# Patent

## Title
Methods of preparing tertiary carbinamine compounds

## Abstract

The present invention relates to a method for the preparation of tertiary carbinamine compounds from diastereoselective allylation and crotylation of N-unsubstituted imines derived from ketones.

## Background
The present application claims the benefit of priority under 35 U.S.C. §119(e) from U.S. provisional patent application No. 60/828,288, filed Oct. 5, 2006.


FIELD OF THE INVENTION
The present invention relates to a method for the preparation of tertiary carbinamine compounds, particularly the preparation of tertiary carbinamine compounds, from diastereoselective allylation and crotylation of N-unsubstituted imines derived from ketones.
BACKGROUND OF THE INVENTION
Research into the addition of allyl organometallics to carbonyl compounds and their derivatives continues to proceed unabated—a consequence of the fact that the resulting homoallylic products have proven to be valuable synthons [S. E. Denmark and N. G. Almstead, Modern Carbonyl Chemistry, ed. J. Otera, Wiley-VCH, Weinheim, 2000, ch. 10; Y. Yamamoto and N. Asao, Chem. Rev., 1993, 93, 2207; and W. R. Roush, Comprehensive Organic Synthesis, ed. B. M. Trost, I. Fleming and C. H. Heathcock, Pergamon, Oxford, 2nd edn., 1991, vol. 2, pp 1-53]. The majority of the research, however, has focused on the addition of these organometallics to aldehydes. For example, the reaction of




has previously been described by Kobayashi et al. [M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182; S. Kobayashi, K. Hirano, M. Sugiura, Chem. Commun., 2005, 104].

Although to a lesser extent, there have been some recent examples of allylation of ketones [L. F. Tietze, K. Schiemann, C. Wegner and C. Wulff, Chem. Eur. J., 1998, 4, 1862; S. Casolari, D. D'Addario and E. Tagliavini, Org. Lett., 1999, 1, 1061; R. Hamasaki, Y. Chounan, H. Horino and Y. Yamamoto, Tetrahedron Lett., 2000, 41, 9883; R. M. Kamble and V. K. Singh, Tetrahedron Lett., 2001, 42, 7525; J. G. Kim, K. M. Waltz, I. F. Garcia, D. Kwiatkowski and P. J. Walsh, J. Am. Chem. Soc., 2004, 126, 12580; T. R. Wu, L. Shen and J. M. Chong, Org. Lett., 2004, 6, 2701; and Y.-C. Teo, J.-D. Goh and T.-P. Loh, Org. Lett., 2005, 7, 2743]. Until recently, the expansion of the substrate scope to include imines and their derivatives had received limited attention. Some recent examples of the addition of allylorganometallics to aldimine derivatives can be found in the following references [C. Bellucci, P. G. Cozzi and A. Umani-Ronchi, Tetrahedron Lett., 1995, 36, 7289; H. Nakamura, K. Nakamura and Y. Yamamoto, J. Am. Chem. Soc., 1998, 120, 4242; F. Fang, M. Johannsen, S. Yao, N. Gathergood, R. G. Hazell and K. A. Jørgensen, J. Org. Chem., 1999, 64, 4844; T. Gastner, H. Ishitani, R. Akiyama and S. Kobayashi, Angew. Chem., Int. Ed., 2001, 40, 1896; H. C. Aspinall, J. S. Bissett, N. Greeves and D. Levin, Tetrahedron Lett., 2002, 43, 323; M. Sugiura, F. Robvieux and S. Kobayashi, Synlett, 2003, 1749; R. A. Fernandes and Y. Yamamoto, J. Org. Chem., 2004, 69, 735; S.-W. Li and R. A. Batey, Chem. Commun., 2004, 1382; I. Shibata, K. Nose, K. Sakamoto, M. Yasuda and A. Baba, J. Org. Chem., 2004, 69, 2185; and C. Ogawa, M. Sugiura and S. Kobayashi, Angew Chem., Int. Ed., 2004, 43, 6491]. As for the addition of allylorganometallics to ketimine derivatives, some recent examples have also been reported [C. Ogawa, M. Sugiura and S. Kobayashi, J. Org. Chem., 2002, 67, 5359; S. Yamasaki, K. Fujii, R. Wada, M. Kanai and M. Shibasaki, J. Am. Chem. Soc., 2002, 124, 6536; R. Berger, K. Duff and J. L. Leighton, J. Am. Chem. Soc., 2004, 126, 5686; H. Ding and G. K. Friestad, Synthesis, 2004, 2216].
However, there is yet no known synthetic methodology for the preparation of tertiary carbinamine compounds through diastereoselective allylation and crotylation of N-unsubstituted ketimines. New methodologies to solve the difficulties associated with making these valuable tertiary carbinamine compounds will no doubt have a tremendous impact in organic synthesis and in the chemical industry. New methodologies may also provide a new class of tertiary carbinamine compounds that cannot be obtained using conventional protocols. For example, the recent report of aminoallylation of aldehydes by Kobayshi and coworkers has already had a tremendous impact in organic synthesis [M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182; S. Kobayashi, K. Hirano, M. Sugiura, Chem. Commun., 2005, 104].
SUMMARY OF THE INVENTION
A new method for the preparation of tertiary carbinamine compounds from the diastereoselective allylation and crotylation of in situ generated N-unsubstituted ketimines has been developed. The method has been shown to provide the homoallylic amines in good to excellent yields through simple acid-base extraction. Also, the crotylation of N-unsubstituted ketimines has been shown to be highly diastereoselective.
Accordingly, the present invention relates to a method of preparing an amine of the formula Ia and/or Ib comprising reacting a compound of formula II with a compound of formula III:




wherein

R1 and R2 are independently selected from C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, all of which are optionally substituted and one or more of the carbons in C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl and C3-20cycloalkoxy is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11;

or

R1 and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms including the carbonyl to which R1 and R2 are bonded, and one or more of the carbons of the ring system is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11;

R3 to R7 are independently selected from H, C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups being optionally substituted and one or more of the carbons in C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl and C3-20cycloalkoxy, is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11;

R8 and R9 are independently selected from H, C1-20alkyl, C3-20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted;

or

R8 and R9 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms, including the B and O atoms to which R8 and R9 are bonded;

R10 and R11 are independently selected from H, C1-20alkyl, C3-20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted,

in the presence of ammonia NH3 or an ammonia equivalent of the formula NH4+X−, wherein X is an anionic ligand.

Other features and advantages of the present invention will become apparent from the following detailed description. It should be understood, however, that the detailed description and the specific examples while indicating preferred embodiments of the invention are given by way of illustration only, since various changes and modifications within the spirit and scope of the invention will become apparent to those skilled in the art from this detailed description.


DETAILED DESCRIPTION OF THE INVENTION
It has been demonstrated for the first time that tertiary carbinamine compounds can be efficiently and effectively generated through diastereoselective allylation and crotylation of N-unsubstituted imines that are derived from a diverse range of ketones. The method has been shown to be a simple three-component reaction of a ketone, excess ammonia or ammonia salt and an allylorganometallic reagent.
Accordingly, the present invention relates to a method of preparing an amine of the formula Ia and/or Ib comprising reacting a compound of formula II with a compound of formula III:




wherein

R1 and R2 are independently selected from C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, all of which are optionally substituted and one or more of the carbons in C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl and C3-20cycloalkoxy, is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11;

or

R1 and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms including the carbonyl to which R1 and R2 are bonded, and one or more of the carbons of the ring system is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11;

R3 to R7 are independently selected from H, C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups being optionally substituted and one or more of the carbons in C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl and C3-20cycloalkoxy is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11;

R8 and R9 are independently selected from H, C1-20alkyl, C3-20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted;

or

R8 and R9 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms, including the B and O atoms to which R8 and R9 are bonded;

R10 and R11 are independently selected from H, C1-20alkyl, C3-20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted,

in the presence of ammonia NH3 or an ammonia equivalent of the formula NH4+X−, wherein X is an anionic ligand.

The term “C1-nalkyl” as used herein means straight and/or branched chain alkyl groups containing from one to n carbon atoms and includes, depending on the identity of n, methyl, ethyl, propyl, isopropyl, t-butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, hexadecyl, octadecyl, icosyl and the like and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term “C3-ncycloalkyl” as used herein means saturated cyclic or polycyclic alkyl groups containing from three to n carbon atoms and includes, depending on the identity of n, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, cyclodecyl, cycloundecyl, cyclododecyl, cyclohexadecyl, cyclooctadecyl, cycloicosyl, adamantyl and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term “C1-nalkoxy” as used herein means straight and/or branched chain alkoxy groups containing from one to n carbon atoms and includes, depending on the identity of n, methoxy, ethoxy, propyoxy, isopropyloxy, t-butoxy, pentoxy, hexoxy, heptoxy, octoxy, nonoxy, decoxy, undecoxy, dodecoxy, hexadecoxy, octadecoxy, icosoxy and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term “C3-ncycloalkoxy” as used herein means saturated cyclic or polycyclic alkyoxy groups containing from three to n carbon atoms and includes, depending on the identity of n, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, cycloheptoxy, cyclooctoxy, cyclononoxy, cyclodecoxy, cycloundecoxy, cyclododecoxy, cyclohexadecoxy, cyclooctadecoxy, cycloicosoxy and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term “C2-nalkenyl” as used herein means straight and/or branched chain alkenyl groups containing from two to n carbon atoms and one to six double bonds and includes, depending on the identity of n, vinyl, allyl, 1-butenyl, 2-hexenyl and the like, and wherein n is an integer representing the maximum number of carbon atoms in the group.
The term “aryl” as used herein means a monocyclic or polycyclic carbocyclic ring system containing one or two aromatic rings and from 6 to 14 carbon atoms and includes phenyl, naphthyl, anthraceneyl, 1,2-dihydronaphthyl, 1,2,3,4-tetrahydronaphthyl, fluorenyl, indanyl, indenyl and the like.
The term “heteroaryl” as used herein means mono- or polycyclic heteroaromatic radicals containing from 5 to 14 atoms, of which 1 to 4 atoms are a heteroatom selected from nitrogen, oxygen and sulfur and includes furanyl, thienyl, pyrrolo, pyridyl, indolo, benzofuranyl and the like.
The term “halo” as used herein means halogen and includes chloro, fluoro, bromo and iodo.
The term “one or more” as used herein means that from one to the maximum allowable substitutions are allowed.
The present invention includes combinations of groups and substituents that are permitted and would provide a stable chemical entity according to standard chemical knowledge as would be known to those skilled in the art.
The term “polycyclic” or “ring system” as used herein means a cyclic group containing more than one ring in its structure, and includes bicyclic, tricyclic, bridged and spiro ring systems and the like.
It is an embodiment of the invention that the compounds of formulae Ia, Ib and II include those in which R1 and R2 are independently selected from C1-10alkyl, C2-10alkenyl, aryl and heteroaryl, all of which are optionally substituted. In a further embodiment of the invention, R1 and R2 in the compounds of the formulae Ia, Ib and II are independently selected from methyl, ethyl, propyl, butyl, pentyl, ethene, styrene, phenyl, benzyl, thiophene and indole, all of which are optionally substituted.
It is another embodiment of the invention that the compounds of formulae Ia, Ib and II include those in which R1 and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 6 to 16 carbon atoms including the carbonyl to which R1 and R2 are bonded. In a further embodiment of the invention, one or more of the carbons of this ring system is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11, in which R10 and R11 are independently selected from H, C1-6alkyl and aryl. In a still further embodiment of the invention, R1 and R2 in the compounds of the formulae Ia, Ib and II are linked to form a ring system selected from cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene and fluorene, all of which are optionally substituted, and/or one or more of the carbons of cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene or fluorene is optionally replaced with a heteromoiety selected from O, S, N and NR10; in which R10 is H or benzyl.
In an embodiment of the invention, the optional substituents on R1 and R2 in the compounds of the formulae Ia, Ib and II are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl. More particularly, in another embodiment of the invention, the optional substituents on R1 and R2 in the compounds of the formulae Ia, Ib and II are independently selected from OH, F, Cl, Br, CN, NO2, phenyl and C1-4alkyl. Still more particularly, the optional substituents on R1 and R2 in the compounds of the formulae Ia, Ib and II further comprise at least one stereocenter.
It is an embodiment of the invention that R3 to R7 in the compounds of the formulae Ia, Ib and III are independently selected from H, C1-10alkyl, C3-12cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted. In another embodiment of the invention, one or more of the carbons in C1-10alkyl and C3-10cycloalkyl is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11 in which R10 and R11 are independently selected from H and C1-6alkyl. In a particular embodiment of the invention, R3 to R7 in the compounds of the formulae Ia, Ib and III are independently selected from H and C1-6alkyl. In a more particular embodiment of the invention, R3 to R7 in the compounds of the formulae Ia, Ib and III are independently selected from H and methyl. Still further, in an embodiment of the invention, the optional substituents on R3 and R7 in the compounds of the formulae Ia, Ib and III are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl.
It is an embodiment of the invention that R3 and R9 in the compound of the formula III are independently selected from H, C1-10alkyl, C3-12cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted. In a more particular embodiment of the invention, R8 and R9 in the compound of the formula III are independently selected from H or C1-6alkyl. In another embodiment of the invention, R8 and R9 in the compound of the formula III are linked to form an optionally substituted monocyclic or polycyclic ring system having 5 to 12 atoms, including the B and O atoms to which R8 and R9 are bonded. In a more particular embodiment of the invention, R8 and R9 in the compound of the formula III are linked to form an optionally substituted monocyclic or bicyclic ring system having 5 to 12 atoms, including the B and O atoms to which R8 and R9 are bonded. It is an embodiment of the invention that the optional substituents on R8 and R9 in the compound of the formula III are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl. Still further, it is an embodiment of the invention that the optional substituent on R8 and R9 in the compound of the formula III is C1-4alkyl.
In an embodiment of the invention, the method is performed in the presence of ammonia. In yet another embodiment of the invention, the method is performed in the presence of an ammonia salt NH3+X− in which X is an anionic ligand. In a further embodiment of the invention, X is selected from halo, R12COO, R12SO4 and BF4 in which R12 is selected from C1-10alkyl, C3-20cycloalkyl, aryl and heteroaryl, all of which are optionally substituted. In an embodiment of the invention, X is selected from Cl, Br, R12COO, R12SO4 and BF4 and in which R12 is selected from C1-4alkyl, C3-12cycloalkyl, aryl and heteroaryl, all of which are optionally substituted. In a still further embodiment of the invention, the optional substituents on R12 are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl.
In an embodiment of the invention, the method is performed in an inert organic solvent. More particularly, the organic solvent is selected from methanol, ethanol, propanol, butanol, toluene, tetrahydrofuran, acetonitrile, benzene, methylene chloride. Still more particularly, the organic solvent is methanol.
Also within the scope of the invention, the method is performed at room temperature or above or below room temperature for example at a temperature of from −40° C. to 100° C., suitably 0° C. to 50° C. more suitably 10° C. to 30° C. Suitably, the method is performed at room temperature. A person skilled in the art would appreciate that the reaction temperature may vary depending on a number of variables, including, but not limited to the structure of the starting materials (compounds of formulae II and III), the solvent, reaction pressure and the choice of ammonia or ammonia equivalent. A person skilled in the art would be able to optimize the reaction temperature to obtain the best yields and overall performance of the reaction.
Although there are a number of methods which have been surveyed to synthesize and isolate N-unsubstituted ketimines of the compound of the formula IV [P. L. Pickard and T. L. Tolbert, J. Org. Chem., 1961, 26, 4886; D. R. Boyd, K. M. McCombe and N. D. Sharma, Tetrahedron Lett., 1982, 23, 2907; A. J. Bailey and B. R. James, Chem. Commun., 1996, 2343; Y. Bergman, P. Perlmutter and N. Thienthong, Green Chem., 2004, 6, 539; and R. W. Layer, Chem. Rev., 1963, 63, 489], the present inventors have found that the three-component reaction of the ketone of the compound of the formula II, excess ammonia and the allylorganometallic of the compound of the formula III was the most efficient and effective protocol to generate the desired homoallylic amines of the compounds of formulae Ia and Ib (Scheme I).




While not wishing to be limited by theory, it is believed that the N-unsubstituted ketimine of the compound of formula IV is formed in situ prior to its reaction with the allylorganometallic of the compound of formula III [M. Sugiura, K. Hirano and S. Kobayashi, J. Am. Chem. Soc., 2004, 126, 7182; S. Kobayashi, K. Hirano, M. Sugiura, Chem. Commun., 2005, 104; B. Davis, J. Labelled Compd. Radiopharm., 1987, 24, 1221; and N. Haider, G. Heinisch, I. Kurzmann-Rauscher and M. Wolf, Liebigs Ann. Chem., 1985, 167]. The addition of a series of allyl organometallics to the in situ generated ketimine of the compound of formula IV (R1=4-BrC6H4, R2=Me) have been investigated.

The following non-limiting examples are illustrative of the present invention:
EXAMPLES
Materials and Methods
All ketones in liquid form were distilled prior to use. All ketones in solid form were used as received. All other reagents were used as received (Aldrich, Acros, Strem). MeOH was dried over magnesium methoxide and distilled prior to use. 2 M solutions of allyl, (E)- and (Z)-crotylboronic acid in anhydrous MeOH were prepared just prior to use (exact molarities were confirmed by titration with benzaldehyde) [H. C. Brown, U.S. Racherla and P. J. Pellechia, J. Org. Chem., 1990, 55, 1868].
Melting points were uncorrected and were measured on a Fisher-Johns melting point apparatus. 1H and 13C NMR were recorded at 300 or 500 MHz and 75 or 125 MHz respectively on a Bruker Spectrospin 300 or 500 MHz spectrometer. Proton chemical shifts were internally referenced to the residual proton resonance in CDCl3 (δ 7.26). Carbon chemical shifts were internally referenced to the deuterated solvent signals in CDCl3 (δ 77.00). Infrared spectra were obtained on a Bruker VECTOR22 FT-IR spectrometer. HRMS-Cl and HRMS-ESI were performed on a Waters/Micromass GCT time-of-flight mass spectrometer and a Waters/Micromass Q-TOF Global quadrupole time-of-flight mass spectrometer respectively.
Example 1
General Procedure for the Allylation of N-Unsubstituted Imines Derived from Ketones
To the ketone (0.5 mmol) was added a solution of ammonia in methanol (ca. 7M in MeOH, 0.75 mL, ca. 10 equiv.). The resulting solution was stirred for 15 min at rt. A freshly prepared solution of allylboronic acid (5e) (2M in MeOH, 0.4 ml, 0.8 mmol) was then added dropwise over 5 min. The reaction mixture was subsequently stirred for 16 h at rt. All volatiles were removed in vacuo and the residue re-dissolved in Et2O (15 mL). The desired amine was then extracted with 1 N HCl (15 ml). The acidic aqueous extract was washed with Et2O (3×15 mL). The aqueous extract was next made alkaline by addition of solid NaOH (ca. 5 g). The alkaline aqueous layer was then extracted with dichloromethane (3×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated in vacuo to afford the desired tertiary carbamine (6).
(i) 1-(4-Bromophenyl)-1-methylbut-3-enylamine (6a)




6a was isolated as a clear, colorless oil: 1H NMR (CDCl3, 500 MHz) δ 7.44 (2H, d, J=8.5 Hz), 7.35 (2H, d, J=8.5 Hz), 5.55 (1H, dddd, J=18.0, 9.5, 8.0, 7.0 Hz), 5.09-5.04 (2H, m), 2.53 (1H, dd, J=13.5, 7.0 Hz), 2.38 (1H, dd, J=13.5, 8.0 Hz), 1.49 (2H, br s), 1.44 (3H, s); 13C NMR (CDCl3, 125 MHz) δ 147.79, 133.89, 131.14, 127.26, 120.12, 118.81, 54.45, 49.64, 30.93; IR (film)  3423, 1638 cm−1; HRMS (Cl) m/z calcd. for C11H15BrN (MH+) 240.0388, found 240.0395.
(ii) 1,1-Diethylbut-3-enylamine (6b)




6b was isolated as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.77 (1H, ddt, J=16.0, 11.0, 7.5 Hz)), 5.04 (1H, d, J=11.0 Hz), 5.03 (1H, d, J=16.0 Hz), 2.03 (2H, d, J=7.5 Hz), 1.32 (4H, q, J=7.5 Hz), 1.18 (2H, br s), 0.81 (6H, t, J=7.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 134.44, 117.69, 53.36, 43.85, 31.66, 7.70; IR (film) ν 3420, 1636 cm−1; HRMS (ESI) m/z calcd. for C8H18N (MH+) 128.1439, found 128.1444.
(iii) 2-Amino-2-methylpent-4-en-1-ol (6c)




6c was isolated as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.79 (1H, ddt, J=16.5, 10.5, 7.5 Hz), 5.12-5.01 (2H, m), 3.30 (1H, d, J=10.5 Hz), 3.25 (1H, d, J=10.5 Hz), 2.45 (3H, br s), 2.11 (2H, d, J=7.5 Hz), 1.01 (3H, s); 13C NMR (CDCl3, 75 MHz) δ 133.77, 118.51, 68.07, 52.70, 44.28, 24.53; IR (film) ν 0.3345, 3157, 1639 cm−1; HRMS (Cl) m/z calcd. for C6H14NO (MH+) 116.1075, found 116.1072.
(iv) 1-Benzyl-1-phenylbut-3-enylamine (6d)




6d was isolated as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.38-7.08 (8H, m), 6.90-6.84 (2H, m), 5.53 (1H, dddd, J=17.0, 10.0, 8.5, 5.5 Hz), 5.15-5.00 (2H, m), 3.12 (1H, d, J=13.0 Hz), 2.97 (1H, d, J=13.0 Hz), 2.86 (1H, dd, J=13.5, 5.5 Hz), 2.44 (1H, dd, J=13.5, 8.5 Hz), 1.50 (2H, brs); 13C NMR (CDCl3, 75 MHz) δ 146.52, 137.09, 134.08, 130.68, 128.07, 127.86, 126.46, 126.30, 126.19, 118.81, 57.97, 50.54, 47.62; IR (film)  3401, 1677 cm−1; HRMS (ESI) m/z calcd. for C17H20N (MH+) 238.1596, found 238.1585.
(v) 1-Methyl-1-(3-methylbutyl)but-3-enylamine (6e)




6e was isolated as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ 5.74 (1H, ddt, J=17.0, 10.0, 7.5 Hz), 5.05-4.93 (2H, m), 2.00 (2H, d, J=7.5 Hz), 1.40 (1H, septet, J=6.5 Hz), 1.29-1.20 (2H, m), 1.19-1.03 (4H, m), 0.95 (3H, s), 0.80 (6H, d, J=6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 134.50, 117.77, 51.14, 47.15, 40.36, 32.82, 28.45, 27.71, 22.53; IR (film) 3385, 1636 cm−1; HRMS (ESI) m/z calcd. for C10H22N (MH+) 156.1752, found 156.1745.
(vi) 1-Ethyl-1-(4-Methoxyphenyl)but-3-enylamine (6f)




6f was isolated as a clear, colorless oil: 1H NMR (CDCl3, 500 MHz) δ 7.31 (2H, d, J=9.0 Hz), 6.86 (2H, d, J=9.0 Hz), 5.53 (1H, dddd, J=17.5, 10.0, 8.5, 6.0 Hz), 5.06 (1H, d, J=17.5 Hz), 5.03 (1H, d, J=10.0 Hz), 3.80 (3H, s), 2.59 (1H, dd, J=13.5, 6.0 Hz), 2.36 (1H, dd, J=13.5, 8.5 Hz), 1.85 (1H, dq, J=14.0, 7.5 Hz), 1.66 (1H, dq, J=14.0, 7.5 Hz), 1.52 (2H, br s), 0.71 (3H, t, J=7.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 157.72, 138.66, 134.32, 126.93, 118.34, 113.27, 57.06, 55.16, 48.37, 36.05, 8.04; IR (film) 3420, 1638, 1610, 1511, 1248 cm−1; HRMS (Cl) m/z calcd. for C13H20NO (MH+) 206.1545, found 206.1565.
(vii) 4-(1-Amino-1-methylbut-3-enyl)benzonitrile (6g)




6g was isolated as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.57 (4H, apparent s), 5.55-5.40 (1H, m), 5.07-4.97 (2H, m), 2.51 (1H, dd, J=13.5, 6.5 Hz), 2.36 (1H, dd, J=13.5, 8.0 Hz), 1.46 (2H, br s), 1.43 (3H, s); 13C NMR (CDCl3, 75 MHz) δ 154.26, 133.32, 131.99, 126.36, 119.37, 119.03, 110.05, 54.94, 49.50, 30.85; IR (film) 3499, 2228, 1639 cm−1; HRMS (Cl) m/z calcd. for C12H15N2 (MH+) 187.1235, found 187.1235.
(viii) 1-Methyl-1-(4-nitrophenyl)but-3-enylamine (6h)




6h was isolated as a clear, colorless oil: 1H NMR (CDCl3, 500 MHz) δ 8.16 (2H, d, J=9.0 Hz), 7.66 (2H, d, J=9.0 Hz), 5.53 (1H, dddd, J=17.0, 10.5, 8.0, 7.0 Hz), 5.07 (1H, d, J=10.5 Hz), 5.06 (1H, d, J=17.0 Hz), 2.57 (1H, dd, J=13.5, 7.0 Hz), 2.42 (1H, dd, J=13.5, 8.0 Hz), 1.54 (2H, br s), 1.50 (3H, s); 13C NMR (CDCl3, 125 MHz) δ 156.28, 146.47, 133.13, 126.45, 123.30, 119.43, 55.01, 49.55, 30.92; IR (film) ν3375, 1639, 1526, 1351 cm−1; HRMS (Cl) m/z calcd. for C11H15N2O2 (MH+) 207.1134, found 207.1132.
(ix) 1-Methyl-1E-styrylbut-3-enylamine (6i)




6i was isolated as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.45-7.15 (5H, m), 6.46 (1H, d, J=16.0 Hz), 6.28 (1H, d, J=16.0 Hz), 5.87-5.72 (1H, m), 5.18-5.05 (2H, m), 2.31 (1H, dd, J=16.5, 7.5 Hz), 2.23 (1H, dd, J=16.5, 8.0 Hz), 1.41 (2H, br s), 1.27 (3H, s); 13C NMR (CDCl3, 75 MHz) δ 138.42, 137.22, 133.95, 128.39, 128.27, 127.06, 126.14, 118.45, 52.96, 48.00, 28.57; IR (film) ν 3545, 1638 cm−1; HRMS (Cl) m/z calcd. for C13H18N (MH+) 118.1439, found 118.1449.
(x) 9-Allyl-9H-fluoren-9-ylamine (6j)




6j was isolated as a clear, colorless oil: 1H NMR (CDCl3, 500 MHz) δ 7.66 (2H, d, J=7.5 Hz), 7.51 (2H, d, J=7.0 Hz), 7.38-7.30 (4H, m), 5.57 (1H, ddt, J=17.0, 10.0, 7.5 Hz), 5.01 (1H, dd, J=17.0, 1.5 Hz), 4.96 (1H, d, J=10.0 Hz), 2.70 (2H, d, J=7.5 Hz), 1.81 (2H, br s); 13C NMR (CDCl3, 125 MHz) δ 150.86, 139.28, 133.22, 128.00, 127.53, 123.26, 119.85, 118.60, 64.71, 45.46; IR (film) ν3360, 1640 cm−1; HRMS (ESI) m/z calcd. for C16H16N (MH+) 222.1283, found 222.1278.
(xi) 4-Allyl-1-benzylpiperidin-4-ylamine (6k)




6k was isolated as a clear, colorless oil: 1H NMR (CDCl3, 300 MHz) δ 7.32-7.15 (5H, m), 5.81 (1H, ddt, J=17.0, 10.0, 7.5 Hz), 5.12-5.01 (2H, m), 3.48 (2H, s), 2.58-2.48 (2H, dq, J=12.0, 4.0 Hz), 2.30 (2H, dt, J=11.0, 3.0 Hz), 2.09 (2H, d, J=7.5 Hz), 1.61 (2H, ddd, J=13.0, 10.5, 4.0 Hz), 1.41-1.31 (2H, m), 1.08 (2H, br s); 13C NMR (CDCl3, 75 MHz) δ 138.43, 133.51, 128.88, 127.95, 126.69, 118.29, 63.08, 49.39, 48.67, 47.60, 37.83; IR (film) ν3422, 1639 cm−1; HRMS (ESI) m/z calcd. for C15H23N2 (MH+) 231.1861, found 231.1862.
(xii) 1-Phenyl-1-thiophen-2-ylbut-3-enylamine (6l)




6l was isolated as a clear, colorless oil: 1H NMR (CDCl3, 500 MHz) δ 7.49 (2H, dt, J=7.5, 1.0 Hz), 7.33 (2H, t, J=8.0 Hz), 7.27-7.17 (2H, m), 6.94 (1H, dd, J=5.0, 3.5 Hz), 6.90 (1H, dd, J=3.5, 1.0 Hz), 5.62 (1H, ddt, J=17.0, 10.0, 7.0 Hz), 5.19 (1H, d, J=17.0, 1.5 Hz), 5.13 (1H, ddd, J=10.0, 1.5, 1.0 Hz), 3.08 (1H, dd, J=14.0, 7.0 Hz), 3.01 (1H, dd, J=14.0, 7.5 Hz), 2.09 (2H, br s); 13C NMR (CDCl3, 75 MHz) δ 154.78, 147.10, 133.63, 128.15, 126.77, 126.50, 126.01, 124.22, 123.64, 119.55, 59.32, 49.15; IR (film) 3410, 1639 cm−1; HRMS (Cl) m/z calcd. for C14H16NS (MH+) 230.1003, found 230.1017.
(xiii) 1-(1H-Indol-3-yl)-1-methylbut-3-enylamine (6m)




6m was isolated as a clear, colorless oil: 1H NMR (CDCl3, 500 MHz) δ 8.03 (1H, br s), 7.84 (1H, d, J=8.0 Hz), 7.37 (1H, d, J=8.0 Hz), 7.19 (1H, dt, J=7.5, 1.0 Hz), 7.12 (1H, dt, J=7.5, 1.0 Hz), 7.07 (1H, d, J=2.5 Hz), 5.65 (1H, ddt, J=17.5, 10.0, 7.5 Hz), 5.06 (1H, d, J=17.5 Hz), 5.03 (1H, d, J=10.0 Hz), 2.79 (1H, dd, J=13.5, 7.5 Hz), 2.63 (1H, dd, J=13.5, 7.5 Hz), 1.85 (2H, br s), 1.61 (3H, s); 13C NMR (CDCl3, 75 MHz) δ 137.30, 134.93, 125.20, 124.74, 121.77, 120.91, 120.51, 119.21, 117.92, 111.35, 52.39, 48.20, 30.00; IR (film) 3205, 1639 cm−1.
(xiv) 1-Allyl-4-tert-butylcyclohexylamine (6n)




6n was isolated as a clear, colorless oil (d.r.=87:13). The diastereomeric ratio was determined by 1H NMR of the crude sample. Main diastereomer: 1H NMR (CDCl3, 300 MHz) δ 5.83 (1H, ddt, J=17.0, 10.5, 7.5 Hz), 5.08-4.98 (2H, m), 2.02 (2H, d, J=7.5 Hz), 1.60-1.40 (4H, m), 1.34-1.00 (6H, m), 0.90-0.83 (1H, m), 0.83 (9H, s); 13C NMR (CDCl3, 75 MHz) δ 134.26, 117.87, 50.16, 49.94, 48.11, 38.43, 32.30, 27.50, 22.42; IR (film) 3368, 1638 cm−1; HRMS (Cl) m/z calcd. for C13H26N (MH+) 196.2065, found 196.2068. The stereochemistry of 6n (axial NH2) was confirmed by converting it (allylbromide, iPr2NEt, CH2Cl2; 49%) to the previously known compound N-Allyl-1-Allyl-4-tert-butylcyclohexylamine (axial NHCH2CH═CH) [D. L. Wright, J. P. Schulte, II and M. A. Page, Org. Lett., 2000, 2, 1847].
(xv) 2-Allyl-bicyclo[2.2.1]hept-2-ylamine (6o)




6o was isolated as a clear, colorless oil (d.r.=94:6). The diastereomeric ratio was determined by 1H NMR of the crude sample. Main diastereomer: 1H NMR (CDCl3, 300 MHz) δ 5.78 (1H, ddt, J=17.0, 10.5, 7.5 Hz), 5.08-4.97 (2H, m), 2.10 (2H, d, J=7.5 Hz), 1.88 (1H, d, J=3.5 Hz), 1.78 (1H, ddt, J=12.5, 9.0, 3.0 Hz), 1.60-1.42 (3H, m), 1.24-1.08 (6H, m), 0.82 (1H, dd, J=12.5, 3.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 134.57, 117.95, 57.99, 47.41, 46.69, 46.48, 38.30, 37.54, 28.43, 22.92; IR (film) 3400, 1638 cm−1; HRMS (Cl) m/z calcd. for C10H18N (MH+) 152.1439, found 152.1435.
(xvi) 2-Amino-1,2-diphenylpent-4-en-1-ol (6p)




6p was isolated as a clear, colorless crystalline solid. The diastereomeric ratio (d.r.=88:12) was determined by 1H NMR of the crude sample. Main diastereomer: m.p.=85-86° C. (CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.30-7.06 (8H, m), 6.90-6.85 (2H, m), 5.56-5.40 (1H, m), 5.12 (1H, d, J=17.0 Hz), 5.00 (1H, d, J=10.0 Hz), 4.74 (1H, s), 2.95 (1H, dd, J=14.0, 5.5 Hz), 2.65 (1H, dd, J=14.0, 9.0 Hz), 2.08 (3H, br s); 13C NMR (CDCl3, 75 MHz) δ142.54, 140.02, 133.74, 127.62, 127.42, 127.24, 127.10, 126.71, 126.50, 118.96, 79.91, 61.70, 43.45; IR (film) 3422, 1638 cm−1; HRMS (Cl) m/z calcd. for C17H20NO (MH+) 254.1545, found 254.1543.
(xvii) (1S*,2R*,5R*)-2-Allyl-4,6,6-trimethylbicyclo[3.1.1]hept-3-en-2-ylamine (6q)




6q was isolated as a clear, colorless oil (d.r.=97:3). The diastereomeric ratio was determined by 1H NMR of the crude sample. 1H NMR (CDCl3, 300 MHz) δ 5.85 (1H, ddt, J=17.5, 10.5, 7.5 Hz), 5.13-5.02 (3H, m), 2.36 (1H, dt, J=9.0, 5.5 Hz), 2.20 (1H, dd, J=13.5, 7.0 Hz), 2.13 (1H, dd, J=13.5, 8.0 Hz), 1.98-1.88 (2H, m), 1.68 (3H, d, J=1.5 Hz), 1.60-1.35 (3H, m), 1.33 (3H, s), 1.05 (3H, s); 13C NMR (CDCl3, 75 MHz) δ 143.51, 133.89, 124.42, 118.23, 57.24, 52.84, 47.64, 45.88, 41.87, 33.78, 27.36, 23.85, 22.77; IR (film) 3410, 1713, 1681, 1623 cm−1; HRMS (ESI) m/z calcd. for C13H22N (MH+) 192.1752, found 192.1756.
Example 2
Results for the Allylation of N-Unsubstituted Imines Derived from Ketones
The allylboron class of reagents were demonstrably superior in terms of reactivity and chemoselectivity [W. R. Roush, in Houben-Weyl, Stereoselective Synthesis, ed. G. Helmchen, R. W. Hoffmann, J. Mulzer and E. Schaumann, Georg Thieme Verlag, Stuttgart, 1995, vol. E21b, pp 1410-1486; D. S. Matteson, in Stereodirected Synthesis with Organoboranes, Springer-Verlag, Berlin, 1995]. In order to ascertain the reagent of choice, the present inventors have investigated the addition of a range of allylboron compounds to N-unsubstituted ketimines which are derived from ketones. The results are shown in Table 1. As can be seen from the Table, the more reactive allylboron reagents, 5d and 5e [H. C. Brown, U.S. Racherla and P. J. Pellechia, J. Org. Chem., 1990, 55, 1868] displayed the highest efficacy in terms of isolated yields of homollylic amine 6a (entries 4 and 5). A major issue of concern in all these reactions—chemoselectivity of imine versus ketone addition—was addressed by analyzing the organic extracts from the acid-base workup of 6a (entries 4, 5). It was determined that the corresponding homoallylic alcohol of 6a was formed in minor amounts (≦5%).
Due to the ease of the preparation of the allylboron reagent 5e and the simple purification of the resulting products, the present inventors have further investigated a series of ketones with reagent 5e in methanolic ammonia (Table 2). Aliphatic (entries 1-4), electron rich aromatic (entry 5), electron deficient aromatic (entries 6 and 7), α,β-unsaturated (entry 8), cyclic (entries 9 and 10) and heterocyclic-substituted (entries 11 and 12) ketones were successfully allylated under the standard conditions. The resulting homoallylic amines (6) were easily isolated in high yields through simple acid-base extraction, and in all cases but one, did not require any further purification. A variety of functional groups were also found to be tolerated in the reaction sequence including the nitro (entry 7), cyano (entry 6), unprotected hydroxy (entry 2) and amino groups (entry 12).
Still further, the present inventors have expanded the scope of the study to include the allylation of ketones containing a pre-existing stereocenter. The substrates (1n-q) were subjected to the standard set of reaction and work-up conditions, the results of which are shown in Table 3. Good to excellent yields of tertiary carbinamines 6n-q were obtained in all cases, while the observed diastereoselectivities, as determined by 1H NMR, varied from modest for the reaction of 4-tert-butylcyclohexanone, norchamphor, and benzoin (equations 1, 2 and 3 respectively) to excellent for verbenone (equation 4).
Example 3
General Procedure for the Crotylation of N-Unsubstituted Imines Derived from Ketones
The protocol for the allylation of N-unsubstituted imines derived from ketones was followed with the exception that the boron reagent was changed to either either (E)- or (Z)-crotylboronic acid (2M in MeOH, 0.5 mL, 1.00 mmol).
(i) (1S*,2S*)-1,2-Dimethyl-1-(4-trifluoromethylphenyl)but-3-enylamine (4a)




4a was isolated as a clear, colorless oil (d.r.=97:3). The diastereomeric ratio was determined by 1H NMR of the crude sample. 1H NMR (CDCl3, 300 MHz) δ 7.60 (2H, d, J=9.0 Hz), 7.56 (2H, d, J=9.0 Hz), 5.66-5.53 (1H, m), 5.10-5.00 (2H, m), 2.53 (1H, pentet, J=7.0 Hz), 1.49 (2H, br s), 1.46 (3H, s), 0.91 (3H, d, J=7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 152.45, 139.63, 128.52 (q, J=30 Hz), 126.37, 124.79 (q, J=3.5 Hz), 124.64 (q, J=270 Hz), 116.45, 55.96, 48.82, 27.13, 14.30; IR (film) 3378, 1636 cm−1; HRMS (ESI) m/z calcd. for C13H17F3N (MH+) 244.1313, found 244.1305.
(ii) (1S*,2R*)-1,2-Dimethyl-1-(4-trifluoromethylphenyl)but-3-enylamine (4b)




4b was isolated as a clear, colorless oil (d.r.=96:4). The diastereomeric ratio was determined by 1H NMR of the crude sample. 1H NMR (CDCl3, 300 MHz) δ 7.56 (4H, apparent s), 5.75 (1H, ddd, J=18.5, 10.5, 8.0 Hz), 5.13-5.03 (2H, m), 2.53 (1H, pentet, J=7.5 Hz), 1.58 (2H, br s), 1.43 (3H, s), 0.78 (3H, d, J=7.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 152.10, 139.46, 128.02 (q, J=30 Hz), 126.23, 125.83 (q, J=270 Hz), 124.73 (q, J=3.5 Hz), 116.34, 55.56, 48.65, 29.51, 14.51; IR (film) ν3390, 1637 cm−1; HRMS (ESI) m/z calcd. for C13H17F3N (MH+) 244.1313, found 244.1304.
(iii) (2S*,3S*)-2-Amino-3-methyl-2-phenylpent-4-enoic acid amide (4c)




4c was isolated as a clear, colorless, crystalline solid (d.r.=97:3): m.p=90° C. (CH2Cl2); 1H NMR (CDCl3, 300 MHz) δ 7.65-7.58 (2H, m), 7.35-7.18 (4H, m), 6.20 (1H, brs), 5.46 (1H, ddd, J=17.5, 10.0, 6.5 Hz), 5.05-4.95 (2H, m), 3.59 (1H, pentet, J=6.5 Hz), 1.59 (2H, br s), 1.08 (3H, d, J=6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 176.99, 141.60, 138.23, 128.16, 127.04, 125.64, 116.69, 65.54, 42.58, 12.27; IR (film) ν3441, 3207, 1710, 1620, 1637 cm−1; HRMS (Cl) m/z calcd. for C11H17N2O (MH+) 205.1341, found 205.1332.
(iv) (2S*,3R*)-2-Amino-3-methyl-2-phenylpent-4-enoic acid amide (4d)




4d was isolated as a clear, colorless, crystalline solid (d.r.=96:4): m.p=136° C. (CH2Cl2); 1H NMR (CDCl3, 500 MHz) δ 7.64-7.60 (2H, m), 7.35-7.24 (4H, m), 6.02 (1H, ddd, J=17.5, 10.5, 5.0 Hz), 5.59 (1H, br s), 5.26 (1H, dt, J=10.5, 1.5 Hz), 5.17 (1H, dt, J=17.5, 1.5 Hz), 3.76-3.69 (1H, m), 1.63 (2H, br s), 0.73 (3H, d, J=7.0 Hz); 13C NMR (CDCl3, 125 MHz) δ 177.15, 141.16, 139.07, 128.24, 127.06, 125.54, 117.21, 65.47, 41.87, 10.97; IR (film) ν3432, 3170, 1715, 1633 cm−1; HRMS (Cl) m/z calcd. for C11H17N2O (MH+) 205.1341, found 205.1337.
(v) (1S*,2S*)-1,2-Dimethyl-1-phenylbut-3-enylamine (4e)




4e was isolated as a clear, colorless oil (d.r.=97:3). The diastereomeric ratio was determined by 1H NMR of the crude sample. 1H NMR (CDCl3, 300 MHz) δ 7.42-7.10 (4H, m), 5.65-5.55 (1H, m), 4.96-5.02 (2H, m), 2.45 (1H, dq, J=7.0 Hz), 1.50 (2H, br s), 1.38 (3H, s), 0.83 (3H, d, J=7.0 Hz); 13C NMR (CDCl3, 75 MHz) δ 148.22, 140.30, 127.87, 126.13, 125.79, 115.90, 56.81, 49.02, 26.68, 14.49 [C. Ogawa, M. Sugiura and S. Kobayashi, J. Org. Chem., 2002, 67, 5359].
(vi) 2-Amino-2,3-dimethylpent-4-enoicacid amide (4f)




4f was isolated as a clear, colorless oil (d.r.=60:40). The diastereomeric ratio was determined by 1H NMR of the crude sample. Main diastereomer: 1H NMR (CDCl3, 300 MHz) δ 7.41 (1H, br s), 5.95-5.60 (2H, m), 5.15-5.05 (2H, m), 2.81 (1H, pentet, J=6.5 Hz), 1.28 (3H, s), 1.26 (2H, br s), 0.99 (3H, d, J=6.5 Hz); 13C NMR (CDCl3, 75 MHz) δ 180.06, 139.33, 116.28, 59.62, 43.29, 25.10, 11.88; IR (film) ν3444, 3250, 1691, 1654, 1557 cm−1; HRMS (Cl) m/z calcd. for C7H14N2O (MH+) 143.1184, found 143.1186.
Example 4
Results for the Crotylation of N-Unsubstituted Imines Derived from Ketones
The crotylation of a select number of ketones was examined under a slightly modified set of conditions (2.0 equiv of 5e, 10 equiv. of NH3, rt, 24 h) (Table 4). Excellent diastereoselectivities were obtained with acetophenone derivatives (entries 1-4). The anti diastereomer (4a/c) was formed when (E)-crotylboronic acid (7a) was employed as the reagent, while (Z)-crotylboronic acid (7b) afforded the syn diastereomer (4b/d). The stereochemistry of the crotylated products 4 were assigned based upon the reaction of 7a with acetophenone (entry 5) which afforded the previously known anti diastereomer 4e in moderate yield and excellent diastereoselectivity (d.r.=97:3) [C. Ogawa, M. Sugiura and S. Kobayashi, J. Org. Chem., 2002, 67, 5359]. Crotylation of methyl pyruvate (entry 6), on the other hand, was not diastereoselective likely due to the similar steric sizes of the methyl and methylformate groups. The results from entries 3-5 also constitute a convenient route to α-allylated amino acid derivatives.
While the present invention has been described with reference to what are presently considered to be the preferred examples, it is to be understood that the invention is not limited to the disclosed examples. To the contrary, the invention is intended to cover various modifications and equivalent arrangements included within the spirit and scope of the appended claims.
All publications, patents and patent applications are herein incorporated by reference in their entirety to the same extent as if each individual publication, patent or patent application was specifically and individually indicated to be incorporated by reference in its entirety. Where a term in the present application is found to be defined differently in a document incorporated herein by reference, the definition provided herein is to serve as the definition for the term.







TABLE 1







Addition of allyl boron reagents (5) to


N-unsubstituted ketimine derived from 1a.








 











Yield of 6a


Entry
5
(%)a





1




35


 


2




29


 


3




43


 


4




 70b,c


 


5




 79b





aIsolated yield after acid-base extraction.


bAnalysis (1H NMR, 2.4,6-trimethylbenzene standard) of the organic phase from the acid-base work-up revealed ≦5% of the corresponding homoallylic alcohol.


cIsolated yield after acid-base extraction and preparative TLC.













TABLE 2







Reaction of N-unsubstituted imines derived from


ketones with allylboronic acid (5e)a.








 









Entry
Ketone
Yield (%)b













1
Et2C═O
(1b)
73 (6b)


 


2




(1c)
80 (6c)


 


3




(1d)
78 (6d)


 


4




(1e)
85 (6e)


 


5
4-MeOC6H4C(O)CH2CH3
(1f)
72 (6f)


6
4-NCC6H4C(O)CH3
(1g)
80 (6g)


7
4-O2NC6H4C(O)CH3
(1h)
87 (6h)


 


8




(1i)
 70 (6i)c


 


9




(1j)
78 (6j)


 


10




(1k)
92 (6k)


 


11




(1l)
75 (6l)


 


12




(1m)
80 (6m)





aStandard reaction conditions: A solution of the ketone (0.5 mmol), ammonia (ca. 7N in MeOH, 0.75 mL, ca. 10 equiv.) and allylboronic acid (5e) (2M in MeOH, 0.40 mL, 0.80 mmol) was stirred for 16 h at rt.


bIsolated yield after acid-base extraction.


cIsolated yield after acid-base extraction, and preparative TLC.













TABLE 3





Reaction of N-unsubstituted imines derived from ketones with


allylboronic acid (5e) in which


the ketones contain a pre-existing stereocentre.













 








 








 






















TABLE 4







Reaction of N-unsubstituted ketimines with


(E)- and (Z)-crotylboronic acid (7a/b)a








 












Crotyl

Yield



Entry
reagent
Product
(%)b
d.r.





1
7a




80 (4a)
97:3


 


2
7b




73 (4b)c
96:4


 


3
7a




95 (4c)d
97:3


 


4
7b




92 (4d)d
96:4


 


5
7a




50 (4e)
97:3


 


6
7a




88 (4f)e
60:40





aStandard reaction conditions: ketone (0.5 mmol), ammonia (ca. 7N in MeOH, 0.75 mL, ca. 10 equiv.) and crotylboronic acid (7a/b) (2M in MeOH, 0.50 mL, 1.00 mmol) were stirred for 24 h at rt.


bIsolated yield after acid-base extraction.


cIsolated yield after acid-base extraction, and preparative TLC.


dMethyl benzoylformate was employed as the starting ketone, and aminolysis of the ester was observed.


eMethylpyruvate was employed as the starting ketone, and aminolysis of the ester was observed.

## Claims

1. A method of preparing an amine of the formula Ia and/or Ib comprising reacting a compound of formula II with a compound of formula III:



wherein
R1 and R2 are independently selected from C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, all of which are optionally substituted and one or more of the carbons in C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl and C3-20cycloalkoxy, is optionally replaced with a heteromoiety selected from 0, S, N, NR10 and NR10R11;
or
R1 and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms including the carbonyl to which R1 and R2 are bonded, and one or more of the carbons of the ring system is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11;
R3 to R7 are independently selected from H, C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl, C3-20cycloalkoxy, aryl, aryloxy, heteroaryl and heteroaryloxy, the latter 9 groups being optionally substituted and one or more of the carbons in C1-20alkyl, C1-20alkoxy, C2-20alkenyl, C3-20cycloalkyl and C3-20cycloalkoxy, is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11;
R8 and R9 are independently selected from H, C1-20alkyl, C3-20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted;
or
R8 and R9 are linked to form an optionally substituted monocyclic or polycyclic ring system having 4 to 20 atoms, including the B and O atoms to which R8 and R9 are bonded;
R10 and R11 are independently selected from H, C1-20alkyl, C3-20cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted,
in the presence of ammonia NH3 or an ammonia equivalent of the formula NH4+X−, wherein X is an anionic ligand,
wherein the amine of the formula Ia and/or Ib is produced in a yield of 50% or more.

2. The method according to claim 1, wherein R1 and R2 in the compounds of the formulae Ia, Ib and II are independently selected from C1-10alkyl, C2-10alkenyl, aryl and heteroaryl, all of which being optionally substituted; or R1 and R2 are linked to form an optionally substituted monocyclic or polycyclic ring system having 6 to 16 carbons including the carbonyl to which R1 and R2 are bonded and one or more of the carbons of the ring system is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11, in which R10 and R11 are independently selected from H, C1-6alkyl and aryl.

3. The method according to claim 2, wherein R1 and R2 in the compounds of the formulae Ia, Ib and II are independently selected from methyl, ethyl, propyl, butyl, pentyl, ethene, styrene, phenyl, benzyl, thiophene and indole, all of which are optionally substituted.

4. The method according to claim 1, wherein R1 and R2 in the compounds of the formulae Ia, Ib and II are linked to form a ring system selected from cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene and fluorene, all of which are optionally substituted, and one or more of the carbons of cyclohexane, bicyclo[2.2.1]heptane, bicyclo[3.1.1]hept-2-ene or fluorene is optionally replaced with a heteromoiety selected from O, S, N and NR10; in which R10 is H or benzyl.

5. The method according to claim 1, wherein the optional substituents on R1 and R2 in the compounds of the formulae Ia, Ib and II are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl.

6. The method according to claim 5, wherein the optional substituents on R1 and R2 in the compounds of the formulae Ia, Ib and II are independently selected from OH, F, Cl, Br, CN, NO2, phenyl and C1-4alkyl.

7. The method according to claim 1, wherein the optional substituents on R1 and R2 in the compounds of the formulae Ia, Ib and II further comprise at least one stereocenter.

8. The method according to claim 1, wherein R3 to R7 in the compounds of the formulae Ia, Ib and III are independently selected from H, C1-10alkyl, C3-12cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted and one or more of the carbons in C1-10alkyl and C3-10cycloalkyl is optionally replaced with a heteromoiety selected from O, S, N, NR10 and NR10R11 in which R10 and R11 are independently selected from H and C1-6alkyl.

9. The method according to claim 8, wherein R3 to R7 in the compounds of the formulae Ia, Ib and III are independently selected from H and C1-6alkyl.

10. The method according to claim 9, wherein R3 to R7 in the compounds of the formulae Ia, Ib and III are independently selected from H and methyl.

11. The method according to claim 1, wherein the optional substituents on R3 and R7 in the compounds of the formulae Ia, Ib and III are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl.

12. The method according to claim 1, wherein R8 and R9 in the compound of the formula III are independently selected from H, C1-10alkyl, C3-12cycloalkyl, aryl and heteroaryl, the latter 4 groups being optionally substituted; or R8 and R9 in the compound of the formula III are linked to form an optionally substituted monocyclic or polycyclic ring system having 5 to 12 atoms, including the B and O atoms to which R8 and R9 are bonded.

13. The method according to claim 12, wherein R8 and R9 in the compound of the formula III are independently selected from H or C1-6alkyl; or R8 and R9 in the compound of the formula III are linked to form an optionally substituted monocyclic or bicyclic ring system having 5 to 12 atoms, including the B and O atoms to which R8 and R9 are bonded.

14. The method according to claim 1, wherein the optional substituents on R8 and R9 in the compound of the formula III are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl.

15. The method according to claim 14, wherein the optional substituent on R8 and R9 in the compound of the formula III is C1-4alkyl.

16. The method according to claim 1, wherein X is selected from halo, R12COO, R12SO4 and BF4 in which R12 is selected from C1-10alkyl, C3-20cycloalkyl, aryl and heteroaryl, all of which are optionally substituted; and wherein the optional substituents are independently selected from OH, halo, CN, NO2, phenyl, benzyl, OC1-6alkoxy, C1-6alkyl, C1-6alkenyl, C1-6alkenyloxy, NH2, NH(C1-6alkyl), N(C1-6alkyl)(C1-6alkyl), C(O)C1-6alkyl, C(O)OC1-6alkyl, SO2C1-6alkyl, SO2NH2, SO2NHC1-6alkyl, and SC1-4alkyl.

17. The method according to claim 1, wherein the method is performed in the presence of ammonia.

18. The method according to claim 1, wherein the method is performed in an organic solvent.

19. The method according to claim 18, wherein the organic solvent is selected from methanol, ethanol, propanol, butanol, toluene, tetrahydrofuran, acetonitrile, benzene and methylene chloride.

20. The method according to claim 19, wherein the organic solvent is methanol.

21. The method according to claim 1, wherein the method is performed at a temperature of from −40° C. to +100° C.

22. The method according to claim 21, wherein the method is performed at room temperature.