Abstract
A 1:2 mixture of [(S)-2](AuCl)2 [(S)-2 = (S)-3,5-t-Bu-4-MeO-MeOBIPHEP] and AgBF4 catalyzes the stereoconvergent, intermolecular enantioselective hydroamination of chiral, racemic 1,3-disubstituted allenes with N-unsubstituted carbamates to form N-allylic carbamates in good yield, with high regio- and diastereoselectivity, and up to 92% ee.
Keywords: asymmetric synthesis, allenes, amination, Au, stereoselective catalysis
The intermolecular, enantioselective addition of the N–H bond of an amine or carboxamide derivative across a C–C multiple bond (hydroamination) represents an attractive, atom-economical approach to the synthesis of chiral, non-racemic amines and amine derivatives.[1] Within this family of transformations, the intermolecular enantioselective hydroamination (EHA) of allenes is of interest as a potentially expedient route to enantiomerically enriched α-chiral allylic amines, which are important chiral building blocks utilized in the synthesis of complex nitrogen-containing molecules.[2] However, despite considerable effort in this area,[1] effective intermolecular EHA processes are scarce,[3] and the intermolecular EHA of allenes remains unknown.[4]
One of the challenges associated with the intermolecular EHA of allenes is the regioselectivity of extant hydroamination catalysts, which form predominantly achiral products from electronically unbiased monosubstituted allenes.[4,5] To circumvent this regiochemical bias, we envisioned the stereoconvergent, intermolecular EHA of chiral, racemic 1,3-disubstutited allenes catalyzed by chiral bis(gold) phosphine complexes. This approach builds upon our previous efforts in the area of gold-catalyzed allene hydroamination.[6,7] In particular, we have shown that achiral gold(I) NHC complexes catalyze the regio- and diastereoselective hydroamination of chiral 1,3-disubstituted allenes with carbamates, which was superimposed on rapid allene racemization.[6] Furthermore, both we[7] and Toste[8] have demonstrated the enantioselective intramolecular hydroamination of allenes catalyzed by chiral bis(gold) phosphine complexes.[9] Herein we describe the stereoconvergent, enantioselective, intermolecular hydroamination of chiral, racemic 1,3-disubstituted allenes with carbamates catalyzed by chiral bis(gold) phosphine complexes.[10]
Initial experiments directed toward the intermolecular EHA of allenes were only modestly encouraging and reaction of benzyl carbamate (0.72 M) with 1-phenyl-1,2-butadiene (1; 1 equiv) catalyzed by a 1:2 mixture of [(R)-2](AuCl)2 [(R)-2 = (R)-DTBM-MeOBIPHEP] and AgOTf in dioxane at 24 °C for 24 h led to isolation of N-allylic carbamate (R)-3a in 35% yield as a single diastereomer (≥25:1) with 50% ee (Table 1, entry 1).[11,12] Substitution of ligand (R)-2 with the SEGPHOS ligand (R)-4 led to deterioration in both the yield and enantioselectivity of hydroamination (Table 1, entry 2). Conversely, optimization with respect to silver salt revealed that substitution of AgBF4 for AgOTf led to marked improvement in both yield and enantioselectivity of gold-catalyzed allene hydroamination (Table 1, entry 7). The reaction yield was further improved through employment of a slight excess of allene relative to benzyl carbamate and, in an optimized procedure, treatment of benzyl carbamate (0.72 M) with 1 (1.5 equiv) and a catalytic 1:2 mixture of [(S)-2](AuCl)2 and AgBF4 in dioxane at 24 °C led to isolation of (S)-3a in 89% yield with 72% ee (Table 1, entry 10). A single recrystallization from warm hexanes increased the enantiopurity of (S)-3a to 96% ee.
Table 1.
Effect of supporting ligand, solvent, silver salt and allene concentration on the gold(I)-catalyzed enantioselective hydroamination of 1 with benzyl carbamate.
 | ||||||
|---|---|---|---|---|---|---|
| entry | P–P | AgX | solvent | yield (%)[a] | ee (%) | config |
| 1 | (R)-2 | AgOTf | dioxane | 35 | 50 | R |
| 2 | (R)-4 | AgOTf | dioxane | 15 | 44 | R |
| 3 | (S)-2 | AgSbF6 | dioxane | 20 | 60 | S |
| 4 | (S)-2 | AgPF6 | dioxane | 12 | 66 | S |
| 5 | (S)-2 | AgClO4 | dioxane | 49 | 63 | S |
| 6 | (S)-2 | AgNTf2 | dioxane | 20 | 45 | S |
| 7 | (S)-2 | AgBF4 | dioxane | 71 | 72 | S |
| 8 | (S)-2 | AgBF4 | toluene | 65 | 50 | S |
| 9[b] | (S)-2 | AgBF4 | THF | 36 | 61 | S |
| 10[c] | (S)-2 | AgBF4 | dioxane | 89 | 72[d] | S |
 | ||||||
Isolated yield; dr ≥25:1.
[1] = [H2NCbz] = 0.4 M, 48 h, GC yield.
[1] = 1.1 M.
96% ee after recrystallization.
In addition to benzyl carbamate, methyl carbamate, 9-fluorenylmethyl carbamate, and trichloroethyl carbamate underwent gold-catalyzed reaction with 1 to form N-allylic carbamates 3b-3d with enantiopurities comparable to that of 3a (Table 2, entries 1–3).[13] Likewise, gold-catalyzed intermolecular EHA was effective for a number of 1-aryl-1,2-butadienes (Table 2, entries 4–13). For example, gold(I)-catalyzed reaction of benzyl carbamate with p-substituted 1-aryl-1,2-butadienes 5a-5d led to isolation of N-allylic carbamates 6a-6d in 82–99% yield with 60–76% ee, albeit without a clear relationship between arene electron donicity and enantioselectivity (Table 2, entries 4–7). Also worth noting is that the enantiopurity of 6d increased from 69% ee to 99% ee after a single recrystallization from warm hexanes (Table 2, entry 7). In comparison, gold-catalyzed hydroamination of the more sterically hindered o-substituted 1-aryl-1,2-butadienes 5e-5h formed N-allylic carbamates 6e-6h with 80–86% ee (Table 2, entries 8–11). Gold(I)-catalyzed intermolecular hydroamination of the more sterically hindered o,o-disubstituted 1-aryl-1,2-butadiene 5i occurred with even higher enantioselectivity (92% ee) but with diminished yield (Table 2, entry 12). Gold-catalyzed intermolecular EHA was not restricted to 1-aryl-1,2-butadienes and gold-catalyzed reaction of 1,3-dialkyl substituted allene 7 with benzyl carbamate led to isolation of N-allylic carbamate 8 in 94% yield with 68% ee (eq 1). Conversely, gold-catalyzed intermolecular EHA was not effective for 1,3-disubstituted allenes lacking a methyl substituent.[14]
Table 2.
Enantioselective hydroamination of allenes (1.1 M) with carbamates (0.71 M) catalyzed by a mixture of [(S)-2](AuCl)2 (2.5 mol %) and AgBF4 (5 mol %) in dioxane at room temperature.
 | |||||
|---|---|---|---|---|---|
| Entry | Ar | R[a] | Product | Yield [%][b] | ee [%][c] |
| 1 | Ph (1) | CO2Me | 3b | 81 | 69 |
| 2 | Ph (1) | Fmoc | 3c | 79 | 71 |
| 3 | Ph (1) | Troc | 3d | 43 | 73 |
 |
|||||
| 4 | X = Me (5a) | Cbz | 6a | 97 | 72 |
| 5 | X = OMe (5b) | Cbz | 6b | 85 | 60 |
| 6 | X = CF3 (5c) | Cbz | 6c | 82 | 76 |
| 7 | X = Br (5d) | Cbz | 6d | 99 | 69[d] |
 |
|||||
| 8 | X = Me (5e) | Cbz | 6e | 82 | 81 |
| 9[e] | X = i-Pr (5f) | Cbz | 6f | 80 | 81 |
| 10 | X = Ph (5g) | Cbz | 6g | 86 | 86 |
| 11 | X = Br (5h) | Cbz | 6h | 69 | 80 |
| 12[e] |  |
Cbz | 6i | 42 | 92 |
| 13[e] |  |
Cbz | 6j | 44 | 72 |
Cbz = benzyloxycarbonyl, Troc = 2,2,2-trichloroethoxycarbonyl, Fmoc = fluorenylmethyloxycarbonyl.
Isolated yield; dr ≥25:1.
Enantiomeric excess determined by HPLC analysis on chiral support. Absolute configuration assigned as S based on analogy to (S)-3a.[11]
99% ee after recrystallization.
Reaction run for 48 h.
 |
eq 1 |
Congruent with our expectations, allene racemization occurred rapidly under reaction conditions. For example, periodic analysis of a solution of enantiomerically enriched (S)-5b (89% ee), benzyl carbamate, and a catalytic mixture of [(S)-2](AuCl)2 and AgBF4 employing chiral stationary phase HPLC revealed complete racemization of (S)-5b prior to any detectable formation of 6b (≤5 min; Table 3). Interestingly, continued analysis of the reaction mixture showed that the enantiopurity of 6b decreased from 69% ee at 21% conversion to a terminal value of 59% ee at ≥74% conversion (Table 3). This phenomenon was not restricted to the formation of 6b and the enantiopurity of 3a formed in the gold-catalyzed reaction of 1 with benzyl carbamate likewise decreased from 78% ee at 22% conversion to a terminal value of 72% ee at ≥83% conversion.
Table 3.
Enantiopurity of allene and N-allylic carbamate as a function of conversion for the gold-catalyzed hydroamination of (S)-5b (89% ee).
 | |||
|---|---|---|---|
| Time [h] | Convn [%] | 5b ee [%] | 6b ee [%] |
| Š0.08 | Š2 | Š2 | –– |
| 1 | 21 | Š2 | 69 |
| 1.5 | 39 | Š2 | 65 |
| 2.0 | 44 | Š2 | 63 |
| 4.0 | 74 | Š2 | 59 |
| 5.0 | 81 | Š2 | 58 |
| 6.0 | >90 | Š2 | 59 |
Although we initially considered that racemization of 3a or 6b under reaction conditions was responsible for the conversion-dependent enantioselectivity displayed by the gold-catalyzed intermolecular EHA of 1 or 5b, respectively, this possibility was excluded. For example, stirring a solution of (S)-3a (72% ee) and a catalytic 1:2 mixture of [(S)-2](AuCl)2 and AgBF4 at room temperature for 8 h either in the presence (1 equiv) or absence of benzyl carbamate led to no detectable decrease in the enantiopurity of (S)-3a (eq 2). Rather, a pair of experiments pointed to the potentially deleterious effect of the N-allylic carbamate product on the enantioselectivity of intermolecular EHA. For example, treatment of a 1.5:1:1 mixture of 1, benzyl carbamate, and (S)-6c with a catalytic mixture of [(S)-2](AuCl)2/AgBF4 at 24 °C for 24 h led to isolation of (S)-3a in 75% yield with 74% ee (Scheme 1), which is nominally higher enantioselectivity than was realized in the absence of (S)-6c (Table 1, entry 10). However, the corresponding reaction of 1, benzyl carbamate, and (S)-6c catalyzed by [(R)-2](AuCl)2/AgBF4 led to isolation of (R)-3a in 71% yield with 62% ee (Scheme 1), which is considerably lower enantioselectivity than was observed in the absence of (S)-6c.
Scheme 1.
 |
eq 2 |
Rapid allene racemization precluded stereochemical analysis of the gold-catalyzed intermolecular EHA of (S)-5b (Table 3). However, we have previously established the anti-stereochemistry of gold(I)-catalyzed intramolecular enantioselective allene hydrofunctionalization,[7,15] which is consistent with the outer-sphere addition of the nucleophile to a gold(I) π-allene complex. Although such a mechanism implicates one of the two gold centers of a bis(gold) catalyst in the allene activation/C–N bond formation process, there is no firm evidence that supports the direct participation of the second gold center in these steps.[10,16] There is, however, evidence that the ligation state of this spectator gold center can affect the enantioselectivity of gold-catalyzed hydrofunctionalization.[8] Given the non-coordinating nature of the BF4− counterion employed in the gold-catalyzed intermolecular EHA of allenes, the spectator gold center is presumably ligated with an allene, benzyl carbamate, or either enantiomer of the N-allylic carbamate product.[17] Therefore, the decreasing enantioselectivity of the gold-catalyzed intermolecular EHA of allenes with increasing conversion presumably reflects the increasing concentration of a less selective N-allylic carbamate ligated catalyst species.
In summary, we have developed a gold(I)-catalyzed protocol for the stereoconvergent, intermolecular enantioselective hydroamination of chiral, racemic 1,3-disubstituted allenes with N-unsubstituted carbamates. In addition, the enantioselectivity versus conversion behavior of intermolecular EHA coupled with independent analysis of the effect of N-allylic carbamate on the enantioselectivity of these transformations suggests that the nature of the catalytically active species changes with increasing concentration of N-allylic carbamate. We continue to work toward the identification of more selective and more general catalytic systems for intermolecular EHA and toward the development of ligand-modulated enantioselective gold catalysis.
Acknowledgments
We thank the NIH (GM-080422) for support of this research. KLB was supported in part through a Charles Bradsher Fellowship (Duke University) and MT was supported in part through a Marco Polo Fellowship (Alma Mater Studiorum - University of Bologna).
Footnotes
Supporting information for this article is available on the WWW under http://www.angewandte.org or from the author.
References
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