (−40 °C, 1 h), the chemical yields and diastereoselectivities decreased obviously (entries 12−16), although comparable yields were obtained for the reactions with imines 6c−e (entries 9−11 versus 14−16). Not only the bromo group but also the methoxy group at the 6position may act as an electron-withdrawing group to enhance the electrophilicity of the imino carbon atom, thereby promoting the reaction even in the absence of a catalyst. These results indicate that the Lewis base-catalyzed reaction proceeds much faster than the uncatalyzed reaction because high enantioselectivities were obtained for the 1,2-syn-2,3-antiproducts. The sequential imino ene-type reaction/reduction of cyclic imine 6a and enamine 2a was also investigated (eq 11).

cases of moderate yields of 7aa. Despite extensive efforts, the absolute configuration of the product has not yet been determined. The scope and limitations of enamines were next examined (Scheme 7). Although cyclopentanone-derived enamine 2d Scheme 7. Reaction of Imine 6a with Various Enamines 2a−e

and acetophenone-derived acyclic enamine 2e provided low enantioselectivities, cyclohexanone-derived enamines 2a−c afforded 1,3-diamines 7aa−ac with high enantioselectivities. Next, the reaction of various cyclic imines 6b−e bearing a methoxy or bromo group at the 7- or 6-position was investigated with enamine 2a (Table 3). In all cases, the desired 1,3-diamines 7ba−ea were obtained in good yields with high enantioselectivities albeit with moderate diaster-

Under the same conditions as the reaction with N-tosylimine 1a (eq 10), three diastereomers were obtained in 68:10:22 dr. The configuration of the major diastereomer was unambiguously determined to be 1,2-syn-2,3-syn by X-ray crystallography (Figure 5).18 Interestingly, a zwitterionic structure was

Table 3. Reaction of Various Imines 6a−e with Enamine 2a

Figure 5. X-ray crystallographic structure of 1,2-syn-2,3-syn-7aa. entry

imine

R

7

yielda (%)

drb

erc

1 2 3 4 5d 6 7e 8e 9e 10e 11e 12e,f 13e,f 14e,f 15e,f 16e,f

6a 6b 6c 6d 6d 6e 6a 6b 6c 6d 6e 6a 6b 6c 6d 6e

H 7-OMe 7-Br 6-OMe 6-OMe 6-Br H 7-OMe 7-Br 6-OMe 6-Br H 7-OMe 7-Br 6-OMe 6-Br

7aa 7ba 7ca 7da 7da 7ea 7aa 7ba 7ca 7da 7ea 7aa 7ba 7ca 7da 7ea

79 66 73 80 64 67 60 56 51 61 50 28 26 40 52 52

78:22 86:14 71:29 69:31 76:24 62:38 78:22 83:17 71:29 71:29 81:19 48:52 55:45 46:54 62:38 73:27

95.6:4.4 99.9:0.1 98.0:2.0 89.2:10.8 95.7:4.3 96.6:3.4 97.9:2.1 96.9:3.1 98.8:1.2 93.6:6.4 96.6:3.4

observed. The other two isomers were identical as the diastereomers obtained in the domino reaction with trichlorosilane (Table 2). This result indicates that the first C−C bond formation between 6a and 2a is syn selective, even under acetic acid catalysis. Scheme 8 depicts the probable reaction mechanisms. For the domino reaction, imine 6a is activated by a trichlorosilane−SEGPHOSO complex. Enamine 2a enantioselectively attacks the activated imine in an antiperiplanar orientation that avoids the sterically demanding SO2 groups (TS-3). The resulting syn iminium ion intermediate is reduced intramolecularly (TS-4) to give 1,2-syn-2,3-anti-7aa after the workup. For the sequential reaction, proton-activated imine 6a can be attacked by enamine 2a in an antiperiplanar fashion (TS-5), which is similar to TS-3, to give 1,2-syn ene-type reaction adduct. Under the acidic condition with AcOH, sodium cyanoborohydride intermolecularly reduces the in situ generated iminium intermediate via TS-6 to give 1,2-syn-2,3-

a

Combined yields of the diastereomers. bdr = 1,2-syn-2,3-anti/1,2-anti2,3-anti. cThe enantiomer ratio of 1,2-syn-2,3-anti-7. dAt −60 °C. eFor 1 h. fWithout catalyst. 10972


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The Journal of Organic Chemistry Scheme 8. Plausible Reaction Mechanism with Cyclic Imines

syn-7aa. Again, reversal of the 2,3-anti and 2,3-syn selectivity is achieved. In the case of chiral Lewis base catalysis, the first C−C bond formation proceeds with high enantioselectivity, and the catalyst would also promote the subsequent intramolecular reduction because the enantioselectivity is slightly dependent on the reaction time (Table 3, entries 1−6 versus 7−11). The major enantiomer of the 1,2-syn iminium ion intermediate may be reduced faster than the other enantiomer with the aid of the catalyst to provide high enantioselectivity for a short reaction time (1 h), whereas the remaining minor enantiomer is gradually reduced during the prolonged reaction (24 h), which lowers the enantioselectivity slightly. Reaction of N-Tosyl Isocyanate and Enamines. To extend the methodology to electrophiles other than imines, we next focused on the reaction of isocyanates. Although the reported method employed N-alkyl or aryl isocyanates,2 we chose N-tosyl isocyanate (8) as an analogue of Nsulfonylimines 1 and 6. First, the sequential ene-type reaction/reduction of 8 with enamine 2a was investigated (eq 12). When acetic acid (1 equiv) was used as the promoter, the reaction resulted in a low yield (23%), although cis-amino amide 9a was obtained as expected, with high diastereoselectivity. We reasoned that isocyanate 8 decomposed in the presence of acetic acid before addition of the enamine because of its high electrophilicity. Therefore, the

reaction was performed in the absence of acetic acid, and the yield was greatly improved (98%). Under the optimized conditions, the reaction of isocyanate 8 with other enamines 2b−d also furnished the cis-amino amides 9b−d in good yields with good cis selectivities (Scheme 9). Next, the domino reaction of 8, enamines 2, and trichlorosilane was investigated (Scheme 10). After optimization of the reaction conditions (reaction time, quenching method, solvent), exclusive trans selectivity was attained when the reaction was conducted in dichloromethane at 0 °C for 24 h and quenched with aqueous KF/HCO2H (1.5 M/3.0 M, pH = 3.5). Although the yields were moderate, only trans isomers were obtained in all cases. The trans configuration was determined according to the NMR analysis of product 9b (see the Supporting Information). When the reaction was quenched after 1 h, the diastereoselectivity was lower. We speculate that the hydrosilane species, generated by partial 10973


The Journal of Organic Chemistry Scheme 9. Reaction of 8 with Other Enamines

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CONCLUSION

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EXPERIMENTAL SECTION

We have demonstrated stereochemical control on the synthesis of nitrogen-containing compounds from cyclic ketone-derived enamines and electrophiles (imines, N-tosyl isocyanate, or diethyl azodicarboxylate). A domino reaction with trichlorosilane provided the trans-amine, whereas the cisamine was obtained by a sequential imino ene-type reaction/ NaBH3CN reduction. High enantioselectivity has also been accomplished for the domino reaction of cyclic imines by using chiral Lewis base catalysts. Further extension of the methodology and study of synthetic applications are now underway.

General Methods. Dichloromethane was dried over 4 Å MS. A dichloromethane solution of trichlorosilane (ca. 3 M) was prepared and stocked in a screw-top test tube with PTFE-lined screw cap. Enamines1 and imines19,23 were prepared according to the literature. All other solvents and chemicals were purified based on standard procedures. Melting points (mp) were uncorrected. 1H and 13C{1H} NMR spectra were measured in CDCl3, (CD3)2SO, or C6D6 with 400 or 600 MHz spectrometers. Tetramethylsilane (TMS) (δ 0 ppm) served as internal standards for 1H NMR. The solvent signals (CDCl3: δ 77.0 ppm; (CD3)2SO: δ 39.52 ppm) served as internal standards for 13C NMR. Infrared spectra were recorded on an FT-IR spectrometer. High-resolution mass spectra were recorded on a double-focusing magnetic-sector mass analyzer operating in a FAB mode. Thin-layer chromatography (TLC) was visualized with UV light, phosphomolybdic acid, and/or anisaldehyde. Column chromatography was performed using silica gel (spherical, neutral, 63-210 nm mesh) or 3-aminopropyl-functionalized silica gel (spherical, 200− 350 nm mesh). The reactions under anhydrous conditions were carried out using oven- and heating gun-dried glassware with a rubber septum and a PTFE-coated magnetic stirring bar under argon atmosphere. General Procedure for Domino Reaction of Imine 1, Enamine 2, and Trichlorosilane. To a solution of HMPA (20 mol %) and imine 1 (0.25 mmol) in dichloromethane (0.5 mL) were added trichlorosilane in dichloromethane (ca. 3 M, 1.5 equiv) at −40 °C and then enamine 2 (1.2 equiv) in dichloromethane (0.5 mL). After being stirred at −40 °C for 1 h, the reaction was quenched with saturated aqueous NaHCO3 (2 mL). The mixture was stirred for 1 h at rt, filtered through a Celite pad, and extracted with AcOEt (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 7:1−1:1) to give the corresponding 1,2-anti-2,3-anti diamine 3. For spectroscopic data of 1,2-anti-2,3-anti-3, see ref 9a. The diastereoselectivity was determined by 1H NMR analysis of the crude product. General Procedure for Sequential Imino Ene-Type Reaction/Reduction of Imine 1, Enamine 2, and NaBH3CN. To a solution of imine 1 (0.5 mmol) and acetic acid (1.0 equiv) in dichloromethane (2 mL) was added enamine 2 (1.2 equiv) at −78 °C. After being stirred at −78 °C for 3 h, the reaction mixture was treated with glacial acetic acid (9 equiv) and then NaBH3CN (2 equiv) in methanol (0.7 mL) and stirred at −45 °C for 1 h. After addition of 5% NaOH aqueous solution (pH ca. 10), the mixture was warmed to rt and extracted with dichloromethane (3 × 40 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (hexane/AcOEt = 7:1−1:1) to give the corresponding 1,2-anti-2,3-syn diamine 3. For spectroscopic data of 1,2-anti-2,3-syn-3, see ref 9b. The diastereoselectivity was determined by 1H NMR analysis of the crude product. General Procedure for Enantioselective Domino Catalysis for 1,3-Diamine Synthesis from Cyclic Imines, Enamines, and Trichlorosilane. To a solution of (S)-SEGPHOSO (10 mol %) and imine 6 (0.25 mmol) in dichloromethane (6 mL) was added

Scheme 10. Reaction of 8 and Enamines 2a−d with Trichlorosilane

hydrolysis of trichlorosilane upon quenching after 1 h, reduces the iminium ion intermediate with low diastereoselectivity. Reaction of Diethyl Azodicarboxylate and Enamine. It has been reported that the reaction of enamines with azodicarboxylates afforded α-hydrazonoketones after aqueous workup.22 Therefore, both the domino and sequential reactions of diethyl azodicarboxylate (10) and enamine 2a were investigated (Scheme 11). Again, high trans selectivity was observed for the domino reaction with trichlorosilane, whereas only the cis isomer was obtained for the sequential reaction. Scheme 11. Reaction of Diethyl Azodicarboxylate 10 and Enamine 2a

10974


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The Journal of Organic Chemistry trichlorosilane in dichloromethane (ca. 3 M, 1.5 equiv) at −40 °C. Then enamine 2 (1.2 equiv) in dichloromethane (0.5 mL) was added to the mixture over 5 min using a syringe pump. After being stirred at −40 °C for 24 h, the reaction was quenched with MeOH (2 mL) and then saturated aqueous NaHCO3 (2 mL). The mixture was stirred for 1 h at rt, filtered through a Celite pad, and extracted with AcOEt (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by silica gel column chromatography (hexane/AcOEt = 7:1− 3:1) to give 1,3-syn-2,3-anti-7. The diastereoselectivity was determined by 1H NMR analysis of the crude product. (S*)-4-[(1R*,2R*)-2-(Piperidin-1-yl)cyclohexyl]-3,4dihydrobenzo[e][1,2,3]oxathiazine 2,2-Dioxide (1,3-syn-2,3anti-7aa). Obtained as a colorless oil (53.4 mg as single isomer, 62%, 95.6:4.4 er, 0.248 mmol scale). TLC: Rf 0.57 (hexane/AcOEt = 3:1, stained blue with phosphomolybdic acid/EtOH). IR (film on NaCl, cm−1): 2933, 2856, 1483, 1450, 1375, 1192, 1174, 864, 758. 1 H NMR (CDCl3): δ 1.10−1.66 (m, 10H), 1.75−1.92 (m, 4H), 2.07−2.22 (m, 3H), 2.43 (ddd, 1H, J = 3.2, 11.5, 11.5 Hz), 2.60 (brs, 2H), 4.94 (s, 1H), 7.04 (dd, 1H, J = 0.9, 8.2 Hz), 7.15 (ddd, 1H, J = 0.9, 7.3, 7.8 Hz), 7.29 (dd, 1H, J = 7.3, 8.2 Hz), 7.38 (d, 1H, J = 7.8 Hz). 13C NMR (CDCl3): δ 24.4, 24.6, 25.3, 26.1, 26.3, 30.1, 43.2, 49.5 (br), 60.3, 64.2, 119.2, 122.3, 124.6, 126.5, 128.9, 152.3. HRMS (FAB+, CHCl3 + NBA + NaI): calcd for C18H26N2O3SNa (M + Na+) 373.1562, found 373.1559. [α]D19 −48.5 (c 1.03, CHCl3) for 98:2 er. HPLC (Chiralpak AD-H, hexane/2-propanol = 19:1, flow rate = 1.0 mL/min, UV detection at 254 nm): tR = 10.9 min (major), 17.7 min (minor). (R*)-4-[(1R*,2R*)-2-(Piperidin-1-yl)cyclohexyl]-3,4dihydrobenzo[e][1,2,3]oxathiazine 2,2-Dioxide (1,3-anti-2,3anti-7aa). Chromatography with hexane/AcOEt (7:1−3:1) gave a mixture of recovered imine 6a and 1,3-anti-2,3-anti-7aa. Further chromatography eluted with hexane/CH2Cl2 (1:1) and then hexane/ AcOEt (3:1) gave 1,3-anti-2,3-anti-7aa as colorless solid (15.1 mg as single isomer, 17%, racemic, 0.248 mmol scale). This product was recrystallized from dichloromethane for X-ray crystallography to give colorless prisms. Mp: 140−141 °C. TLC: Rf 0.19 (hexane/AcOEt = 3:1, stained blue with phosphomolybdic acid/EtOH). IR (ATR, cm−1): 2936, 2922, 2855, 1611, 1578, 1480, 1449, 1370, 1169, 887, 758. 1H NMR (CDCl3): δ 0.95−1.42 (m, 6H), 1.50−1.74 (m, 4H), 1.76−1.86 (m, 2H), 1.88−1.94 (m, 1H), 1.95−2.06 (m, 2H), 2.13 (ddt, 1H, J = 3.7, 11.4, 11.9 Hz), 2.37−2.76 (m, 3H), 2.59 (ddd, 1H, J = 3.2, 11.0, 11.0 Hz), 4.58 (d, 1H, J = 3.6 Hz), 6.99 (dd, 1H, J = 0.9, 8.2 Hz), 7.15 (ddd, 1H, J = 0.9, 7.4, 8.2 Hz), 7.22 (d, 1H, J = 7.4 Hz), 7.27 (ddd, 1H, J = 0.9, 7.4, 8.2 Hz), 11.08 (brs, 1 H). 13C NMR (CDCl3): δ 24.2, 24.3, 25.1, 26.2, 26.5 (br), 34.5, 42.7, 45.6 (br), 52.2 (br), 62.0, 67.5, 119.0, 124.6, 124.8, 126.1, 128.8, 151.0. HRMS (FAB+, CHCl3+NBA): calcd for C18H27N2O3S (M + H+) 351.1742, found 351.1733. HPLC (Chiralpak AD-H, hexane/2propanol = 19:1, flow rate = 1.0 mL/min, UV detection at 220 nm): tR = 14.1 min, 16.7 min. (S*)-4-[(1R*,2R*)-2-Morpholinocyclohexyl]-3,4dihydrobenzo[e][1,2,3]oxathiazine 2,2-Dioxide (1,3-syn-2,3anti-7ab). Obtained as a colorless oil (16.6 mg as single isomer, 19%, 96.4:3.6 er, 0.247 mmol scale). TLC: Rf 0.27 (hexane/AcOEt = 3:1, stained blue with phosphomolybdic acid/EtOH). IR (film on NaCl, cm−1): 2931, 2856, 1485, 1452, 1375, 1174, 1115, 854, 762. 1 H NMR (CDCl3): δ 1.14−1.36 (m, 4H), 1.53−1.66 (m, 1H), 1.73−1.88 (m, 2H), 1.91−2.02 (m, 2H), 2.18 (ddt, 1H, J = 3.2, 11.0, 11.9 Hz), 2.38 (br, 2H), 2.55 (ddd, 1H, J = 2.8, 11.0, 11.0 Hz), 2.89 (br, 2H), 3.49 (d, 2H, J = 9.2 Hz), 3.80 (br, 1H), 4.61 (d, 1H, J = 1.8 Hz), 7.01 (d, 1H, J = 8.2 H), 7.16 (dd, 1H, J = 7.4, 7.8 H), 7.22 (d, 1H, J = 7.4 H), 7.28 (dd, 1H, J = 7.8, 8.2 H), 9.02 (brs, 1H). 13C NMR (CDCl3): δ 24.4, 25.1, 26.1, 34.0, 42.9, 45.6 (br), 51.0 (br), 62.0, 66.8, 119.1, 124.3, 125.1, 126.2, 129.0, 150.8. HRMS (FAB+, CHCl3 + NBA): calcd for C17H25N2O4S (M + H+) 353.1535, found 353.1531. [α]D15 −56.8 (c 0.94, CHCl3) for 96.5:3.5 er. HPLC (Chiralpak AD-H, hexane/2-propanol = 4:1, flow rate = 1.0 mL/min, UV detection at 254 nm): tR = 8.0 min (major), 11.9 min (minor).

(S*)-4-[(1R*,2R*)-2-(Pyrrolidin-1-yl)cyclohexyl]-3,4dihydrobenzo[e][1,2,3]oxathiazine 2,2-Dioxide (1,3-syn-2,3anti-7ac). The reaction was conducted for 1 h to give the product as a colorless oil (36.9 mg as single isomer, 44%, 93.9:6.1 er, 0.247 mmol scale). TLC: Rf 0.27 (hexane/AcOEt = 1:1, stained blue with phosphomolybdic acid/EtOH). IR (film on NaCl, cm−1): 2931, 2854, 1483, 1452, 1375, 1174, 856, 758. 1H NMR (CDCl3): δ 1.10− 1.39 (m, 3H), 1.42−1.55 (m, 1H), 1.63−1.88 (m, 8H), 2.14 (ddt, 1H, J = 2.7, 11.4, 12.4 Hz), 2.44−2.52 (m, 2H), 2.59−2.66 (m, 2H), 2.75 (ddd, 1H, J = 3.6, 11.4, 11.4 Hz), 5.06 (d, 1H, J = 1.8 Hz), 6.54 (br, 1H), 7.04 (d, 1H, J = 7.8 H), 7.17 (ddd, 1H, J = 0.9, 7.8, 7.8 H), 7.29 (dd, 1H, J = 7.8, 7.8 H), 7.33 (d, 1H, J = 7.8 H). 13C NMR (CDCl3): δ 23.3, 24.2, 25.2, 26.2, 29.0, 44.8, 47.2, 57.9, 59.8, 119.3, 122.3, 124.8, 126.5, 128.9, 152.3. HRMS (FAB+, CHCl3 + NBA + NaI): calcd for C17H24N2O3SNa (M + Na+) 359.1405, found 359.1413. [α]D16 −34.5 (c 1.00, CHCl3) for 94:6 er. HPLC (Chiralpak AD-H, hexane/2-propanol = 39:1, flow rate = 1.0 mL/ min, UV detection at 254 nm): tR = 23.2 min (major), 27.4 min (minor). (S*)-4-[(1R*,2R*)-2-Morpholinocyclopentyl]-3,4dihydrobenzo[e][1,2,3]oxathiazine 2,2-Dioxide (1,3-syn-2,3anti-7ad). Obtained as a colorless oil (69.4 mg as single isomer, 83%, 68.0:32.0 er, 0.247 mmol scale). TLC: Rf 0.22 (hexane/AcOEt = 1:1, stained blue with phosphomolybdic acid/EtOH). IR (film on NaCl, cm−1) 2956, 2858, 1483, 1452, 1371, 1176, 1117, 879, 762. 1H NMR (CDCl3): δ 1.42−1.61 (m, 4H), 1.68−1.77 (m, 1H), 1.87− 1.95 (m, 1H), 2.48−2.61 (m, 3H), 2.63−2.70 (m, 2H), 2.82 (ddd, 1H, J = 7.8, 8.7, 8.7 Hz), 3.67−3.73 (m, 2H), 3.76−3.82 (m, 2H), 5.11 (d, 1H, J = 3.7 Hz), 7.07 (d, 1H, J = 8.2 H), 7.16−7.23 (m, 2H), 7.30−7.36 (m, 1H), 8.51 (br, 1H). 13C NMR (CDCl3): δ 22.5, 24.0, 27.2, 42.3, 49.4 (br), 59.9, 67.0, 67.3, 119.5, 121.3, 125.0, 127.6, 129.3, 152.4. HRMS (FAB+, CHCl 3 + NBA): calcd for C16H23N2O4S (M + H+) 339.1379, found 339.1383. [α]D17 −28.1 (c 0.98, CHCl3) for 68.5:31.5 er. HPLC (Chiralpak AD-H, hexane/2propanol = 9:1, flow rate = 1.0 mL/min, UV detection at 254 nm) tR = 18.3 min (major), 20.3 min (minor). 4-(2-Phenyl-2-(piperidin-1-yl)ethyl)-3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-Dioxide (7ae). Chromatography with hexane/AcOEt (3:1 to 2:1) followed by PTLC with hexane/AcOEt (1:1) gave 7ae as yellow oil (19.4 mg as single isomer, 26%, 68.5:31.5 er, 0.199 mmol scale). TLC: Rf 0.22 (hexane/AcOEt = 1:1, stained blue with phosphomolybdic acid/EtOH). IR (ATR, cm−1) 2934, 1580, 1486, 1453, 1369, 1170, 1106, 750. 1H NMR (CDCl3): δ 1.24−1.48 (m, 2H), 1.59−1.76 (m, 4H), 2.18−2.70 (br, 3H), 2.25 (apparent dt, 1H, J = 14.2, 3.7 Hz), 2.60−2.76 (m, 2H), 4.07 (dd, 1H, J = 3.2, 10.1 Hz), 4.92 (dd, 1H, J = 3.6, 11.2 Hz), 5.38 (br, 1H), 7.02 (d, 1H, J = 8.2 Hz), 7.10 (d, 1H, J = 7.3 H), 7.15 (t, 1H, J = 7.3 H), 7.17−7.22 (m, 2H), 7.29 (t, 1H, J = 7.3 H), 7.33−7.43 (m, 3H). 13C NMR (CDCl3): δ 23.8, 25.6, 34.6, 49.8 (br), 57.3, 68.6, 119.2, 123.5, 125.0, 126.1, 128.3, 128.4, 128.8, 129.1, 134.9, 150.9. HRMS (FAB+, CHCl3 + NBA): calcd for C20H25N2O3S (M + H+) 373.1586, found 373.1577. [α]D27 −16.1 (c 0.865, CHCl3) for 68.5:31.5 er. HPLC (Chiralpak AD-H, hexane/2-propanol = 9:1, flow rate = 1.0 mL/min, UV detection at 254 nm): tR = 10.9 min (major), 12.3 min (minor). (S*)-7-Methoxy-4-[(1R*,2R*)-2-(piperidin-1-yl)cyclohexyl]3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (1,3-syn2,3-anti-7ba). Obtained as a colorless oil (53.4 mg as single isomer, 56%, 99.9:0.1 er, 0.250 mmol scale). TLC: Rf 0.39 (hexane/ AcOEt = 3:1, stained blue with phosphomolybdic acid/EtOH). IR (film on NaCl, cm−1): 2933, 2856, 1624, 1576, 1506, 1375, 1201, 1099, 1033, 957, 810. 1H NMR (CDCl3): δ 1.05−1.24 (m, 3H), 1.32 (apparent dq, 1H, J = 2.8, 11.9 Hz), 1.45−1.67 (m, 5H), 1.74−1.85 (m, 3H), 1.89 (apparent d, 1H, J = 12.4 Hz), 2.06−2.19 (m, 3H), 2.43 (ddd, 1H, J = 3.7, 11.4, 11.4 Hz), 2.61 (brs, 2H), 3.80 (s, 3H), 4.82 (d, 1 H, J = 1.4 Hz), 6.57 (d, 1H, J = 2.8 Hz), 6.71 (dd, 1H, J = 2.8, 8.7 Hz), 7.29 (d, 1H, J = 8.7 Hz) (the NH proton missing). 13 C NMR (CDCl3): δ 24.4, 24.6, 25.2, 26.0, 26.3, 30.5, 42.9, 50.0 (br), 55.5, 60.4, 64.2, 103.9, 111.3, 113.7, 127.3, 153.1, 159.7. HRMS (FAB+, CHCl3 + NBA): calcd for C19H29N2O4S (M + H+) 10975


Article

The Journal of Organic Chemistry 381.1848, found 381.1832. [α]D29 −52.8 (c 1.03, CHCl3) for 97:3 er. HPLC (Chiralpak AD-H, hexane/2-propanol = 9:1, flow rate = 1.0 mL/min, UV detection at 254 nm): tR = 10.9 min (major), 15.9 min (minor). (S*)-7-Bromo-4-[(1R*,2R*)-2-(piperidin-1-yl)cyclohexyl]-3,4dihydrobenzo[e][1,2,3]oxathiazine 2,2-Dioxide (1,3-syn-2,3anti-7ca). Obtained as a colorless oil (54.7 mg as single isomer, 52%, 98.0:2.0 er, 0.249 mmol scale). TLC: Rf 0.32 (hexane/AcOEt = 3:1, stained blue with phosphomolybdic acid/EtOH). IR (film on NaCl, cm−1): 2933, 2856, 1598, 1564, 1479, 1377, 1203, 1188, 901, 868. 1H NMR (CDCl3): δ 1.05−1.24 (m, 2H), 1.33 (apparent dq, 2H, J = 3.2, 12.4 Hz), 1.46−1.67 (m, 6H), 1.75−1.86 (m, 3H), 1.89 (apparent d, 1H, J = 12.4 Hz), 2.10−2.23 (m, 3H), 2.39 (ddd, 1H, J = 3.7, 11.4, 11.4 Hz), 2.62 (brs, 2H), 4.84 (d, 1 H, J = 2.3 Hz), 7.21 (s, 1H), 7.24−7.32 (m, 2H), 8.36 (br, 1H). 13C NMR (CDCl3): δ 24.3, 24.6, 25.2, 25.9, 26.2, 30.4, 42.9, 50.5 (br), 60.6, 64.4, 121.3, 121.7, 122.3, 127.6, 128.0, 152.9. HRMS (FAB+, CHCl3 + NBA + NaI): calcd for C18H25BrN2O3SNa (M + Na+) 451.0667, found 451.0646. [α]D30 −59.9 (c 1.09, CHCl3) for 98:2 er. HPLC (Chiralpak AD-H, hexane/2-propanol = 19:1, flow rate = 1.0 mL/ min, UV detection at 254 nm): tR = 12.5 min (major), 18.3 min (minor). (S*)-6-Methoxy-4-[(1R*,2R*)-2-(piperidin-1-yl)cyclohexyl]3,4-dihydrobenzo[e][1,2,3]oxathiazine 2,2-Dioxide (1,3-syn2,3-anti-7da). The reaction was conducted at −60 °C for 24 h to give the product as a colorless oil (45.4 mg as single isomer, 49%, 95.7:4.3 er, 0.250 mmol scale). TLC: Rf 0.41 (hexane/AcOEt = 3:1, stained blue with phosphomolybdic acid/EtOH). IR (film on NaCl, cm−1) 2933, 2856, 1489, 1375, 1201, 1174, 1036, 847. 1H NMR (CDCl3): δ 1.06−1.26 (m, 2H), 1.32 (apparent dq, 1H, J = 3.2, 11.9 Hz), 1.44−1.66 (m, 6H), 1.74−1.92 (m, 4H), 2.09−2.20 (m, 3H), 2.45 (ddd, 1H, J = 3.2, 11.0, 11.0 Hz), 2.61 (brs, 2H), 3.80 (s, 3H), 4.90 (s, 1 H), 6.83 (dd, 1H, J = 2.8, 8.7 Hz), 6.88 (d, 1H, J = 2.8 Hz), 6.99 (d, 1H, J = 8.7 Hz) (the NH proton missing). 13C NMR (CDCl3): δ 24.4, 24.6, 25.3, 26.1, 26.3, 30.1, 43.2, 50.3 (br), 55.7, 60.4, 64.2, 112.5, 113.2, 119.9, 123.2, 146.1, 156.0. HRMS (FAB+, CHCl3 + NBA): calcd for C19H29N2O4S (M + H+) 381.1848, found 381.1876; [α]D29 −74.6 (c 1.09, CHCl3) for 95.5:4.5 er. HPLC (Chiralpak AD-H, hexane/2-propanol = 19:1, flow rate = 1.0 mL/ min, UV detection at 254 nm): tR = 12.5 min (major), 18.6 min (minor). (S*)-6-Bromo-4-[(1R*,2R*)-2-(piperidin-1-yl)cyclohexyl]-3,4dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (1,3-syn-2,3anti-7ea). Obtained as a colorless oil (44.4 mg as single isomer, 42%, 96.6:3.4 er, 0.249 mmol scale). TLC: Rf 0.51 (hexane/AcOEt = 3:1, stained blue with phosphomolybdic acid/EtOH). IR (film on NaCl, cm−1): 2929, 2854, 1471, 1375, 1190, 1171, 1113, 818. 1H NMR (CDCl3): δ 1.12−1.27 (m, 2H), 1.34 (apparent dq, 2H, J = 2.7, 11.9 Hz), 1.45−1.66 (m, 6H), 1.77−1.93 (m, 4H), 2.11−2.21 (m, 3H), 2.41 (ddd, 1H, J = 3.7, 11.4, 11.4 Hz), 2.62 (brs, 2H), 4.91 (d, 1 H, J = 1.4 Hz), 6.94 (d, 1H, J = 8.7 Hz), 7.41 (dd, 1H, J = 2.3, 8.7 Hz), 7.50 (d, 1H, J = 2.3 Hz) (the NH proton missing). 13C NMR (CDCl3): δ 24.4, 24.6, 25.2, 26.0, 26.2, 30.3, 43.0, 49.3 (br), 60.3, 64.4, 117.2, 121.0, 124.4, 129.5, 131.9, 151.5. HRMS (FAB+, CHCl3 + NBA + NaI): C18H25BrN2O3SNa (M + Na+) 451.0667, found 451.0648. [α]D32 −76.6 (c 0.92, CHCl3) for 96.5:3.5 er. HPLC (Chiralpak AD-H, hexane/2-propanol = 19:1, flow rate = 1.0 mL/ min, UV detection at 254 nm): tR = 9.5 min (major), 12.5 min (minor). Determination of Relative Configuration of 7aa. According to the literature,19c,20 a solution of isolated 1,3-diamine 7aa (less polar isomer, 70.1 mg, 0.2 mmol) and LiAlH4 (44.1 mg, 5.8 equiv) was heated under reflux in THF (6 mL). After the mixture was stirred for 24 h, the reaction was quenched with water (44 μL), aqueous NaOH (15%, 44 μL), and water (132 μL). The mixture was stirred for 1 h, filtered through a Celite pad with AcOEt (10 mL), and evaporated to give crude aminophenol (33.7 mg). The crude product was dissolved in THF and treated with sodium hydride (11.7 mg, 0.48 mmol) and tosyl chloride (91.7 mg, 0.48 mmol) at rt. After being stirred for 24 h, the reaction was quenched with brine.

The mixture was extracted with AcOEt (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (1 × 10 mL) and brine (1 × 10 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel column chromatography to give the corresponding tosylated product (33.0 mg, 46%). To a suspension of the product (33.0 mg, 0.055 mmol) and NiCl2·6H2O (13.2 mg, 0.0605 mmol) in CHCl3 (1 mL) and MeOH (1 mL) was added NaBH4 (41.8 mg, 1.1 mmol) at 0 °C. The mixture was stirred for 30 min, filtered through a Celite pad with MeOH, and evaporated. The residue was treated with 2 M HCl. The mixture was basified with saturated aqueous NaHCO3 and extracted with AcOEt (3 × 10 mL). The combined organic layers were washed with saturated aqueous NaHCO3 (1 × 10 mL) and brine (1 × 10 mL), dried over Na2SO4, filtered, and evaporated. The residue was purified by silica gel column chromatography to give 1,2syn-2,3-anti-3aa (10.1 mg, 43%). 4-Methyl-N-[(S*)-phenyl[(1R*,2R*)-2-(piperidin-1-yl)cyclohexyl]methyl]benzenesulfonamide (1,2-syn-2,3-anti-3aa). TLC: R f 0.32 (hexane/AcOEt = 1:1, stained blue with phosphomolybdic acid/EtOH). IR (film on NaCl, cm−1): 2929, 2856, 1454, 1323, 1304, 1159, 1093, 704. 1H NMR (CDCl3): δ 0.64 (apparent dq, 1H, J = 3.2, 12.4 Hz), 0.75 (apparent q, 1H, J = 13.3 Hz), 1.08 (apparent tq, 1H, J = 3.2, 12.8 Hz), 1.12−1.36 (m, 2H), 1.48−1.92 (m, 10H), 2.01−2.16 (m, 2H), 2.29 (s, 3H), 2.60 (br, 2H), 3.00 (brs, 1H), 4.39 (s, 1H), 6.89 (d, 2H, J = 6.8 Hz), 6.95 (d, 2H, J = 7.8 Hz), 7.00−7.10 (m, 3H), 7.36 (d, 2H, J = 7.8 Hz), 9.46 (brs, 1H). 13C NMR (CDCl3): δ 21.3, 23.5, 24.8, 24.9, 25.7, 29.7, 30.7, 42.4, 46.4 (br), 53.1 (br), 63.2, 64.5, 126.4, 126.5, 127.5, 128.3, 128.8, 137.7, 139.0, 141.7. HRMS (FAB+, CHCl3 + NBA): calcd for C25H35N2O2S (M + H+) 427.2419, found 427.2438. The same transformation of the other diastereomer 7aa (polar isomer, 36.8 mg) afforded 1,2-anti-2,3-anti-3aa (11.2 mg), whose spectroscopic data were identical to those obtained from the domino reaction of N-tosylimine 1a and enamine 2a with trichlorosilane.9a Imino Ene-Type Reaction/Reduction of Imine 6a and Enamine 2a. To a solution of cyclic imine 6a (46.1 mg, 0.25 mmol) and acetic acid (1.0 equiv) in dichloromethane (1 mL) was added enamine 2a (59.7 mg, 1.4 equiv) at −78 °C. After being stirred at −78 °C for 3 h, the mixture was treated with glacial acetic acid (9.0 equiv) and then NaBH3CN (31.5 mg, 2.0 equiv) in methanol (0.35 mL) and stirred at −45 °C for 1 h. After addition of 5% NaOH aqueous solution (pH ca. 10), the mixture was warmed to rt and extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (hexane/AcOEt) to give 1,2-syn-2,3-syn-7aa (53.1 mg), 1,2syn-2,3-anti-7aa (7.8 mg), and 1,2-anti-2,3-anti-7aa (17.2 mg) (total 89%, 1,2-syn-2,3-syn/1,2-syn-2,3-anti/1,2-anti-2,3-anti = 68:10:22). The major isomer was recrystallized from dichloromethane to give colorless prisms and subjected to X-ray crystallography. (S*)-4-[(1R*,2S*)-2-(Piperidin-1-yl)cyclohexyl]-3,4dihydrobenzo[e][1,2,3]oxathiazine 2,2-dioxide (1,3-syn-2,3syn-7aa). Mp: 221−223 °C. TLC: Rf 0.08 (hexane/AcOEt = 3:1, stained blue with phosphomolybdic acid/EtOH). IR (ATR, cm−1): 3064, 2944, 2657, 1553, 1483, 1448, 1276, 1155, 737. 1H NMR (C6D6, 400 MHz): δ 1.20−1.34 (m, 2H), 1.40−1.80 (m, 10H), 1.84 (apparent d, 1H, J = 11.9 Hz), 2.10 (apparent d, 1H, J = 14.2 Hz), 2.20 (apparent d, 1H, J = 11.0 Hz), 2.69 (brs, 2H), 2.90−3.20 (br, 3H), 5.03 (s, 1H), 7.01 (d, 1H, J = 8.2 Hz), 7.09 (d, 1H, J = 7.3 Hz), 7.15 (t, 1H, J = 7.3 Hz), 7.27 (t, 1H, J = 7.3 Hz), 12.0 (br, 1H). 13C NMR (CDCl3, 400 MHz): δ 20.6, 22.4, 23.3, 24.7, 25.4, 26.1, 43.0, 54.1 (br), 61.5, 65.2, 119.0, 122.0, 124.7, 125.4, 128.7, 152.2. HRMS (FAB+, CHCl3 + NBA) m/z calcd for C18H27N2O3S (M + H+) 351.1742, found 351.1740. General Procedure for Ene-Type Reaction/Reduction between N-Tosyl Isocyanate and Enamines. To a solution of N-tosyl isocyanate (8) (0.25 mmol) in dichloromethane (1 mL) at −78 °C was added enamine 2 (1.2 equiv). After being stirred at −78 °C for 3 h, the mixture was treated with glacial acetic acid (9.0 equiv) and then NaBH3CN (2.0 equiv) in methanol (0.35 mL) and 10976


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The Journal of Organic Chemistry stirred at −45 °C for 1 h. After addition of saturated aqueous NaHCO3, the mixture was warmed to rt and extracted with dichloromethane (3 × 15 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (AcOEt/EtOH = 5:1−3:1) to give the corresponding β-amino amide 9. (1R*,2S*)-2-(Piperidin-1-yl)-N-tosylcyclohexane-1-carboxamide (cis-9a). Obtained as a colorless solid (185.0 mg as single isomer, 98%, 0.522 mmol scale). Mp: 195−197 °C. TLC: Rf 0.43 (AcOEt/EtOH = 5/1, stained blue with phosphomolybdic acid/ EtOH). IR (ATR, cm−1): 3363, 3048, 2933, 2866, 1587, 1248, 1331, 1080, 833. 1H NMR (C6D6, 400 MHz): δ 0.66−0.77 (m, 2H), 0.90 (apparent dq, 1H, J = 2.8, 12.8 Hz), 1.11−1.65 (m, 9H), 1.68 (apparent dt, 1H, J = 3.7, 12.5 Hz), 1.82 (s, 3H), 1.98 (br, 3H), 2.11 (brs, 1H), 2.46 (apparent dt, 1H, J = 2.4, 13.2 Hz), 6.82 (d, 2H, J = 8.3 Hz), 8.34 (d, 2H, J = 8.3 Hz) (the NH proton missing). 13C NMR (CDCl3, 400 MHz): δ 21.1, 21.4, 23.0, 24.6, 25.1, 25.3, 26.2, 40.1, 49.8 (br), 65.2, 127.5, 128.8, 139.4, 142.2, 172.5. HRMS (FAB +, CHCl3 + NBA): m/z calcd for C19H29 N2O3S (M + H+) 365.1899, found 365.1900. (1R*,2S*)-2-Morpholino-N-tosylcyclohexane-1-carboxamide (cis-9b). Obtained as a colorless solid (69.8 mg as single isomer, 79%, 0.246 mmol scale). Mp: 117−119 °C. TLC: Rf 0.31 (AcOEt/ EtOH = 5:1, stained blue with phosphomolybdic acid/EtOH). IR (KBr, cm−1): 2924, 2863, 1622, 1444, 1250, 1133, 1082, 869, 664. 1 H NMR (C6D6, 400 MHz): δ 0.64−0.77 (m, 2H), 0.84 (apparent dq, 1H, J = 3.2, 12.5 Hz), 1.17−1.38 (m, 4H), 1.62 (apparent dt, 1H, J = 3.7, 12.4 Hz), 1.83 (s, 3H), 1.90 (br, 4H), 2.08 (brs, 1H), 2.45 (apparent d, 1H, J = 13.7 Hz), 3.58−3.71 (m, 4H), 6.83 (d, 2H, J = 8.1 Hz), 8.27 (d, 2H, J = 8.1 Hz) (the NH proton missing). 13C NMR (CDCl3, 400 MHz): δ 21.4, 21.6, 25.1, 25.5, 25.9, 40.5, 49.7, 64.4, 66.6, 128.0, 129.4, 136.9, 144.1, 170.7. HRMS (FAB+, CHCl3 + NBA) m/z calcd for C18H27N2O4S (M + H+) 367.1692, found 367.1697. (1R*,2S*)-2-(Pyrrolidin-1-yl)-N-tosylcyclohexane-1-carboxamide (cis-9c). Obtained as a colorless solid (62.8 mg, cis/trans = 85:15, 70%, 0.257 mmol scale). Mp: 91−92 °C. TLC: Rf 0.20 (AcOEt/EtOH = 5:1, stained blue with phosphomolybdic acid/ EtOH). IR (KBr, cm−1): 3452, 2932, 2862, 1593, 1443, 1258, 1129, 1079, 838, 823, 679; 1H NMR (C6D6, 400 MHz). δ 0.69−0.88 (m, 2H), 1.10−1.40 (m, 5H), 1.41−1.55 (m, 5H), 1.72 (apparent dt, 1H, J = 3.7, 12.4 Hz), 1.82 (s, 3H), 2.09 (br, 4H), 2.14 (brs, 2H), 2.49 (apparent d, 1H, J = 13.3 Hz), 6.81 (d, 2H, J = 8.2 Hz), 8.32 (d, 2H, J = 8.2 Hz). 13C NMR (CDCl3, 400 MHz): δ 21.3, 21.4, 22.9, 24.8, 26.5, 27.1, 42.2, 50.5, 65.2, 127.4, 128.9, 139.4, 142.3, 173.1. HRMS (FAB+, CHCl3 + NBA) m/z calcd for C18H27N2O3S (M + H+) 351.1742, found 351.1740. (1R*,2S*)-2-Morpholino-N-tosylcyclopentane-1-carboxamide (cis-9d). Obtained as a colorless solid (66.5 mg, cis/trans = 86:14, 76%, 0.248 mmol scale). Mp: 115−116 °C. TLC: Rf 0.31 (AcOEt/EtOH = 5:1, stained blue with phosphomolybdic acid/ EtOH). IR (KBr, cm−1): 2960, 2871, 1623, 1559, 1450, 1378, 1242, 1138, 1084, 827, 654; 1H NMR (C6D6, 400 MHz): δ 0.96−1.34 (m, 5H), 1.71−1.81 (m, 1H), 1.82 (s, 3H), 1.88 (br, 4H), 2.10−2.18 (m, 1H), 2.30−2.39 (m, 1H), 3.57−3.70 (m, 4H), 6.80 (d, 2H, J = 8.2 Hz), 8.26 (d, 2H, J = 8.2 Hz) (the NH proton missing). 13C NMR (CDCl3, 400 MHz): δ 20.1, 21.6, 26.3, 26.6, 44.9, 52.1, 66.3, 67.8, 128.0, 129.4, 136.6, 144.3, 171.6. HRMS (FAB+, CHCl3 + NBA) m/ z calcd for C17H25N2O4S (M + H+) 353.1535, found 353.1542. General Procedure for Domino Reaction between N-Tosyl Isocyanate and Enamines. To a solution of a N-tosyl isocyanate (8) (0.25 mmol) in dichloromethane (1 mL) were added trichlorosilane in dichloromethane (ca. 3.0 M, 1.5 equiv) and then enamine 2 (1.2 equiv) at 0 °C. After the mixture was stirred at 0 °C for 24 h, the reaction was quenched with aqueous KF/HCOOH (1.5 M/3.0 M, pH = 3.5, 1.25 mL). The mixture was warmed to rt and stirred for 0.5 h. After addition of saturated aqueous NaHCO3 (4 mL, pH ca. 10), the mixture was warmed to rt and extracted with dichloromethane (3 × 20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue

was purified by column chromatography on silica gel (AcOEt/EtOH = 5:1−3:1) to give the corresponding β-amino amide 9. (1R*,2R*)-2-(Piperidin-1-yl)-N-tosylcyclohexane-1-carboxamide (trans-9a). Obtained as a colorless solid (45.5 mg as single isomer, 49%, 0.255 mmol scale). Mp: 234−235 °C. TLC: Rf 0.43 (AcOEt/EtOH = 5:1, stained blue with phosphomolybdic acid/ EtOH). IR (ATR, cm−1): 2937, 2862, 1635, 1450, 1311, 1273, 1142, 1086, 843, 729, 665. 1H NMR (C6D6, 400 MHz): δ 0.32−0.75 (m, 5H), 0.98 (apparent q, 1H, J = 12.2 Hz), 1.13 (apparent d, 1 H, J = 12.2 Hz), 1.21 (brs, 2 H), 1.26−1.42 (m, 2H), 1.47 (apparent d, 1H, J = 12.1 Hz), 1.57 (brs, 2H), 1.69 (brs, 2H), 1.79−1.93 (m, 1H), 1.85 (s, 3H), 1.99−2.10 (m, 2H), 2.39 (apparent d, 1H, J = 14.6 Hz), 6.86 (d, 2H, J = 8.3 Hz), 8.39 (d, 2H, J = 8.8 Hz), 15.9 (brs, 1H). 13C NMR (CDCl3, 400 MHz): δ 21.4, 23.1, 24.2, 24.3, 24.97, 25.02, 27.4, 42.6, 48.6 (br), 66.6, 127.6, 128.8, 139.3, 142.2, 173.7. HRMS (FAB+, CHCl3 + NBA) m/z calcd for C19H29N2O3S (M + H+) 365.1899, found 365.1899. (1R*,2R*)-2-Morpholino-N-tosylcyclohexane-1-carboxamide (trans-9b). Obtained as a colorless solid (31.9 mg as single isomer, 35%, 0.247 mmol scale). Mp: 182−183 °C. TLC: Rf 0.36 (AcOEt, stained blue with phosphomolybdic acid/EtOH). IR (KBr, cm−1): 2927, 2859, 1635, 1451, 1270, 1140, 1112, 1086, 863, 843, 660. 1H NMR (C6D6, 400 MHz): δ 1.07−1.23 (m, 4H), 1.54 (brs, 1H), 1.63−1.66 (m, 1H), 1.72−1.74 (m, 1H), 1.83−1.86 (m, 1H), 2.02 (td, 1H, J = 4.0, 11.4 Hz), 2.21−2.29 (m, 1H), 2.31 (s, 3H), 2.45 (td, 1H, J = 3.2, 10.8 Hz), 2.50−2.55 (m, 2H), 2.74 (brs, 2H), 3.72− 3.77 (m, 2H), 3.82−3.87 (m, 2H), 7.20 (d, 2H, J = 8.4 Hz), 7.84 (d, 2H, J = 8.0 Hz), 14.70 (brs, 1H). 13C NMR (CDCl3, 400 MHz): δ 21.6, 24.3, 25.1, 27.2, 42.4, 47.7 (br), 64.6, 66.3, 128.0, 129.4, 137.0, 144.1, 171.9. HRMS (FAB+, CHCl3 +NBA) m/z calcd for C18H27N2O4S (M + H+) 367.1692, found 367.1696. (1R*,2R*)-2-(Pyrrolidin-1-yl)-N-tosylcyclohexane-1-carboxamide (trans-9c). Obtained as a colorless solid (36.4 mg as single isomer, 42%, 0.250 mmol scale). Mp: 177−179 °C. TLC: Rf 0.23 (AcOEt/EtOH = 5:1, stained blue with phosphomolybdic acid/ EtOH). IR (KBr, cm−1): 2928, 2859, 1610, 1556, 1451, 1265, 1253, 1145, 1125, 1086, 836, 657. 1H NMR (C6D6, 400 MHz): δ 0.40 (apparent q, 1H, J = 12.4 Hz), 0.52−0.72 (m, 2H), 0.85−1.06 (m, 2H), 1.23−1.57 (m, 8H), 1.85 (s, 3H), 2.00−2.19 (m, 5H), 2.35 (apparent d, 1H, J = 14.2 Hz), 6.85 (d, 2H, J = 8.4 Hz), 8.39 (d, 2H, J = 8.4 Hz) (the NH proton missing). 13C NMR (CDCl3, 400 MHz): δ 21.4, 23.4, 24.1, 24.7, 25.0, 28.0, 45.1, 47.0, 61.5, 127.5, 128.8, 139.5, 142.0, 174.6. HRMS (FAB+, CHCl3 + NBA): m/z calcd for C18H27N2O3S (M + H+) 351.1742, found 351.1746. (1R*,2R*)-2-Morpholino-N-tosylcyclopentane-1-carboxamide (trans-9d). Obtained as a colorless solid (41.7 mg as single isomer, 44%, 0.271 mmol scale). Mp: 178−179 °C. TLC: Rf 0.26 (AcOEt/EtOH = 5:1, stained blue with phosphomolybdic acid/ EtOH). IR (KBr, cm−1): 2959, 2872, 1616, 1448, 1243, 1129, 1082, 844, 663. 1H NMR (C6D6, 400 MHz): δ 0.70−0.82 (m, 1H), 0.88− 1.13 (m, 3H), 1.45−1.58 (m, 1H), 1.68−1.80 (m, 2H), 1.82 (s, 3H), 1.84−1.98 (m, 4H), 2.11 (apparent dt, 1H, J = 6.4, 10.8 Hz), 3.50− 3.60 (m, 2H), 3.64−3.73 (m, 2H), 6.81 (d, 2H, J = 8.2 Hz,), 8.29 (d, 2H, J = 8.2 Hz). 13C NMR (CDCl3, 400 MHz): δ 20.7, 21.7, 22.4, 22.5, 44.2, 67.0, 68.8, 128.1, 129.5, 136.4, 144.5, 171.4. HRMS (FAB +, CHCl3 + NBA) m/z calcd for C17H25N2O4S (M + H+) 353.1535, found 353.1540. Diethyl 1-((1R*,2R*)-2-(Piperidin-1-yl)cyclohexyl)hydrazine1,2-dicarboxylate (trans-11a). To a solution of diethyl azodicarboxylate (43.6 mg, 0.25 mmol) and HMPA (8.7 μL, 20 mol %) in dichloromethane (0.5 mL) were successively added trichlorosilane (3.13 M in dichloromethane, 0.12 mL) and a solution of enamine 2a (53.5 mg, 0.3 mmol) in dichloromethane (0.5 mL) at −40 °C. After the mixture was stirred at −40 °C for 24 h, the reaction was quenched with saturated aqueous NaHCO3. The mixture was stirred at rt for 1 h, filtered through a Celite pad, and extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on silica gel (AcOEt) to give product 11a (59.2 mg, 69%, trans/cis = >99:1) as viscous oil. 10977


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(b) Hickmott, P. W. Tetrahedron 1982, 38, 1975−2050. (c) Hickmott, P. W. Tetrahedron 1982, 38, 3363−3446. (d) Cook, G. Enamines: Synthesis, Structure, and Reactions; Marcel Dekker, Inc.: New York, 1988. (2) (a) Kane, M. P.; Szmuszkovicz, J. J. Org. Chem. 1981, 46, 3728−3730. (b) Ghattas, A. B. A. G.; Jørgensen, K. A.; Lawesson, S. O.; Nishida, T.; Enzell, C. R.; Berg, J.-E. Acta Chem. Scand. 1982, 36b, 505−511. (3) (a) Renaud, P.; Schubert, S. Angew. Chem., Int. Ed. Engl. 1990, 29, 433−434. (b) Renaud, P.; Schubert, S. Synlett 1990, 1990, 624− 626. (4) (a) Merla, B.; Arend, M.; Risch, N. Synlett 1997, 1997, 177− 178. See also: (b) Merla, B.; Risch, N. Synthesis 2002, 1365−1372. (5) Netz, A.; Polborn, K.; Nöth, H.; Müller, T. J. J. Eur. J. Org. Chem. 2005, 2005, 1823−1833. (6) Funabiki, K.; Murase, Y.; Furuno, Y.; Kubota, Y.; Ebihara, M.; Matsui, M. Tetrahedron 2010, 66, 3283−3289. (7) (a) Halli, J.; Bolte, M.; Bats, J.; Manolikakes, G. Org. Lett. 2017, 19, 674−677. For related reactions of enamides, see: (b) Matsubara, R.; Nakamura, Y.; Kobayashi, S. Angew. Chem., Int. Ed. 2004, 43, 1679−1681. (c) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2006, 45, 2254−2257. (d) Terada, M.; Machioka, K.; Sorimachi, K. Angew. Chem., Int. Ed. 2009, 48, 2553−2556. (e) Dagousset, G.; Drouet, F.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 5546−5549. (8) (a) Tietze, L. F. Chem. Rev. 1996, 96, 115−136. (b) Pellissier, H. Tetrahedron 2006, 62, 2143−2173. (9) For preliminary communications, see: (a) Kashiwagi, T.; Kotani, S.; Nakajima, M.; Sugiura, M. Tetrahedron Lett. 2014, 55, 1924− 1926. (b) Ito, M.; Kashiwagi, T.; Kotani, S.; Nakajima, M.; Sugiura, M. Tetrahedron Lett. 2014, 55, 4082−4085. For related reactions of enamines with aldehydes instead of imines, see: (c) Kashiwagi, T.; Kotani, S.; Sugiura, M.; Nakajima, M. Tetrahedron 2011, 67, 531− 539. (10) For reviews on Lewis base-catalyzed stereoselective reduction with trichlorosilane, see: (a) Rossi, S.; Benaglia, M.; Massolo, E.; Raimondi, L. Catal. Sci. Technol. 2014, 4, 2708−2723. (b) Jones, S.; Warner, C. J. Org. Biomol. Chem. 2012, 10, 2189−200. (c) Guizzetti, S.; Benaglia, M. Eur. J. Org. Chem. 2010, 2010, 5529−5541. (11) For selected examples of stereoselective reduction of CN bonds with trichlorosilane, see: (a) Iwasaki, F.; Onomura, O.; Mishima, K.; Kanematsu, T.; Maki, T.; Matsumura, Y. Tetrahedron Lett. 2001, 42, 2525−2527. (b) Onomura, O.; Kouchi, Y.; Iwasaki, F.; Matsumura, Y. Tetrahedron Lett. 2006, 47, 3751−3754. (c) Malkov, A. V.; Mariani, A.; MacDougall, K. N.; Kočovský, P. Org. Lett. 2004, 6, 2253−2256. (d) Malkov, A. V.; Stončius, S.; Vranková, K.; Arndt, M.; Kočovský, P. Chem. - Eur. J. 2008, 14, 8082−8085. (e) Pei, D.; Wang, Z.; Wei, S.; Zhang, Y.; Sun, J. Org. Lett. 2006, 8, 5913−5915. (f) Ye, J.; Wang, C.; Chen, L.; Wu, X.; Zhou, L.; Sun, J. Adv. Synth. Catal. 2016, 358, 1042−1047. (g) Guizzetti, S.; Benaglia, M.; Bonsignore, M.; Raimondi, L. Org. Biomol. Chem. 2011, 9, 739−743. (h) Gautier, F.-M.; Jones, S.; Martin, S. J. Org. Biomol. Chem. 2009, 7, 229−231. (i) Li, A. T.; Torri, F.; Adams, H.; Jones, S. Org. Biomol. Chem. 2017, 15, 2422− 2435. (j) Chelouan, A.; Recio, R.; Borrego, L. G.; Á lvarez, E.; Khiar, N.; Fernández, I. Org. Lett. 2016, 18, 3258−3261. (k) Wagner, C.; Kotthaus, A. F.; Kirsch, S. F. Chem. Commun. 2017, 53, 4513−4516. (12) For conjugate reduction of enones with trichlorosilane, see: (a) Sugiura, M.; Sato, N.; Kotani, S.; Nakajima, M. Chem. Commun. 2008, 4309−4311. (b) Sugiura, M.; Kumahara, M.; Nakajima, M. Chem. Commun. 2009, 3585−3587. (c) Sugiura, M.; Sato, N.; Sonoda, Y.; Kotani, S.; Nakajima, M. Chem. - Asian J. 2010, 5, 478− 481. (d) Han, Z. S.; Zhang, L.; Xu, Y.; Sieber, J. D.; Marsini, M. A.; Li, Z.; Reeves, J. T.; Fandrick, K. R.; Patel, N. D.; Desrosiers, J. N.; Qu, B.; Chen, A.; Rudzinski, D. M.; Samankumara, L. P.; Ma, S.; Grinberg, N.; Roschangar, F.; Yee, N. K.; Wang, G.; Song, J. J.; Senanayake, C. H. Angew. Chem., Int. Ed. 2015, 54, 5474−5477. (13) For reviews on Lewis base catalysts for activation of chlorosilane reagents, see: (a) Rendler, S.; Oestreich, M. Synthesis

TLC: Rf 0.25 (AcOEt, stained blue with phosphomolybdic acid/ EtOH). IR (film on NaCl, cm−1) 2931, 2856, 1757, 1711, 1468, 1414, 1381, 1306, 1213, 1065. 1H NMR ((CD3)2SO, 80 °C): δ 1.00−1.23 (m, 9H), 1.29−1.40 (m, 5H), 1.46 (brs, 2H), 1.65 (apparent t, 2H, J = 11.9 Hz), 1.77−1.86 (m, 2H), 2.25−2.37 (m, 3H), 2.52−2.60 (m, 2H), 3.93 (brs, 1H), 4.01−4.12 (m, 4H), 7.91 (brs, 1H). 13C NMR ((CD3)2SO, 80 °C): δ 14.0, 22.8, 24.2, 24.49, 24.54, 26.1, 29.3, 48.9, 57.2 (br), 60.3 (br), 60.8 (br), 63.9, 155.5, 156.3. HRMS (FAB+, CHCl3 + NBA): calcd for C17H32N3O4 (M + H+) 342.2393, found 342.2395. Diethyl 1-((1R*,2S*)-2-(Piperidin-1-yl)cyclohexyl)hydrazine1,2-dicarboxylate (cis-11a). To a solution of diethyl azodicarboxylate (87.4 mg, 0.50 mmol) and acetic acid (29 μL) in dichloromethane (1.5 mL) was added a solution of enamine 2a (103.0 mg, 1.24 equiv) in dichloromethane (0.5 mL) at −78 °C. After being stirred at −78 °C for 3 h, the mixture was treated with glacial acetic acid (257 μL, 9.0 equiv) and then NaBH3CN (62.8 mg, 2.0 equiv) in methanol (0.7 mL) and stirred at −45 °C for 1 h. After addition of saturated aqueous NaHCO3, the mixture was warmed to rt and extracted with dichloromethane (3 × 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered, and evaporated. The residue was purified by column chromatography on 3-aminopropyl-functionalized silica gel (hexane/AcOEt = 20:1−10:1) to give the corresponding adduct cis-11a as viscous oil. (159.3 mg, 93%). TLC: Rf 0.33 (3-aminopropyl-functionalized silica TLC, hexane/AcOEt = 5:1, stained brown with I2/silica gel). IR (ATR, cm−1) 2932, 1753, 1704, 1416, 1306, 1209, 1054, 759. 1H NMR ((CD3)2SO, 80 °C, major rotamer): δ 1.14−1.22 (m, 6H), 1.22− 1.40 (m, 4H), 1.40−1.49 (m, 4H), 1.50−1.85 (m, 5H), 1.88−1.98 (m, 1H), 2.36−2.58 (m, 5H), 4.01−4.12 (m, 4H), 4.33 (q, 1H, J = 4.6 Hz), 8.33 (brs, 1H). 13C NMR ((CD3)2SO, 80 °C): δ 14.0, 21.2, 23.86, 23.92, 24.1, 26.0, 27.6, 51.0, 53.5 (br), 60.2, 60.9, 63.0 (br), 155.5, 155.6. HRMS (FAB+, CHCl3 + NBA): calcd for C17H32N3O4 (M + H+) 342.2393, found 342.2396.

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01923. 1 H and 13C NMR spectra of new compounds, HPLC chromatograms of optically active compounds, and Xray structure reports (PDF) X-ray data for compound anti,syn-3aa (CIF) X-ray data for compound syn,syn-3aa (CIF) X-ray data for compound syn,syn-7aa (CIF)

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. ORCID

Masaharu Sugiura: 0000-0002-7173-4568 Shunsuke Kotani: 0000-0003-4801-8341 Author Contributions

All authors have given approval to the final version of the manuscript. Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS This work was partially supported by JSPS KAKENHI (Grant Nos. 16KT0164 and 26460010). REFERENCES

(1) (a) Stork, G.; Brizzolara, A.; Landesman, H.; Szmuszkovicz, J.; Terrell, R. J. Am. Chem. Soc. 1963, 85, 207−222. For reviews, see: 10978


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The Journal of Organic Chemistry 2005, 2005, 1727−1747. (b) Orito, Y.; Nakajima, M. Synthesis 2006, 2006, 1391−1401. (c) Benaglia, M.; Guizzetti, S.; Pignataro, L. Coord. Chem. Rev. 2008, 252, 492−512. (d) Denmark, S. E.; Beutner, G. L. Angew. Chem., Int. Ed. 2008, 47, 1560−1638. (14) For reviews on synthetic methods for 1,3-diamines, see: (a) Ji, X.; Huang, H. Org. Biomol. Chem. 2016, 14, 10557−10566. (b) Robak, M. T.; Herbage, M. A.; Ellman, J. A. Chem. Rev. 2010, 110, 3600−3740. (15) (a) Appel, R.; Mayr, H. J. Am. Chem. Soc. 2011, 133, 8240− 8251. (b) Kempf, B.; Hampel, N.; Ofial, A. R.; Mayr, H. Chem. - Eur. J. 2003, 9, 2209−2218. (c) Mayr, H.; Ofial, A. R. J. Phys. Org. Chem. 2008, 21, 584−595. (16) The imino ene-type reaction was found to be reversible at 0 °C but irreversible at −78 °C. The reversibility at 0 °C was confirmed with control experiments. For example, addition of benzaldehyde-derived N-mesylimine 1b to adduct 4aa resulted in formation of an imino ene-type product between 1b and 2a. However, the diastereomeric ratio of 4aa generated at 0 °C (anti/syn = 88:12) was not changed after it had been left to stand at −78 °C for 3 h with acetic acid (1.0 equiv), which implies that the higher diastereoselectivity (anti/syn = 95:5) at −78 °C was kinetically controlled. See ref 9b. (17) Borch, R. F.; Bernstein, M. D.; Durst, H. D. J. Am. Chem. Soc. 1971, 93, 2897−2904. (18) The crystallographic data, CCDC 991772 (1,2-anti-2,3-syn3aa), CCDC 991773 (1,2-syn-2,3-syn-3aa), and CCDC 1563169 (1,2-syn-2,3-syn-7aa) are available from the Cambridge Crystallographic Data Centre. (19) For selected examples of C−C bond formation of cyclic imines 6, see: (a) Nishimura, T.; Ebe, Y.; Fujimoto, H.; Hayashi, T. Chem. Commun. 2013, 49, 5504−5506. (b) Wang, H.; Jiang, T.; Xu, M. H. J. Am. Chem. Soc. 2013, 135, 971−974. (c) Nishimura, T.; Noishiki, A.; Tsui, G. C.; Hayashi, T. J. Am. Chem. Soc. 2012, 134, 5056−5059. (d) Luo, Y.; Carnell, A. J.; Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 6762−6766. (e) Luo, Y.; Hepburn, H. B.; Chotsaeng, N.; Lam, H. W. Angew. Chem., Int. Ed. 2012, 51, 8309− 8313. (f) Saeidian, H.; Abdoli, M.; Mirjafary, Z. Synthesis 2015, 47, 1057−1075. (20) Wang, F.; Chiba, K.; Tada, M. J. Chem. Soc., Perkin Trans. 1 1992, 1897−1900. (21) For use of (S)-BINAPO or (S)-SEGPHOSO as chiral Lewis base catalysts in our laboratory, see: (a) Kotani, S.; Sugiura, M.; Nakajima, M. Chem. Rec. 2013, 13, 362−370. (b) Kotani, S.; Sugiura, M.; Nakajima, M. Synlett 2014, 25, 631−640. (c) Kotani, S.; Ito, M.; Nozaki, H.; Sugiura, M.; Ogasawara, M.; Nakajima, M. Tetrahedron Lett. 2013, 54, 6430−6433. (d) Kotani, S.; Hanamure, T.; Nozaki, H.; Sugiura, M.; Nakajima, M. Tetrahedron: Asymmetry 2017, 28, 282−287. (22) Kanzian, T.; Mayr, H. Chem. - Eur. J. 2010, 16, 11670−11677. (23) For preparation of imines 1, see: (a) McKay, W. R.; Proctor, G. R. J. Chem. Soc., Perkin Trans. 1 1981, 2435−2442. (b) Chemla, F.; Hebbe, V.; Normant, J.-F. Synthesis 2000, 2000, 75−77.

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