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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
Synlett. Author manuscript; available in PMC 2010 June 1.
Published in final edited form as:
Synlett. 2009 June 1; 2009(10): 1680–1684.
PMCID: PMC2787453

Bifunctional Asymmetric Catalysis with Hydrogen Chloride: Enantioselective Ring-Opening of Aziridines Catalyzed by a Phosphinothiourea


Ring-opening of aziridines with hydrogen chloride to form β-chloroamine derivatives is catalyzed by a chiral phosphinothiourea derivative in high yields and with high enantioselectivities. On the basis of 31P NMR studies, activation of HCl appears to proceed via quantitative protonation of the catalyst to afford a phosphonium chloride complex.

Keywords: asymmetric catalysis, halogenation, ring-opening, carbocations, aziridines

Hydrogen chloride (HCl) is a commodity chemical used in many industrial processes.1 HCl is also a convenient and inexpensive reagent for use in laboratory-scale chemical synthesis, such as for the hydrochlorination of carbon-carbon double2 and triple3 bonds. However its utility in catalytic enantioselective transformations has thus far been limited.4 Indeed, few of the common chiral catalysts are likely to be compatible with HCl given its extremely high acidity.5

Over the past several years, chiral thioureas have emerged as a useful class of catalysts for a broad range of asymmetric transformations.6 We discovered recently that chiral thiourea derivatives catalyze enantioselective additions to N-acyliminium/chloride ion pairs7a–c and α-chlorethers.7d These observations have led to the proposal that thiourea catalysts engage these weakly basic electrophiles by an anion abstraction mechanism that involves a thiourea-chloride hydrogen-bonding interaction.7b We have found that urea and thiourea catalysts are stable to strong mineral acids,8 suggesting that these catalysts might be amenable to productive activation of HCl. In particular, we considered the possibility that a bifunctional chiral catalyst9 containing a basic group could undergo protonation by HCl with binding of the chloride counterion to the thiourea (Figure 1), thereby activating the molecule to additions to polar organic electrophiles. Although many Lewis or Brønsted basic functional groups are expected to be protonated by HCl, the weak basicity of phosphines (Ph2CyP+H: pKa = 5.1 in H2O),10 suggested that chiral phosphinothiourea catalysts such as 1, originally developed in our laboratory for the [3+2] cycloaddition of allenes with imines,11 might be particularly effective in the context of productive HCl activation. Herein, we report the use of chiral phosphinothioureas to catalyze the catalytic enantioselective addition of HCl to N-acylaziridines.12

Figure 1
Proposed activation mode of HCl by catalyst 1.

Enantioselective desymmetrization of meso epoxides with various chloride sources is a well-studied method for the preparation of optically active chlorohydrins, and many examples using stoichiometric promoters13 as well as chiral catalysts14 have both been reported. Interestingly, the direct use of HCl for the enantioselective variant of this transformation has not been reported.15 In pioneering studies, Denmark reported that Lewis basic, chiral phosphoramides catalyze enantioselective opening of meso epoxides with SiCl4.14a Under the reaction conditions developed by Denmark, HCl mediates competitive, unselective epoxide ring-opening, and careful distillation of SiCl4 was necessary to ensure that reproducible enantioselectivity was obtained. HCl is also very reactive towards aziridines in the absence of any promoters,16 suggesting that a control over background reaction is necessary for achieving efficient asymmetric catalysis.

We began our study by investigating different thiourea catalysts using benzoyl protected aziridine 2a as a model substrate (Figure 2).17 In the absence of a chiral catalyst, hydrochlorination of 2a is complete within 30 min, even under relatively dilute reaction conditions and low temperatures (0.025 M, −78 °C), indicating that acceleration of a catalytic pathway and/or suppression of background reactivity would be necessary in order to achieve high enantioselectivities. 1,2-Diaminocyclohexane-derived catalysts 1a–1d (20 mol %) promoted formation of product 3a with very modest enantioselectivities (3–29% ee). Slow addition of HCl (0.25 M in Et2O) over 110 min, led only to minor improvements (up to 40% ee for both catalysts 1a and 1b), suggesting that background reactivity was only partially responsible for the low ee’s. While phosphine oxide catalyst 1e as well as thioureas 1g and 1h also led to product formation with poor enantioselectivity, phosphinothiourea catalyst 1f promoted hydrochlorination of 2a within 10 min in 60% ee.18 In this case, neither slow addition of HCl nor increased catalyst loading had any beneficial effect on enantioselectivity, suggesting that the catalytic pathway was significantly more rapid than the background reaction. This hypothesis was confirmed by in situ IR spectroscopic experiments with cycloheptene-derived aziridine 2c: in these studies, the initial reaction rate of hydrochlorination with catalyst 1f (20 mol% at −40 °C) was measured to be 140 times greater than in the absence of catalyst.

Figure 2
Screen of thiourea catalysts

The α-amino acid component of catalyst 1 was varied systematically in an effort to improve the enantioselectivity in the model reaction (Figure 3). It was found that ee’s were responsive to increasing steric demand of the α-substituent (catalysts 1i–1f). Accordingly, highly hindered unnatural amino acids were prepared, taking advantage of recently-developed thiourea-catalyzed asymmetric Strecker methodology,19 and incorporated into the new set of phosphinothiourea derivatives 1m–1p. A measurable improvement in ee was observed with these more hindered catalysts. The amino acid used for the preparation of catalyst 1m is readily accessible in optically pure form,20 so 1m was selected as the preferred catalyst for further study.

Figure 3
Optimization of the amino acid component of the catalyst.

Absolute concentration has proven to be an important parameter in thiourea-catalyzed reactions, with improvements in both enantioselectivity and rate resulting in certain cases from increased dilution.2b,21 This proved to be the case in the aziridine hydrochlorination reaction as well, with highest enantioselectivities obtained under highly dilute conditions (0.0025 M, compare entries 1–4, Table 1). However, further dilution led to significant decreases in reaction rate, necessitating higher reaction temperatures in order to achieve high conversion at the expense of ee (entries 5–6). Given that the racemic uncatalyzed reaction is not competitive with the catalytic pathway (entry 4),22 it appears that the increased enantioselectivity obtained at low concentrations may be ascribed to the existence competing catalyzed pathways of varying kinetic order in catalyst and/or reactants.

Table 1
Concentration Effect

The optimal conditions were successfully applied to a variety of aziridines to provide β-chloroamine products with high yields and good enantioselectivities with 10–20 mol% catalyst loadings (Table 2). Cyclooctene-derived substrate 2d (entry 4) was unreactive under highly dilute conditions (0.0025 M), but efficient hydrochlorination of this challenging substrate could be achieved at higher concentrations (0.025 M). The scope of enantioselective hydrochlorinations catalyzed by 1m is noteworthy given that Lewis base-catalyzed variants of this reaction, which generally afford only modest ee’s with cyclic substrates. 14

Table 2
Substrate Scope

cis-Stilbene-derived aziridine 2g also underwent the ring-opening in the presence of phosphinothiourea catalyst in reactions carried at 0.025 M (Table 3). Uncatalyzed openings of 2g lead to mixtures of diastereomeric products, with the ratio dependent on the chloride source used: SiCl4 leads to selective formation of syn-3g,23 the result of retentive ring-opening (entry 1). In contrast, HCl provides 1:1 mixture of anti- and syn-products (entry 2). Interestingly, anti-3g23 was obtained in high diastereo- and enantioselectivity (up to 90% ee) in reactions promoted by chiral phosphinothiourea catalysts 1f and 1m (entries 4 and 5). The observation of predominantly invertive ring-opening suggests an SN2-type pathway in the catalytic reaction. Other chiral thiourea derivatives 1a and 1h provided lower levels of selectivity (entries 6 and 7), indicating that a bifunctional phosphinothiourea catalyst was important for this substrate as well.

Table 3
Hydrochlorination of cis-Stilbene Derived Aziridine 2g

The absolute configuration of 3a (71% ee) prepared using 1f was determined by conversion to the known cis-amino alcohol 524 in two steps (Scheme 1).

Scheme 1
Determination of absolute configuration.

In order to glean insight into the mechanism of the phosphinothiourea-catalyzed additions of HCl to aziridines, we undertook 31P NMR studies of the interaction of catalyst 1f with HCl. An anhydrous, ethereal solution of 1f was cooled to −78 °C, and excess HCl in Et2O (10 equiv) was added dropwise via syringe. The solution became cloudy immediately, and was stirred for 30 min at −78 °C. Solvent removal by gradual evaporation under reduced pressure at low temperature (−78 °C to ca. −30 °C) afforded a white solid. Analysis of this material as a CDCl3 solution by 31P NMR spectroscopy revealed a single resonance (δ = 4.6 ppm, JP-H = 508 Hz) distinct from that of 1f (δ = −8.0 ppm). The chemical shift and P-H coupling constant are similar to those of previously characterized protonated phosphines.25,26 Enantioselective hydrochlorination of 2a (0.0025 M) using the solid, protonated species without added HCl gave the ring-opened product 3a quantitatively within 1 h in 70% ee,27 comparable to the enantioselectivity obtained under catalytic conditions (77% ee). On the basis of these results, it appears that catalytic hydrochlorinations of benzoyl aziridines such as 2a catalyzed by phosphinothioureas may involve initial heterolysis of HCl to afford a phosphonium chloride complex as depicted in Figure 1.

A proposed catalytic cycle for the ring-opening of aziridine 2a is provided in Figure 4. Aliphatic aziridines 2a2f undergo ring-opening exclusively with inversion of stereochemistry to provide trans-addition products 3a3f. Rates of invertive ring-openings of epoxides and aziridines derived from medium-ring cyclic alkenes are typically highly sensitive to the steric environment defined by the ring.28 This is observed in the present case as well, with reactions of five- and six-membered ring substrates 2a and 2b being considerably more rapid than those of seven- and eight-membered substrates 2c and 2d. The reactivity profiles and the observation of exclusive formation of trans products points to an SN2-type mechanism (Figure 4). We propose that HCl-1 complex 6 is generated in the first step, and that the phosphonium ion serves to activate substrate 2a by a general-acid mechanism. Chloride addition is suggested to occur from the thiourea-bound complex, resulting in a highly-ordered enantiodetermining step. Although stilbene-derived aziridines are generally more prone to SN1-type pathways, the observation of high enantioselectivity and in the predominant invertive pathway suggests a common SN2 mechanism for all the aziridines described in this study.

Figure 4
Proposed catalytic cycle for aliphatic aziridine 2a.

In summary, we have a developed a catalytic enantioselective ring-opening reaction of meso aziridines with HCl catalyzed by phosphinothioureas. A broad range of cyclic as well as acyclic substrates undergo clean addition to afford the corresponding β-chlorobenzamide derivatives in high yields and with high enantioselectivities. Investigations of other classes of acidic nucleophiles (HX) and potential electrophiles, as well as more detailed mechanistic studies are underway.

Representative Procedure for Catalytic Enantioselective Ring-Opening Reaction with HCl

To a mixture of catalyst 1m (3.0 mg, 0.005 mmol, 10 mol %) and aziridine 2a (10.1 mg, 0.050 mmol) in Et2O (20 mL, 0.0025 M), HCl (1 M stock solution in Et2O, 60 μL, 0.06 mmol, 1.2 equiv) was added at −78 °C. After 4 h, the solvent was evaporated under reduced pressure, and the residue was purified by automated column chromatography (silica gel, hexane-AcOEt, 19:1 to 3:2) to afford (1R,2R)-N-(2-chlorocyclohexyl)benzamide (3a) (11.6 mg, 0.0488 mmol) in 98% yield as colorless solid. The enantiomeric excess of the product was determined by HPLC analysis to be 83% ee.

IR (neat): 3230, 3059, 2950, 2859, 1635, 1575, 1452, 1330, 1125 cm−1; 1H NMR (CDCl3): δ = 7.78 (d, J = 7.6 Hz, 2H), 7.50 (t, J = 7.6 Hz, 1H), 7.44 (t, J = 7.6 Hz, 2H), 6.18 (brd, J = 4.5 Hz, 1H), 4.06 (ddd, J = 3.8, 9.3, 17.5 Hz, 1H), 3.88 (dt, J = 3.8, 10.5 Hz, 1H), 2.34-2.30 (m, 2H), 1.84-1.74 (m, 3H), 1.52-1.44 (m, 1H), 1.40-1.31 (m, 2H); 13C NMR (CDCl3): δ = 167.2, 134.7, 131.4, 128.5, 127.0, 62.5, 55.6, 36.1, 32.8, 25.4, 24.2; HRMS (ESI): m/z calcd for C13H16ClNNaO [M+Na+]: 260.0813, 262.0783 (chlorine isotope). Found: 260.0810, 262.0782 (chlorine isotope); [α]D23 −54.1 (c = 0.58, CHCl3) (83% ee); HPLC (Daicel Chiralpak AD-H, 2-propanol/hexane 1/10, flow rate 1.0 mL/min, detection at both 210 nm and 254 nm): tR 13.8 min (major) and 23.4 min (minor).


This research was supported by the NIH (GM-43214). T. M. thanks the Japan Society for the Promotion of Science (JSPS) for scholarship support. We thank Mr. Stephan J. Zuend for helpful discussion.

References and Notes

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