. Author manuscript; available in PMC: 2012 Oct 28.

Published in final edited form as: Tetrahedron. 2011 Oct 28;67(43):8229–8234. doi: 10.1016/j.tet.2011.08.054

Stereochemical investigation of conjugate additions of carbon- and heteronucleophiles to ring-substituted nitrosocyclohexenes

Ritobroto Sengupta ¹, Jason A Witek ¹, Steven M Weinreb ¹

PMCID: PMC3224044 NIHMSID: NIHMS322686 PMID: 22125343

Abstract

Intermolecular Michael-type conjugate additions of some in situ-generated ring-substituted nitrosocyclohexenes with both carbon- and heteronucleophiles have been found to be highly stereoselective, leading predominantly (or exclusively) to products resulting from axial attack on a half-chair conformation of the nitrosoalkene substrate.

Keywords: Stereoselectivity, Michael-type additions, Enolonium ion equivalents, Organocuprate additions

1. Introduction and Background

We have recently been involved in exploring synthetic methodology based on inter-¹ and intramolecular² conjugate additions of nucleophiles to highly reactive, transient nitrosoalkenes.³ In particular, we have been interested in using this type of transformation to evaluate the synthetic potential of nitrosoalkenes as enolonium ion equivalents.⁴ At the outset of these investigations it became evident to us that there are a number of fundamental stereochemical issues relevant to this type of conjugate addition that have never been addressed. For example, in a recent publication we described stereochemical studies on nucleophilic additions to acyclic nitrosoalkenes bearing a γ-stereogenic center, a process found to be highly diastereoselective, leading exclusively to the anti adducts.⁵ We now report some new stereochemical investigations of conjugate additions of various carbon- and heteronucleophiles to cyclic systems.

2. Results and discussion

Our current studies focussed on probing the stereochemical outcome of nucleophilic additions to substituted nitrosocyclohexenes 3 to form α-substituted oxime products 4 (Scheme 1). For comparison purposes in the exploratory stages of this investigation, the requisite nitrosoalkenes 3 were generated and reacted with the nucleophile via two different procedures: 1) treatment of the α-chlorooxime 1, formed from a ring-substituted α-chlorocyclohexanone, with 2.3 equivalents of the potassium salt of the nucleophile in THF at –78 °C (Method A) and 2) the Denmark procedure⁶ involving treatment of an α-chloro-O-silyloxime 2 with tetrabutylammonium fluoride in THF in the presence of 1.2 equivalents of the potassium salt of the nucleophile (Method B).

Scheme 1 — Addition of nucleophiles to substituted nitrosocyclohexenes

Initial experiments involved examining the addition of various malonate ester enolates to in situ-produced 4-t-butylnitrosocyclohexene. Thus, the known^6a,7 racemic cis-α-chloro-4-t-butylcyclohexanone oxime 5a and the corresponding trans-isomer 5b were combined with the potassium enolate of diethyl malonate (6a) under the conditions of Method A (see Experimental for details) to afford exclusively trans adduct 8a (R′ = H) in good yields (Table 1, >20:1 8:9 estimated by ¹H NMR). In both experiments only one oxime geometric isomer of 8a was produced. Although we cannot definitively assign geometry in this case, the fact that we have generally observed formation of the (E)-oximes as the exclusive (or predominant) product in other examples (vide infra) has led us to tentatively propose this geometry for adduct 8a. The configuration and chair conformation of 8a, as shown in Scheme 2, were established by NMR analysis.⁸ Exposure of cis-α-chloro-O-silyloxime 5c^6a to the Denmark conditions in the presence of diethyl malonate potassium enolate (Method B) also afforded a comparable yield of the same trans-adduct 8a as the sole product. It seems reasonable that adduct 8a is formed in all three cases via preferred axial attack⁹ on the half-chair conformation of 4-t-butylnitrosocyclohexene (7). These experiments also indicated that the stereoselectivity and yield of the addition products are independent of the precursor and method of generation of the nitrosoalkene.^6a

Table 1.

Malonate additions to 4-tert-butylnitrosocyclohexene


			Total Yield (8 + 9)	Isomer Ratio (8:9)
a R = H, α-CI	a R′ = H	Method A	85%	>20:1
b R = H, β-CI		Method A	93%
c R = TBS, α-CI		Method B	86%

a R = H, α-CI	b R′ = Me	Method A	89%	6.2:1
b R = H, β-CI		Method A	85%
c R = TBS, α-CI		Method B	81%

a R = H, α-CI	c R′ = Et	Method A	76%	>20:1
b R = H, β-CI		Method A	88%
c R = TBS, α-CI		Method B	72%

a R = H, α-CI	d R′ = allyl	Method A	89%	9.1:1
c R = TBS, α-CI		Method B	72%	9.1:1

Open in a new tab

Scheme 2 — Configurations and conformations of malonate adducts of 4-t-butylnitrosocyclohexene

Further studies were subsequently carried out with α-alkyl-substituted malonate nucleophiles. It was found that repeating the above experiments with oxime derivatives 5a–c using α-methyl diethyl malonate (6b) in most runs afforded an inseparable 6.2:1 mixture of adducts (E)-trans-8b and (E)-cis-9b in good total yield. However, in one reaction conducted with oxime 5a, only the trans product 8b was formed, thereby providing a pure sample of this material. Interestingly, the major trans-product 8b apparently exists in the twist boat conformation shown in Scheme 2 as determined by 2D NMR nOe analysis of the pure isomer. We have again assumed the oxime geometry to be (E) in this system since the stereochemistry could not be determined unambiguously by spectral methods. The fact that 8b is a twist boat is not too surprising since Allinger has reported that trans-1,3-di-t-butylcyclohexane exists in this conformation.¹¹

Addition of the potassium enolate of α-ethyl diethyl malonate (6c) to the nitrosocycloalkene derived from the three oxime derivatives 5a–c as was done with malonates 6a and 6b also afforded a single trans adduct 8c with the (E)-oxime configuration. As was the case with 8b, NMR analysis indicated that this system exists in a twist boat conformation (Scheme 2). Finally, addition of α-allyl diethyl malonate (6d) to α-chlorooximes 5a via Method A and 5c via Method B led to an inseparable 9.1:1 mixture of (E)-trans-adduct 8d and (E)-cis-compound 9d. It was possible in this case to crystallize the major (E)-trans isomer 8d from the mixture, and X-ray analysis of this compound showed it indeed to exist in a twist boat conformation and confirmed the (E)-oxime geometry.¹²

It is also possible to add heteronucleophiles to vinylnitroso compound 7 with a high degree of stereoselectivity. Therefore, N-methyl-p-toluenesulfonamide undergoes smooth axial addition to the nitrosoalkene formed from α-chloro-O-TBS-oxime 5c under the conditions of Method B to afford exclusively the trans-(E)-oxime product 10 (Scheme 3). The structure and stereochemistry of this adduct were firmly established by X-ray analysis.

Scheme 3 — Addition of heteronucleophiles to 4-t-butylnitrosocyclohexene

Similarly, potassium thiophenoxide undergoes highly axial-stereoselective addition to the nitrosoalkene derived from α-chlorooxime 5a via Method A, as well as using the Denmark procedure from O-silyloxime 5c (Method B).¹³ Both procedures led to a chromatographically separable ~19:1 mixture of the (E)-trans product 11 and the (E)-cis isomer 12 in high yields. The structure of the minor product 12 was confirmed by X-ray analysis.

We have also investigated the stereochemistry of the addition of organocuprates to 4-t-butylnitrosocyclohexene (7). For example, treatment of α-chlorooxime 5a with two equivalents of dimethylcopper lithium afforded a chromatographically separable 4:1 mixture of trans α-methyl product 13a derived from axial attack on nitrosoalkene 7, and the corresponding cis isomer 14a in excellent total yield (Scheme 4). A small amount (~10%) of the reductive dechlorination product of starting oxime 5a was also formed in this reaction. In addition, the major isomer 13a was found to be an inseparable 1:1 mixture of (E/Z)-oxime geometric isomers⁸ whereas the minor product 14a was exclusively (E) as determined by X-ray analysis. Similar but improved stereoselectivity was observed in the conjugate addition reactions with aryl cuprates. Therefore, the phenyl cuprate addition gave a 12:1 mixture of trans-13b and cis-14b in high overall yield, whereas the p–tolyl cuprate cleanly afforded a 9:1 mixture of 13c and 14c. It should also be noted that in the aryl cuprate additions diastereomer and (E/Z)-oxime ratios were observed to be quite variable from run to run, probably due to equilibration during workup and/or purification. However, we have been unable to determine if similar isomerizations occurred in the malonate reactions (cf. Table 1).

Scheme 4 — Addition of cuprates to 4-t-butylnitrosocyclohexene

Finally, we have briefly investigated the stereochemistry of the addition of diethyl malonate to some other nitrosocyclohexenes. For example, treatment of α-chloro-O-TBS-oxime 15b, prepared from the corresponding known α-chloroketone 15a (mixture of isomers),¹¹ with the potassium salt of diethyl malonate, followed by TBAF led to a single diastereomeric adduct 17 (yield unoptimized) (Scheme 5). This product, which is a 5:1 (E/Z) mixture of oxime isomers, has the cis-stereochemistry and conformation as shown based upon NMR analysis. The adduct 17 probably arises via axial attack by the malonate enolate on the half-chair vinylnitroso intermediate 16.

Scheme 5 — Addition of diethyl malonate to ring-substituted nitrosocyclohexenes

Similarly, addition of malonate anion to the nitrosoalkene derived from known α-chloro-O-silyloxime 18^6c led to the trans product 20 as an 11:1 (E/Z) oxime mixture. It seems reasonable that this adduct is formed via axial attack on the preferred (due to A^1,2-strain)¹⁴ quasi-axial-ethyl half-chair nitrosoalkene 19.

3. Conclusion

Analogous to the work described here, a number of studies have appeared probing the stereochemistry of Michael additions to cyclohexenes bearing electron-withdrawing groups such as cyano, phenylazo, acetyl, carboxylate, etc.¹⁵ Interestingly, with many of these Michael acceptors the preference for axial or equatorial attack varies widely depending on the particular nucleophile, solvent and reaction conditions, as well as steric factors. In the case of the nitrosocyclohexene systems described here, axial attack is generally favored by varying degrees using a wide variety of carbon- and heteronucleophiles. It should be noted that due to the high electrophilicity of nitrosoalkenes, as well as the methods of generation of these species, we are limited to use of non-nucleophilic solvents such as THF.

The studies outlined here further demonstrate the potential for stereospecific alkylation and arylation of nitrosoalkenes, which can act as effective enolonium ion equivalents. The product α-substituted oximes can be converted back to the parent carbonyl compounds via a plethora of methods.¹⁶ Alternatively, these oximes could potentially be reduced to the corresponding amines or subjected to Beckmann rearrangements to afford ring-expanded lactams. We are continuing to investigate the potential of nitrosoalkenes in organic synthesis.

4. Experimental

4.1. General methods

All non-aqueous reactions were carried out under an inert argon atmosphere in flame dried glassware. Liquid reagents sensitive to air were added via a dry syringe. All solvents and reagents were obtained from commercial sources and used without further purification. EM Science silica gel 60 (230–400 mesh) was used for flash column chromatography, and silica gel 60 PF₂₅₄ plates were used for analytical and preparative thin layer chromatography. ¹H and ¹³C NMR experiments were performed on Bruker CDPX 300, DRX 400 or AV-III-600 MHz spectrometers. All high and low resolution mass spectral data were obtained using a Waters LCT Premier time of flight mass spectrometer (Waters Corporation, Micromass Ltd., Manchester, UK). IR spectra were measured on a Perkin Elmer 1600 Series FTIR.

4.2. Synthesis and characterization

4.2.1. General procedures for intermolecular Michael additions of nucleophiles to in situ-generated 4-tert-butylnitrosocyclohexene

Method A: Addition of malonate and thiophenoxide nucleophiles to 4-tert-butylnitrosocyclohexene generated from α-chlorooximes 5a and 5b

A flame dried 25 mL round bottomed flask containing a stirring bar was purged with Ar. The flask was cooled to −78 °C and charged with dry THF (3 mL). At this temperature, KHMDS (0.5 M in PhMe, 0.9 mL, 0.45 mmol) was added, followed by the nucleophile (0.44 mmol). The mixture was stirred at −78 °C for 45 min. A solution of the α-chlorooxime 5a or 5b (39 mg, 0.19 mmol) in THF (1 mL) was added slowly and the mixture was stirred at −78 °C for 20 min. The reaction was quenched with saturated NH₄Cl solution and was extracted with Et₂O. The combined organics were dried over anhydrous MgSO₄. The residue obtained after solvent removal under reduced pressure was purified by flash column chromatography on silica gel (gradient elution using 10–20% ethyl acetate in hexanes).

Method B: Addition of malonate, sulfonamide and thiophenoxide nucleophiles to 4-tert-butylnitrosocyclohexene generated from α-chloro-O-TBS-oxime 5c

A flame dried 25 mL round bottomed flask containing a stirring bar was purged with Ar. The flask was cooled to −78 °C and charged with dry THF (2 mL), followed by KHMDS (0.5 M in PhMe, 0.45 mL, 0.23 mmol). The nucleophile (0.22 mmol) was added and the mixture was stirred at −78 °C for 45 min. A solution of the α-chloro-O-TBS-oxime 5c (57 mg, 0.18 mmol) in THF (1 mL) was added slowly to the reaction mixture at −78 °C, followed by the dropwise addition of TBAF (1.0 M in THF, 0.56 mL, 0.56 mmol) at this temperature. The temperature of the reaction bath was raised to −60 °C and maintained there for 20 min. The reaction was quenched with saturated NH₄Cl solution at −60 °C, removed from the cold bath and allowed to warm to rt. The reaction mixture was extracted with Et₂O and the combined organics were dried over anhydrous MgSO₄. The residue obtained after solvent removal under reduced pressure was purified by flash column chromatography on silica gel (gradient elution using 10–20% ethyl acetate in hexanes).

2-(5-tert-Butyl-2-hydroximinocyclohexyl)-malonic acid diethyl ester (8a)

Method A: cis-5a (yield: 85%), trans-5b (yield: 93%). Method B: cis-5c (yield: 86%). ¹H NMR (300 MHz, CDCl₃) δ 7.95 (br s, 1H), 4.28-4.13 (m, 4H), 3.77 (d, J = 11.5 Hz, 1H), 3.26 (dt, J = 4.7, 11.5 Hz, 1H), 3.15 (dq, J = 2.1, 15.6 Hz, 1H), 2.07-1.75 (m, 3H), 1.53-1.18 (m, 9H), 0.87 (s, 9H); ¹³C NMR (75 MHz, CDCl₃) δ 168.4, 168.3, 160.2, 62.0, 53.7, 42.6, 40.3, 32.9, 30.0, 27.7, 25.5, 22.5, 14.6, 14.4; IR (thin film) 3460, 3307, 2954, 2872, 1731, 1655, 1249, 1179, 1149, 1102, 1032, 926 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₇H₃₀NO₅: 328.2124, found: 328.2127.

2-(5-tert-Butyl-2-hydroxyiminocyclohexyl)-2-methylmalonic acid diethyl ester (8b)

Method A: cis-5a (yield: 89%), trans-5b (yield: 85%). Method: B: cis-5c (yield: 81%). Product was isolated as an inseparable 6.2:1 mixture of trans-8b:cis-9b. ¹H NMR (300 MHz, CDCl₃, cis isomer 9b) δ 7.38 (br s, 1H), 4.25-4.07 (m, 4H), 3.41 (dm, J = 15.6 Hz, 1H), 3.17 (dd, J = 3.3, 12.4 Hz, 1H), 1.93-1.58 (m, 4H), 1.54 (s, 3H), 1.43-1.16 (m, 8H), 0.85 (s, 9H). ¹H NMR (300 MHz, CDCl₃, trans isomer 8b) δ 7.60 (br s, 1H), 4.25-4.07 (m, 4H), 3.33 (t, J = 8.2 Hz, 1H), 2.71 (dm, J = 17.4 Hz, 1H), 2.33-2.20 (m, 1H), 1.83-1.57 (m, 3H), 1.52 (s, 3H), 1.43-1.16 (m, 8H), 0.85 (s, 9H); ¹³C NMR (100 MHz, CDCl₃, trans isomer 8b) δ 172.0, 171.9, 160.2, 61.8, 61.7, 56.2, 43.8, 42.1, 33.5, 27.4, 26.4, 25.1, 22.0, 18.0, 14.4, 14.3; IR (thin film) 3448, 2954, 2872, 1725, 1655, 1296, 1243, 1179, 1108, 1020, 932 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₈H₃₂NO₅: 342.2280, found: 342.2281.

2-(5-tert-Butyl-2-hydroxyiminocyclohexyl)-2-ethylmalonic acid diethyl ester (8c)

Method A: cis-5a (yield: 76%), trans-5b (yield: 88%). Method B, cis-5c (yield: 72%). ¹H NMR (300 MHz, CDCl₃) δ 7.44 (br s, 1H), 4.31-4.14 (m, 4H), 3.20 (t, J = 6.6 Hz, 1H), 2.89 (br d, J = 14.5 Hz, 1H), 2.24-2.06 (m, 3H), 1.97-1.85 (m, 1H), 1.79-1.76 (m, 1H), 1.69-1.61 (m, 1H), 1.32-1.22 (m, 8H), 0.96-0.87 (m, 12H); ¹³C NMR (100 MHz, CDCl₃) δ 172.1, 171.2, 160.3, 61.2, 59.7, 43.0, 42.3, 32.9, 28.3, 28.0, 27.3, 23.8, 14.2, 14.0, 9.5; IR (thin film) 3460, 2954, 2872, 1725, 1655, 1296, 1232, 1114, 1026, 955 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₉H₃₄NO₅: 356.2437, found: 356.2444.

2-Allyl-2-(5-tert-butyl-2-hydroxyiminocyclohexyl)-malonic acid diethyl ester (8d)

Method A: cis-5a (yield: 89%). Method B: cis-5c (yield: 72%). Product was isolated as an inseparable 9.1:1 mixture of 8d/9d. X-Ray quality crystals of the major trans isomer 8d were obtained from the mixture by slow evaporation from acetone/ethyl acetate. ¹H NMR (400 MHz, CDCl₃, cis isomer 9d) δ 7.44 (br s, 1H), 5.99-5.89 (m, 1H), 5.05 (br d, J = 8.3 Hz, 1H), 5.03 (br s, 1H), 4.30-4.12 (m, 4H), 3.42 (br d, J = 13.2 Hz, 1H), 2.97 (dd, J = 5.8, 14.0 Hz, 1H), 2.91-2.65 (m, 3H), 2.09 (br d, J = 12.4 Hz, 1H), 1.91 (br d, J = 10.5 Hz, 1H), 1.65-1.54 (m, 1H), 1.30-1.18 (m, 8H), 0.88 (s, 9H). ¹H NMR (400 MHz, CDCl₃, trans isomer 8d) δ 7.52 (br s, 1H), 5.99-5.89 (m, 1H), 5.05 (br d, J = 8.3 Hz, 1H), 5.03 (br s, 1H), 4.30-4.12 (m, 4H), 3.16 (t, J = 7.4 Hz, 1H), 2.91-2.65 (m, 3H), 2.29-2.17 (m, 2H), 1.75-1.57 (m, 2H), 1.30-1.18 (m, 8H), 0.87(s, 9H); ¹³C NMR (100 MHz, CDCl₃, trans isomer 8d) δ 171.7, 171.0, 160.3, 134.5, 118.6, 61.6, 61.5, 59.8, 43.7, 42.6, 39.8, 33.3, 27.8, 27.5, 24.6, 23.1, 14.5, 14.4; IR (thin film, 8d/9d mixture) 3448, 2954, 2873, 1725, 1655, 1249, 1167, 1108, 1020, 930 cm⁻¹; HRMS-ES [M+H]⁺ (8d/9d mixture) calcd for C₂₀H₃₄NO₅: 368.2437, found: 368.2422.

N-(5-tert-Butyl-2-hydroxyiminocyclohexyl)-4,N-dimethylbenzenesulfonamide (10)

Method B: cis-5c (yield: 83%). X-ray quality crystals were obtained by slow evaporation from acetone/ethyl acetate. ¹H NMR (300 MHz, CDCl₃) δ 8.59 (s, 1H), 7.72 (d, J = 8.1 Hz, 2H), 7.31 (d, J = 8.1 Hz, 2H), 4.11 (t, J = 6.0 Hz, 1H), 3.05 (dq, J = 2.2, 15.5 Hz, 1H), 2.75 (s, 3H), 2.42 (s, 3H), 2.34-2.22 (m, 1H), 2.15-2.07 (m, 1H), 1.85 (d, J = 10.7 Hz, 1H), 1.65-1.52 (m, 1H), 1.50-1.40 (m, 1H), 1.35-1.21 (m, 1H), 0.86 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 160.9, 143.8, 135.0, 130.0, 128.3, 57.7, 42.4, 33.2, 33.0, 31.1, 27.5, 24.1, 23.7, 22.0; IR (thin film) 3460, 3284, 2954, 2872, 1655, 1337, 961 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₈H₂₉N₂O₃S: 353.1899, found: 353.1890.

trans-4-tert-Butyl-2-phenylsulfanylcyclohexanone oxime (11)

Method A: cis-5a (isolated yield: 87%). Method B: cis-5c (isolated yield: 89%). ¹H NMR (400 MHz, CDCl₃) δ 8.05 (br s, 1H), 7.43 (d, J = 7.0 Hz, 2H), 7.31-7.23 (m, 3H), 4.05 (br s, 1H), 3.25 (br d, J = 14.6 Hz, 1H), 2.32-2.19 (m, 2H), 2.01-1.97 (m, 1H), 1.79 (br t, J = 12.4 Hz, 1H) 1.70 (dq, J = 4.5, 12.7 Hz, 1H), 1.20 (qd, J = 4.2, 13.0 Hz, 1H), 0.90 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 160.0, 134.8, 133.1, 129.3, 127.8, 50.4, 42.5, 33.9, 32.6, 27.8, 26.9, 20.8; IR (thin film) 3248, 3070, 2954, 2860, 1708, 926 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₆H₂₄NOS: 278.1579, found: 278.1571.

cis-4-tert-Butyl-2-phenylsulfanylcyclohexanone oxime (12)

Method A: cis-5a (isolated yield: 5%). Method B: cis-5c (isolated yield: 5%). X-ray quality crystals were obtained by slow evaporation from dichloromethane/acetone, mp 142–144 °C. ¹H NMR (600 MHz, CDCl₃) δ 7.88 (br s, 1H), 7.39 (d, J = 7.5 Hz, 2H), 7.27 (t, J = 7.4 Hz, 2H), 7.27 (t, J = 7.4 Hz, 1H), 3.77 (dd, J = 4.4, 11.7 Hz, 1H), 3.47 (dt, J = 3.9, 14.7 Hz, 1H), 2.25-2.22 (m, 1H), 1.93-1.90 (m, 1H), 1.76 (td, J = 5.64, 13.3 Hz, 1H), 1.58-1.19 (m, 3H), 0.82 (s, 9H); ¹³C NMR (150 MHz, CDCl₃) δ 159.0, 134.8, 131.6, 128.8, 126.8, 49.8, 47.6, 36.0, 32.6, 27.4, 26.1, 24.6; IR (thin film) 3260, 2943, 2872, 932 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₆H₂₄NOS: 278.1579, found: 278.1571.

4.2.2. Addition of organocuprates to 4-tert-butyl nitrosocyclohexene generated from cis -α-chlorooxime 5a

CuI powder (75 mg, 0.40 mmol) in a round-bottomed flask was dried by heating at 150 °C for 2 h under vacuum. The heating was discontinued and the flask was allowed to cool to rt under Ar. The flask was then transferred to an ice bath and charged with dry THF (1 mL). The mixture was maintained at 0 °C and a solution of the organolithium reagent (0.80 mmol) was added slowly. A turbid green coloration was observed after addition of the first equivalent of the organolithium reagent, but the mixture turned transparent or clear tan after the addition of the second equivalent. The mixture was stirred at this temperature for 2 min and then the reaction flask was transferred to an acetone/dry ice bath at −78 °C. A solution of the α-chlorooxime cis-5a (41 mg, 0.20 mmol) in THF (2 mL) was added slowly to this mixture at −78 °C whereby the solution turned bright yellow. The reaction mixture was stirred for 30 min at −78 °C and quenched with concentrated HCl (12.1 M, 1 mL, 12.1 mmol) at this temperature. The dry-ice bath was removed and ethylenediamine (3 mL, 45 mmol) was added to the cold mixture followed by the addition of ice-cold water (10 mL). The addition of ethylenediamine was exothermic and the flask was properly vented to prevent the buildup of pressure. The reaction mixture turned turbid blue on the initial addition of ethylenediamine and later changed to clear Prussian blue on the addition of water. Stirring was discontinued after 2 min and the organic layer was extracted with ether, dried over anhydrous MgSO₄ and the solvent was removed under vacuum. The product was purified by flash column chromatography on silica gel eluting with dichloromethane (100%) followed by ethyl acetate/hexanes (gradient, 10%–20% ethyl acetate in hexanes).

trans-4-tert-Butyl-2-methylcyclohexanone oxime (13a)

Isolated yield: 71%. ¹H NMR (300 MHz, CDCl_3, inseparable ~1:1 mixture of oxime Z/E isomers) δ 8.75 (br s, 1H), 3.65-3.61 (m, 0.5H, Z), 3.15 (br d, J = 8.7 Hz, 0.5H), 2.67-2.64 (m, 0.5H, E), 2.34-2.22 (m, 1H), 1.95-1.85 (m, 1.5H), 1.67-1.63 (m, 1H), 1.49-1.36 (m, 2H), 1.20-1.11 (m, 4H), 0.86 (s, 9H); ¹³C NMR (100 MHz, CDCl_3, inseparable ~1: 1 mixture of oxime Z/E isomers) δ 164.7, 164.6, 41.9, 41.8, 34.8, 34.0, 33.2, 32.7, 32.6, 29.0, 28.1, 27.9, 27.8, 27.0, 26.3, 21.5, 19.0, 17.2; IR (thin film) 3237, 2954, 2872, 1660, 944 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₁H₂₂NO: 184.1701, found: 184.1709.

cis-4-tert-Butyl-2-methylcyclohexanone oxime (14a)

Isolated yield: 18%. X-ray quality crystals were obtained by slow evaporation from chloroform/ethyl acetate, mp 143–145 °C. ¹H NMR (300 MHz, CDCl₃) δ 9.62 (br, s, 1H), 3.44 (dm, J = 14.0 Hz, 1H), 2.25 (m, 1H), 1.92 (dm, J = 12.3 Hz, 2H), 1.62 (td, J = 5.1, 14.0 Hz, 1H), 1.30 (tt, J = 2.9, 12.0 Hz, 1H), 1.25-1.10 (m, 4H), 1.01 (q, J = 9.4 Hz, 1H), 0.87 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 163.5, 47.8, 37.9, 37.7, 32.8, 28.0, 27.3, 24.8, 17.0; IR (thin film) 3260, 2943, 2872, 1660, 932 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₁H₂₂NO: 184.1701, found: 184.1708.

trans-4-tert-Butyl-2-phenylcyclohexanone oxime (13b)

Isolated yield: 85% as an inseparable 36:1 mixture of oxime E/Z diastereomers. ¹H NMR (300 MHz, CDCl_3, Z isomer) δ 8.92 (br s, 1H), 7.40-7.24 (m, 5H), 4.93 (br s, 1H), 2.58-2.53 (m, 1H), 2.45 (br d, J = 14.0 Hz, 1H), 1.92-1.21 (m, 5H), 0.94 (s, 9H). ¹H NMR (300 MHz, CDCl_3, E isomer) δ 8.92 (br s, 1H), 7.40-7.24 (m, 5H), 3.88 (br s, 1H), 3.33 (dm, J = 12.2 Hz, 1H), 2.60 (dm, J = 13.7 Hz, 1H), 1.92-1.6 (m, 3H), 1.50 (tm, J = 9.3 Hz, 1H), 1.36-1.21 (m, 1H), 0.94 (s, 9H); ¹³C NMR (75 MHz, CDCl₃, E isomer) δ 162.7, 141.0, 129.0, 127.7, 126.6, 44.3, 42.3, 32.9, 31.2, 27.8, 27.0, 22.5; IR (thin film) 3260, 2954, 2872, 1666, 932 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₆H₂₄NO: 246.1858, found: 246.1855.

cis-4-tert-Butyl-2-phenylcyclohexanone oxime (14b)

Isolated yield: 7%. ¹H NMR (400 MHz, CDCl₃) δ 7.36-7.21 (m, 5H), 3.50 (dm, J = 13.2 Hz, 1H), 3.40 (dd, J = 4.1, 12.9 Hz, 1H), 2.12-1.98 (m, 2H), 1.79 (td, J = 5.4, 13.9 Hz, 1H), 1.64 (q, J = 12.4 Hz, 1H), 1.49-1.43 (m, 1H), 1.37-1.22 (m, 2H), 0.92 (s, 9H); ¹³C NMR (100 MHz, CDCl₃) δ 162.9, 141.3, 129.1, 128.7, 127.1, 49.8, 48.1, 36.1, 33.0, 28.0, 26.9, 24.9; IR (thin film) 3247, 2950, 2868, 1668, 928 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₆H₂₄NO: 246.1858, found: 246.1855.

trans-4-tert-Butyl-2-p-tolylcyclohexanone oxime (13c)

Isolated yield: 85% as an inseparable 5.5:1 mixture of oxime E/Z isomers. ¹H NMR (400 MHz, CDCl_3, Z isomer) δ 8.77 (br s, 1H), 7.19-7.14 (m, 4H), 4.84 (br s, 1H), 2.51-2.47 (m, 1H), 2.41 (dm, J = 14.2 Hz, 1H), 2.34 (s, 3H), 2.16 (td, J = 4.8, 13.9 Hz, 1H), 1.87-1.20 (m, 4H), 0.91 (s, 9H). ¹H NMR (400 MHz, CDCl_3, E isomer) δ 8.77 (br s, 1H), 7.19-7.14 (m, 4H), 3.80 (br s, 1H), 3.29 (br d, J = 14.4 Hz, 1H), 2.55 (dm, J = 13.7 Hz, 1H), 2.34 (s, 3H), 1.87-1.73 (m, 2H), 1.66 (td, J = 5.1, 12.2 Hz, 1H), 1.51-1.40 (m, 1H), 1.27 (td, J = 4.4, 12.5 Hz, 1H), 0.91 (s, 9H); ¹³C NMR (100 MHz, CDCl_3, E isomer) δ 162.8, 137.9, 136.1, 129.8, 127.5, 43.9, 42.2, 32.9, 31.2, 27.8, 27.0, 22.4, 21.4; IR (thin film) 3237, 3107, 2942, 2872, 1655, 932 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₇H₂₆NO: 260.2014, found: 260.2011.

cis-4-tert-Butyl-2-p-tolylcyclohexanone oxime (14c)

Isolated yield: 9%. ¹H NMR (400 MHz, THF-d₈) δ 10.82 (s, 1H), 7.01 (dd, J = 7.9, 9.2 Hz, 4H), 3.49 (br d, J = 14.4 Hz, 1H), 3.30 (dd, J = 4.05, 12.8 Hz, 1H), 2.26 (s, 3H), 2.00-1.89 (m, 2H), 1.69-1.64 (m, 1H), 1.56 (t, J = 12.0 Hz, 1H), 1.48-1.42 (m, 1H), 1.25-1.21 (m, 1H), 0.91 (s, 9H); ¹³C NMR (100 MHz_, THF-d₈, compound has extremely low solubility leading to reduced signal intensity and therefore the oxime carbon peak could not be observed) δ 140.8, 136.2, 130.3, 129.4, 50.6, 49.4, 37.7, 33.7, 31.2, 28.5, 28.1, 21.7; IR (thin film) 3232, 2954, 2922, 2859, 1664, 930 cm⁻¹; HRMS-ES [M+H]⁺ calcd for C₁₇H₂₆NO: 260.2014, found: 260.2011.

2-Chloro-5-methylcyclohexanone O-(tert-butyldimethylsilyl) oxime (15b)

To a stirred solution of the α-chloroketone 15a (3.41 mmol) in CH₂Cl₂ (7 mL) and a spatula of 4 Å molecular sieves was added H₂NOTBS (529 mg, 3.41 mmol) and PPTS (spatula tip full). The reaction mixture was stirred at rt for 12 h and then filtered through a pad of Celite. The solution was concentrated in vacuo and the residue was purified by flash column chromatography on silica gel eluting with a mixture of ethyl acetate in hexanes (5–30%) to provide the product 15b as a clear oil (632 mg) in 67% yield as a mixture of (E/Z)-isomers and diastereomers: ¹H NMR (360 MHz, CDCl₃) δ 5.64 (br s, 0.4H), 5.50 (br s, 0.1H), 4.72 (br s, 0.4H), 4.57 (br s, 0.1H), 3.31 (t, J = 5.7 Hz, 1H), 2.40-2.30 (m, 1H), 2.23-2.18 (m, 1H), 2.10-2.05 (m, 1H), 1.94-1.76 (m, 3H), 1.69-1.45 (m, 5H), 1.11-1.04 (m, 6H), 0.96-0.94 (m, 18H), 0.22-0.19 (m, 12H); ¹³C NMR (90 MHz, CDCl₃) δ 162.7, 161.9, 160.7, 159.3, 66.3, 59.1, 54.5, 49.3, 47.4, 47.0, 38.7, 37.1, 35.4, 34.9, 33.6, 33.5, 32.4, 31.4, 31.3, 31.2, 29.7, 29.0, 28.4, 28.2, 27.6, 27.5, 26.6, 26.1, 25.8, 24.5, 23.5, 22.4, 22.1, 21.9, 21.2, 19.9, 18.9, 18.8, 18.2, 16.8; IR (thin film) 2955, 2858, 1744, 1461, 1252, 945 cm⁻¹; LRMS-ES+ m/z (relative intensity) 276 (MH⁺, 10); HRMS-ES [M+H]⁺ calcd for C₁₃H₂₇NOSCl: 276.1550, found: 276.1543.

4.2.3. General procedure for conjugate additions to ring-substituted nitrosoalkenes 16 and 19

To a stirred solution of diethyl malonate (6a, 3 mmol, 481 mg) in THF (6.5 mL) was added KHMDS (6 mL, 0.5 M in PhMe, 3 mmol) at −78 °C. The resulting solution was then stirred for 45 min at that temperature. The O-TBS oxime (15b or 18, 1 mmol) dissolved in THF (600 μL) was added slowly over 1 min, followed by dropwise addition of TBAF (2 mL, 1.0 M in THF, 2 mmol) over 3 min. The resulting solution was immediately transferred to an ice bath and stirred for an additional 2 h. The reaction mixture was diluted with concentrated aqueous NH₄Cl and EtOAc. The organic layer was separated and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na₂SO₄ and concentrated in vacuo to give a residue which was purified by flash column chromatography on silica gel eluting with a mixture of ethyl acetate in hexanes (25–40%).

Diethyl 2-(2-(hydroxyimino)-4-methylcyclohexyl)malonate (17)

The product 17 was obtained as a clear oil (47 mg, 45% yield) as a 5:1 mixture of (E/Z) oxime isomers: ¹H NMR (360 MHz, CDCl₃) δ 8.00-7.50 (br s, 1H), 4.23-4.10 (m, 4H), 3.79 (d, J = 10.0 Hz, 0.2H), 3.71 (d, J = 10.9 Hz), 3.20-3.13 (m, 0.3H), 3.11-3.04 (m, 1H), 2.86-2.72 (m, 0.3H), 2.56 (dd, J = 14.1, 4.7 Hz, 1H), 2.33 (dd, J = 14.0, 7.8 Hz, 1H), 1.93-1.74 (m, 2H), 1.72-1.61 (m, 4H), 1.44-1.37 (m, 2H), 1.30-1.19 (m, 6H), 1.01 (d, J = 7.5 Hz, 1H), 0.96 (d, J = 6.8 Hz, 3H); ¹³C NMR (90 MHz, CDCl₃) δ 168.7, 168.6, 159.3, 158.8, 61.9, 60.8, 53.8, 53.5, 41.4, 33.9, 32.0, 31.4, 30.7, 29.5, 27.7, 23.1, 23.0, 21.5, 20.6, 14.6, 14.5, 14.4, 11.8; IR (thin film) 3279, 2931, 2871, 1732, 1455, 1292, 1178, 1033, 947 cm⁻¹; LRMS-ES+ m/z (relative intensity) 286 (MH⁺, 36); HRMS-ES [M+H]⁺ calcd for C₁₄H₂₅NO₅: 286.1654, found: 286.1649.

Diethyl 2-(2-ethyl-6-(hydroxyimino)cyclohexyl)malonate (20)

The product 20 was obtained as a clear oil (18 mg, 34% yield) as a ~11:1 mixture of (E/Z) oxime isomers: ¹H NMR (300 MHz, CDCl₃) δ 8.31 (s, 1H), 8.10 (s, 0.1H), 4.27-4.05 (m, 4H), 3.83 (d, J = 8.5 Hz, 1H), 3.72 (d, J = 8.1 Hz, 0.09H), 3.13 (d, J = 10.6 Hz, 1H), 3.01 (d, J = 8.5 Hz, 1H), 2.01-1.92 (m, 1H), 1.81-1.74 (m, 1H), 1.73-1.61 (m, 3H), 1.60-1.49 (m, 2H), 1.48-1.39 (m, 1H), 1.36-1.21 (m, 8H), 0.92 (t, J = 5.5 Hz, 3H); ¹³C NMR (75 MHz, CDCl₃) δ 168.3, 159.0, 158.6, 62.0, 61.9, 54.0, 53.5, 45.4, 39.7, 25.4, 25.3, 21.8, 20.5, 14.4, 12.1, 12.0, 11.7; IR (thin film) 3278, 2960, 2874, 1732, 1456, 1262, 1034, 951 cm⁻¹; LRMS-ES+ m/z (relative intensity) 300 (MH⁺, 26); HRMS-ES [M+H]⁺ calcd for C₁₅H₂₆NO₅: 300.1811, found: 300.1799.

Supplementary Material

NIHMS322686-supplement-01.pdf^{(4MB, pdf)}

Acknowledgments

We are grateful to the National Institutes of Health (GM-087733) and the National Science Foundation (CHE-0806807) for financial support of this research. We also thank Dr. H. Yennawar (Penn State Small Molecule X-Ray Cystallographic Facility) for the X-ray crystal structure determinations.

Footnotes

Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

References and notes

1.Li P, Majireck MM, Witek JA, Weinreb SM. Tetrahedron Lett. 2010;51:2032. doi: 10.1016/j.tetlet.2010.02.050. [DOI] [PMC free article] [PubMed] [Google Scholar]
2.(a) Korboukh I, Kumar P, Weinreb SM. J Am Chem Soc. 2007;129:10342. doi: 10.1021/ja074108r. [DOI] [PMC free article] [PubMed] [Google Scholar]; (b) Kumar P, Li P, Korboukh I, Wang TL, Yennawar H, Weinreb SM. J Org Chem. 2011;76:2094. doi: 10.1021/jo1024392. [DOI] [PMC free article] [PubMed] [Google Scholar]
3.For reviews of vinylnitroso compounds see: Gilchrist TL. Chem Soc Rev. 1983;11:53.Lyapkalo IM, Ioffe SL. Russ Chem Rev. 1998;67:467.
4.For examples of enolonium ion equivalents see: Sacks CE, Fuchs PL. J Am Chem Soc. 1975;97:7372.Fuchs PL. J Org Chem. 1976;41:2935.Stork G, Ponaras AA. J Org Chem. 1976;41:2937.Wender PA, Erhardt JM, Letendre LJ. J Am Chem Soc. 1981;103:2114.Hatcher JM, Coltart DM. J Am Chem Soc. 2010;132:4546. doi: 10.1021/ja100932q.Miyoshi T, Miyakawa T, Ueda M, Miyata O. Angew Chem Int Ed. 2011;50:928. doi: 10.1002/anie.201004374.
5.Witek JA, Weinreb SM. Org Lett. 2011;13:1258. doi: 10.1021/ol2000793. [DOI] [PMC free article] [PubMed] [Google Scholar]
6.(a) Denmark SE, Dappen MS. J Org Chem. 1984;49:798. [Google Scholar]; (b) Denmark SE, Dappen MS, Sternberg JA. J Org Chem. 1984;49:4741. [Google Scholar]; (c) Denmark SE, Dappen MS, Sear NL, Jacobs RT. J Am Chem Soc. 1990;112:3466. [Google Scholar]
7.Malosh CF, Ready JM. J Am Chem Soc. 2004;126:10240. doi: 10.1021/ja0467768. [DOI] [PubMed] [Google Scholar]
8.Ribeiro DS, Olivato PR, Rittner R. Magn Reson Chem. 2000;38:627. [Google Scholar]
9.Eisenstein O, Klein J, Lefour JM. Tetrahedron. 1979;35:225. [Google Scholar]
10.Allinger NL, Freiberg LA. J Am Chem Soc. 1960;82:2393. [Google Scholar]
11.Allinger NL, Allinger J, Geller LE, Djerassi C. J Org Chem. 1960;25:6. [Google Scholar]
12.X-ray data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.. CCDC 833440 = 8d; CCDC 833441 = 10; CCDC 833442 = 12; CCDC 833443 = 14a
13.For recent examples of enantioselective additions of thiols to nitrosoalkenes see: Hatcher JM, Kohler MC, Coltart DM. Org Lett. 2011;13:3810. doi: 10.1021/ol2012633.
14.Cf Malhotra SK, Moakley DF, Johnson F. J Chem Soc, Chem Commun. 1967:448. [Google Scholar]
15.See for example: Abramovitch RA, Struble DL. Tetrahedron. 1968;24:357.Abramovitch RA, Rogic MM, Singer SS, Venkateswaran N. J Org Chem. 1972;37:3577.Abramovitch RA, Singer SS, Rogic MM, Struble DL. J Org Chem. 1975;40:34.Alexander CW, Hamdam MS, Jackson WR. J Chem Soc, Chem Commun. 1972:94.Bozzini S, Gratton S, Pellizer G, Risaliti A, Stener A. J Chem Soc, Perkin Trans 1. 1979:869.
16.For reviews of oxime cleavage see: Corsaro A, Chiacchio U, Pistara V. Synthesis. 2001:1903.Corsaro A, Chiacchio U, Pistara V. Curr Org Chem. 2009;13:482.Sahu S, Sahu S, Patel S, Dash S, Mishra BK. Ind J Chem. 2008;47B:259.

Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials