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Volumn 73, Issue 4, 2008, Pages 1297-1305

Ytterbium acetate promoted asymmetric reductive amination: Significantly enhanced stereoselectivity

Author keywords

[No Author keywords available]

Indexed keywords

AMINATION; CHIRALITY; STEREOSELECTIVITY;

EID: 39349094370     PISSN: 00223263     EISSN: None     Source Type: Journal    
DOI: 10.1021/jo7021235     Document Type: Article
Times cited : (29)

References (78)
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    • For recent reviews pertaining to α-chiral amine synthesis, see: a
    • For recent reviews pertaining to α-chiral amine synthesis, see: (a) Kukula, P.; Prins, R. Top. Catal. 2003, 25, 29.
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    • Kukula, P.1    Prins, R.2
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    • T. C. Nugent. Chiral Amine Synthesis - Strategies, Examples, and Limitations. In Process Chemistry in the Pharmaceutical Industry, Second Edition, 2: Challenges in an Ever-Changing Climate, Braish, T. F., Gadamasetti, K., Eds.; CRC Press-Taylor and Francis Group: New York, 2007, pp 137-156.
    • (g) T. C. Nugent. Chiral Amine Synthesis - Strategies, Examples, and Limitations. In Process Chemistry in the Pharmaceutical Industry, Second Edition, Vol 2: Challenges in an Ever-Changing Climate, Braish, T. F., Gadamasetti, K., Eds.; CRC Press-Taylor and Francis Group: New York, 2007, pp 137-156.
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    • A noteworthy and valuable exception is the synthesis of aryl-alkyl substituted α-chiral primary amines via a one-pot enantioselective transfer hydrogenation process for the reductive amination of aryl alkyl ketones, see: Kadyrov, R, Riermeier, T. H. Angew. Chem, Int. Ed. 2003, 42, 5472
    • A noteworthy and valuable exception is the synthesis of aryl-alkyl substituted α-chiral primary amines via a one-pot enantioselective transfer hydrogenation process for the reductive amination of aryl alkyl ketones, see: Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003, 42, 5472.
  • 16
    • 39349087276 scopus 로고    scopus 로고
    • The term reductive amination is sometimes incorrectly associated with the reduction of imines and derivatives thereof. Reductive amination is the one-pot conversion of a ketone to an amine. The term indirect reductive amination can be more tersely and accurately described as imine reduction. For literature pertaining to the origins and definition of reductive amination, see: (a) Emerson, W. S. Org. React. 1948, 4, 174
    • The term reductive amination is sometimes incorrectly associated with the reduction of imines and derivatives thereof. Reductive amination is the one-pot conversion of a ketone to an amine. The term "indirect reductive amination" can be more tersely and accurately described as "imine reduction". For literature pertaining to the origins and definition of reductive amination, see: (a) Emerson, W. S. Org. React. 1948, 4, 174.
  • 18
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    • 5th Ed, Smith, M. B, March, J, Eds, John Wiley & Sons, Inc, New York
    • (c) March's Advanced Organic Chemistry, 5th Ed.; Smith, M. B., March, J., Eds.; John Wiley & Sons, Inc.: New York, 2001; pp 1187-1189.
    • (2001) March's Advanced Organic Chemistry , pp. 1187-1189
  • 19
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    • For a lead reference on the intermolecular direct amination of alkanes, see
    • For a lead reference on the intermolecular direct amination of alkanes, see: Lebel, H.; Huard, K. Org. Lett. 2007, 9, 639.
    • (2007) Org. Lett , vol.9 , pp. 639
    • Lebel, H.1    Huard, K.2
  • 26
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    • For recent titanium alkoxide based asymmetric methods, see ref. 1c and: a
    • For recent titanium alkoxide based asymmetric methods, see ref. 1c and: (a) Borg, G.; Cogan, D. A.; Ellman, J. A. Tetrahedron Lett. 1999, 40, 6709.
    • (1999) Tetrahedron Lett , vol.40 , pp. 6709
    • Borg, G.1    Cogan, D.A.2    Ellman, J.A.3
  • 30
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    • For organocatalytic reductive amination, Brønsted acids in combination with a Hantzsch ester, see
    • For organocatalytic reductive amination, Brønsted acids in combination with a Hantzsch ester, see: Storer, R. I.; Carrera, D. E.; Ni, Y.; MacMillan, D. W. C. J. Am. Chem. Soc. 2006, 128, 84.
    • (2006) J. Am. Chem. Soc , vol.128 , pp. 84
    • Storer, R.I.1    Carrera, D.E.2    Ni, Y.3    MacMillan, D.W.C.4
  • 31
    • 39349113238 scopus 로고    scopus 로고
    • L= e.g. -Ar, -i-Pr, -c-hexyl.
    • L= e.g. -Ar, -i-Pr, -c-hexyl.
  • 32
    • 0015620894 scopus 로고    scopus 로고
    • For advances in the diastereoselective reduction of (R)- or (S)-α-MBA ketimines, see: (a) Nichols, D. E.; Barfknecht, C. F.; Rusterholz, D. B. J. Med. Chem. 1973, 16, 480.
    • For advances in the diastereoselective reduction of (R)- or (S)-α-MBA ketimines, see: (a) Nichols, D. E.; Barfknecht, C. F.; Rusterholz, D. B. J. Med. Chem. 1973, 16, 480.
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    • Storace, L.; Anzalone, L.; Confalone, P. N.; Davis, W. P.; Fortunak, J. M.; Giangiordano, M.; Haley, J. J., Jr.; Kamholz, K.; Li, H.-Y.; Ma, P.; Nugent, W. A.; Parsons, R. L., Jr.; Sheeran, P. J.; Silverman, C. E.; Waltermire, R. E.; Wood, C. C. Org. Process Res. Dev. 2002, 6, 54.
    • (k) Storace, L.; Anzalone, L.; Confalone, P. N.; Davis, W. P.; Fortunak, J. M.; Giangiordano, M.; Haley, J. J., Jr.; Kamholz, K.; Li, H.-Y.; Ma, P.; Nugent, W. A.; Parsons, R. L., Jr.; Sheeran, P. J.; Silverman, C. E.; Waltermire, R. E.; Wood, C. C. Org. Process Res. Dev. 2002, 6, 54.
  • 43
    • 0033516455 scopus 로고    scopus 로고
    • For an extensive general review on the use of (R)- or (S)-α-MBA, see: Juaristi, E.; León-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron: Asymmetry 1999, 10, 2441.
    • For an extensive general review on the use of (R)- or (S)-α-MBA, see: Juaristi, E.; León-Romo, J. L.; Reyes, A.; Escalante, J. Tetrahedron: Asymmetry 1999, 10, 2441.
  • 45
    • 39349104486 scopus 로고    scopus 로고
    • 3 (1.1 equiv)], as shown in Table 1, (±)-2-aminooctanane was consistently observed at 6-7 area % (GC).
    • 3 (1.1 equiv)], as shown in Table 1, (±)-2-aminooctanane was consistently observed at 6-7 area % (GC).
  • 46
    • 39349111218 scopus 로고    scopus 로고
    • Note that in this initial study (Table 1, S)-α-MBA was the limiting reagent. The optimal procedures defined for titanium, aluminum, and boron-based reductive aminations require the ketone as the limiting reagent and reliably provides a de of 72% for 2-octanone in THF (without MeOH, see ref 1c. Under those conditions, Ti(OiPr)4 (1.25 equiv) suppresses alcohol formation below 3, In general, B(OiPr) 3 is less efficient at suppressing alcohol byproduct formation; use of more equivalents of B(OiPr)3 (> 1.25 equiv) is then helpful
    • 3 (> 1.25 equiv) is then helpful.
  • 47
    • 39349089182 scopus 로고    scopus 로고
    • All quoted yield data is after chromatography. Alternatively, these compounds can be isolated in near-qualitative purity (GC and 1H NMR) without the need for flash chromatography using the acid/base workup procedure found in the general Experimental Section. Note that during the ammonium chloride washing, the small excess of (R, or (S)-α-MBA preferentially dissolves in the aqueous layer, while the desired and more lipophilic amine product 2 preferentially dissolves in the organic layer. Note: This has not been tested for product 2f. All amine products 2 should be considered as volatile (< 15 carbons) or semivolatile (< 18 carbons) under high vacuum drying or under prolonged rotary evaporation; HCl salt formation (add ethereal HCl) is required for high vacuum drying
    • 1H NMR) without the need for flash chromatography using the acid/base workup procedure found in the general Experimental Section. Note that during the ammonium chloride washing, the small excess of (R)- or (S)-α-MBA preferentially dissolves in the aqueous layer, while the desired and more lipophilic amine product 2 preferentially dissolves in the organic layer. Note: This has not been tested for product 2f. All amine products 2 should be considered as volatile (< 15 carbons) or semivolatile (< 18 carbons) under high vacuum drying or under prolonged rotary evaporation; HCl salt formation (add ethereal HCl) is required for high vacuum drying.
  • 48
    • 39349117223 scopus 로고    scopus 로고
    • We noted after using several bottles of Yb(OAc)3, which is sold and described as a semihydrated form (Sigma-Aldrich catalog no. 544973, that it was sometimes free flowing while other bottles from the same lot were not. As a consequence, 10 g quantities of Yb(OAc)3 were high vacuum dried to constant weight at 80°C (12 h, and Yb(OAc)3 treated in this way was used for the optimal results shown here. In this manuscript, dry Yb(OAc)3 means dried as just stated. The dried Yb(OAc)3 could be stored in a dry screw cap glass bottle at room temperature, and this container could be repeatedly opened to the atmosphere (at least 6 times without detrimental effect) and the desired quantity of Yb(OAc)3 weighed out without the need for a glovebox. In this way, constant and repeatable results were always observed
    • 3 weighed out without the need for a glovebox. In this way, constant and repeatable results were always observed.
  • 49
    • 39349115078 scopus 로고    scopus 로고
    • Curiously, the noted byproduct 2-aminooctane was a racemate (GC analysis of the trifluoroacetamide derivative, excluding the possibility that it originated from a sequential reductive amination of (S)-α-MBA with 2-octanone followed by in situ hydrogenolysis of the product 2d. It also did not originate from the in situ hydrogenolysis of (S)-α-MBA (forming ammonia and ethylbenzene, followed by reductive amination of ammonia with 2-octanone. This is known because ethylbenzene (relative to an authentic reference standard) was never noted (GC) even when taking care to work up the reaction at 0°C with aqueous NaHCO3/EtOAc to avoid evaporation of ethylbenezene bp, 136°C, While [1,3]-proton shifts of imines are known, they are to our knowledge only accomplished under the presence of a strong base; see ref 23. If a [1,3]-proton shift of the initially formed imine occurred, followed by in situ hydrolysis, 2-aminooctane and acetophenone wou
    • 3 suppressed 2-aminooctane formation below 3 area % (GC).
  • 53
    • 39349093957 scopus 로고    scopus 로고
    • 2-Hexanone is quoted as having a 14% unit increase in de (71% vs 85% de); this is based on comparison with entry 9 of Table 3 of this manuscript. If compared to our earlier findings, ref 1c, the increase would be 19% (66% vs 85 % de). In ref 1c, we speculate that the low de of 2-hexanone is not explainable based on the 2-octanone and 2-butanone results shown therein; thus, we believe 14% more accurately reflects the true difference.
    • 2-Hexanone is quoted as having a 14% unit increase in de (71% vs 85% de); this is based on comparison with entry 9 of Table 3 of this manuscript. If compared to our earlier findings, ref 1c, the increase would be 19% (66% vs 85 % de). In ref 1c, we speculate that the low de of 2-hexanone is not explainable based on the 2-octanone and 2-butanone results shown therein; thus, we believe 14% more accurately reflects the true difference.
  • 54
    • 39349113923 scopus 로고    scopus 로고
    • Ketone substrates with an α-quaternary carbon do not undergo reductive amination with Raney-Ni, even under forcing conditions; instead, Pt-C is the catalyst of choice for this class of prochiral ketones. Examination of pinacolone (1b) with Yb(OAc)3/Pt-C/H2 provided a consistent 92% de Table 2, For this Pt substrate, there is no change in de verses the previously best reported method; see ref 15f
    • 2 provided a consistent 92% de (Table 2). For this Pt substrate, there is no change in de verses the previously best reported method; see ref 15f.
  • 55
    • 39349090582 scopus 로고    scopus 로고
    • Examination of aryl alkyl ketones, e.g, acyclic acetophenone or cyclic benzosuberone, or a non-2-alkanone, e.g, isopropyl n-propyl ketone, proved problematic. Acetophenone required higher temperature, 60°C with 120 psi of H2, and produced the product in 92% de but with large amounts of the corresponding alcohol noted (∼20 area, GC, For benzosuberone and isopropyl n-propyl ketone, repeated attempts to obtain the intended product by heating and/or increasing the hydrogen pressure failed. For these substrates, the desired products can be produced in good yield and de using Ti(O-i-Pr)4 instead of Yb(OAc)3; see ref 1c
    • 3; see ref 1c.
  • 56
    • 39349111610 scopus 로고    scopus 로고
    • 3.
    • 3.
  • 57
    • 39349113062 scopus 로고    scopus 로고
    • 3 529559.
    • 3 529559.
  • 58
    • 39349111427 scopus 로고    scopus 로고
    • A second and larger group of Lewis acids, In(OAc)3, Sc(OAc)3, CuOAc, Er(OAc)3, Gd(OAc)3, Dy(OAc)3, AgOAc, Zn(OAc)2, and Cd(OAc)2, emerged as being useful (15 mol , but always provided larger quantities of the alcohol byproduct, typically 5-15 area, by GC analysis. Use of the corresponding chlorides or triflates of the same elements (15 mol , proved detrimental, with >25 area, of the alcohol byproduct forming in most instances. Exceptions to this general observation were noted for Bi(OTf) 3, AgCl, ScCl3, and scandium hexafluoroacetylacetone, which provided 5-15 area, of the alcohol byproduct and/or observably longer reaction times than Yb(OAc)3 (10 mol , Y(OAc)3 (15 mol , or Ce(OAc)3 (15 mol , Initially, 15 mol, of the metalloids Bi(OAc)3 and Sb(OAc)3 were included as useful as Y(OAc)3 or Ce(OAc)3
    • 3 proved uninteresting, implying that coexisting AcOH had catalyzed the earlier reactions.
  • 59
    • 39349112643 scopus 로고    scopus 로고
    • Farina, V.; Grozinger, K.; Müller-Bötticher, H.; Roth, G. P. Ontazolast: The Evolution of a Process. In Process Chemistry in the Pharmaceutical Industry; Gadamasetti, K. G., Ed.; Marcel Dekker, Inc.: New York, 1999; pp 107-124.
    • Farina, V.; Grozinger, K.; Müller-Bötticher, H.; Roth, G. P. Ontazolast: The Evolution of a Process. In Process Chemistry in the Pharmaceutical Industry; Gadamasetti, K. G., Ed.; Marcel Dekker, Inc.: New York, 1999; pp 107-124.
  • 60
    • 39349106270 scopus 로고    scopus 로고
    • An isolated yield was not determined for the reductive amination reaction catalyzed by phosphorous oxychloride
    • An isolated yield was not determined for the reductive amination reaction catalyzed by phosphorous oxychloride.
  • 61
    • 39349118164 scopus 로고    scopus 로고
    • It should be noted that the strong Brønsted acids mentioned here may act as good acid catalysts for the reductive amination of ketone/amine combinations that are less sterically congested as compared to the ketone/ α-MBA combinations shown here
    • It should be noted that the strong Brønsted acids mentioned here may act as good acid catalysts for the reductive amination of ketone/amine combinations that are less sterically congested as compared to the ketone/ α-MBA combinations shown here.
  • 62
    • 39349083287 scopus 로고    scopus 로고
    • It is important to note that little or no alcohol byproduct formation was noted during these incomplete reactions in THF
    • It is important to note that little or no alcohol byproduct formation was noted during these incomplete reactions in THF.
  • 63
    • 39349108478 scopus 로고    scopus 로고
    • When using 20 mol, AcOH with the sterically hindered ketone substrates benzosuberone, 1-phenylbutanone, or isopropyl n-propyl ketone, the effect of temperature (22-50°C) and hydrogen pressure [120-580 psi (8-40 bar, were independently and then concurrently examined; only 1-phenylbutanone provided the desired product and then only in very low yield (20-25 area, GC) after >24 h of reaction. For these types of substrates, the only effective reductive amination conditions are those employing stoichiometric quantities of Ti(OiPr)4; see ref 1c
    • 4; see ref 1c.
  • 70
    • 39349107642 scopus 로고    scopus 로고
    • The Table 5 study employed the optimal reaction conditions (ketone limiting reagent), when the same study was performed, albeit using (S)-α-MBA as the limiting reagent with excess ketone (1.2 equiv), trivial changes in the Table 5 area % numbers were noted.
    • The Table 5 study employed the optimal reaction conditions (ketone limiting reagent), when the same study was performed, albeit using (S)-α-MBA as the limiting reagent with excess ketone (1.2 equiv), trivial changes in the Table 5 area % numbers were noted.
  • 71
    • 39349104663 scopus 로고    scopus 로고
    • 3 for 20-30 min in MeOH (1.0 M), followed by the addition of Raney-Ni (as a slurry in THF, final reaction molarity 0.5) and immediate pressurization with hydrogen.
    • 3 for 20-30 min in MeOH (1.0 M), followed by the addition of Raney-Ni (as a slurry in THF, final reaction molarity 0.5) and immediate pressurization with hydrogen.
  • 72
    • 39349106068 scopus 로고    scopus 로고
    • In our hands, 1H NMR experiments of the ketone, α-MBA, and Yb(OAc)3 in CD3OH proved unhelpful due to the broadening of resonance patterns. The broadening is likely due to the influence of an NMR active isotope of Yb which is paramagnetic. It should be noted that these mixtures are turbid and attempts to filter them and then record the NMR spectrum also failed to provide useful spectroscopic data
    • 3OH proved unhelpful due to the broadening of resonance patterns. The broadening is likely due to the influence of an NMR active isotope of Yb which is paramagnetic. It should be noted that these mixtures are turbid and attempts to filter them and then record the NMR spectrum also failed to provide useful spectroscopic data.
  • 73
    • 39349087673 scopus 로고    scopus 로고
    • Extending the stirring time from 30 min to 12 h, before the onset of hydrogenation, resulted in the same de
    • Extending the stirring time from 30 min to 12 h, before the onset of hydrogenation, resulted in the same de.
  • 74
    • 39349086922 scopus 로고    scopus 로고
    • We also examined the effect of replacing MeOH with THF, but the de dropped to 77, This can be readily explained by the low observed solubility of Yb(OAc)3 in the THF mixture containing the N-(S)-MBA ketimine of 2-octanone, allowing the back round reaction to occur and showing the importance of having MeOH as a cosolvent
    • 3 in the THF mixture containing the N-(S)-MBA ketimine of 2-octanone, allowing the back round reaction to occur and showing the importance of having MeOH as a cosolvent.
  • 75
    • 39349103754 scopus 로고    scopus 로고
    • The origin of the difference in relative free energy for the Newman projections can be further rationalized by noting that the α- methylbenzyl substituent of nitrogen produces a very large steric in the immediate vicinity of nitrogen, while the ytterbium-nitrogen bond will be expected to be longer than the benzylic carbon-nitrogen bond of the α-methyl-benzyl substituent and thereby reduce the immediate steric next to nitrogen. The conclusion, based on the observed substrate de, is that regardless of the level of branching within the R substituent (Scheme 3, there is always a high degree of steric crowding when the α-methylbenzyl substituent is gauche to it Figures 2, gauche-6, This would not always be the case when comparing the steric crowding of the R substituent with a gauche positioned ytterbium. Thus R substituents having only γ-branching might be expected to hav
    • γ = H). These considerations would support the possibility of cis-ketimine to trans-ketimine isomerization for γ-branched and straight-chain 2-alkanones and thereby their enhanced product de, while at the same time explain why α- and β-branched 2-alkanones would not provide enhanced product de.
  • 76
    • 39349091585 scopus 로고    scopus 로고
    • The mechanism presented here (Scheme 3) is more likely than those in which simple ligation of Yb(OAc)3 to the in situ formed cis- and trans-ketimine mixture allows improved facial selectivity for the addition of hydrogen. This is supported by the fact that no other lanthanide or transition metal acetate, chloride, or triflate (over 30 individual metals were examined) was identified as capable of providing enhanced de; and importantly other ytterbium salts, e.g, YbCl3 and Yb(OTf)3, did not allow enhanced diastereoselectivity (Table 1, Furthermore, the rate of reaction is unchanged in the presence Yb(OAc)3, implying that the ligated ketimine is not the species being reduced but instead the free ketimine. Finally, scenarios in which only one of the ketimine diastereomers is ligated to Yb(OAc)3 are unlikely because catalytic quantities of Yb(OAc) 3 do not allow enhanced diastereoselectivity
    • 3 do not allow enhanced diastereoselectivity.
  • 77
    • 39349100798 scopus 로고    scopus 로고
    • 3 (110 mol %) the desired product 2d was noted, albeit without enhanced stereoselectivity.
    • 3 (110 mol %) the desired product 2d was noted, albeit without enhanced stereoselectivity.
  • 78
    • 39349093958 scopus 로고    scopus 로고
    • For references regarding imine formation in general, see ref 1c, p 1291
    • For references regarding imine formation in general, see ref 1c, p 1291.


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