Note: Descriptions are shown in the official language in which they were submitted.
CA 02562661 2006-10-05
1
B&P File No. 14696-17
TITLE: METHODS OF PREPARING TERTIARY CARBINAMINE
COMPOUNDS
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
aidehydes. For example, the reaction of
~ H 9 NH3, EtOH NH2
R ~ R\ ~ B'O ~
7/ v R ~
R~ R R
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,
CA 02562661 2006-10-05
2
Org. Left., 1999, 1, 1061; R. Hamasaki, Y. Chounan, H. Horino and Y.
Yamamoto, Tetrahedron Left., 2000, 41, 9883; R. M. Kamble and V. K. Singh,
Tetrahedron Left., 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 Left.,
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. Jorgensen, 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
CA 02562661 2006-10-05
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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].
Thus, there remains a need for an efficient diastereoselective synthesis
of tertiary carbinamine compounds that requires mild reaction conditions and
provides good yields.
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 a method of preparing an
amine of the formula Ia and/or lb comprising reacting a compound of formula
II with a compound of formula III:
8
0 R5 o'R HzN R2 R5 H2N R2 R5
RRz + R s B \ O , R s NH3 or NH4'X- R1x Rs Ri) R7
Ra Rs R7 R4R3~R7 R4 R3 R6
II III la lb
wherein
R' and R2 are independently selected from C1_20alkyl, CI_20alkoxy, C2_
20alkenyl, C3_20cycloalkyl, C3_20cycloalkoxy, aryl, aryloxy, heteroaryl and
heteroaryloxy, all of which are optionally substituted and one or more of the
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carbons in Cl-20alkyl, Cl_20alkoxy, C2_20alkenyl, C3_20cycloalkyl, C3_
2ocycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally
replaced
with a heteroatom selected from 0, S, N, NR10 and NR'0R";
or
R' and R2 are linked to form an optionally substituted monocyclic or
polycyclic
ring system having 4 to 20 atoms including the carbonyl to which R' and R2
are bonded, and one or more of the carbons of the ring system is optionally
replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
R3 to R' are independently selected from H, Cl-20alkyl, C1_20alkoxy, C2_
2oalkenyl, 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, Cl_20alkoxy, C2_20alkenyl, C3-20cycloalkyl, C3-
2ocycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally
replaced
with a heteroatom selected from 0, S, N, NR10 and NR10R11;
R 8 and R9 are independently selected from H, Cl-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 0 atoms to which R8
and R9 are bonded;
R10 and R" are independently selected from H, Cl-20alkyl, C3_20cycloalkyl,
aryl
and heteroaryl, the latter 4 groups being optionally substituted,
in the presence of ammonia NHs or an ammonia equivalent of the formula
NH4i'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.
CA 02562661 2006-10-05
DETAILED DESCRIPTION OF THE INVENTION
It has been demonstrated for the first time that tertiary carbinamine
compounds can be efficiently and effectively generated through
5 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 a method of preparing an
amine of the formula Ia and/or lb comprising reacting a compound of formula
II with a compound of formula III:
0 R5 01R8 HzN R2 R5 H2N R2 R5
R, R2 + RsB,O,Rs NH3 or NHq*X Ri Rs R' R~
R4 Rs R7 R4 YR3~R7 R4YR3\YR6
II III la lb
wherein
R' and R2 are independently selected from C1_20alkyl, Cl_20alkoxy, CZ_
20alkenyl, C3_20cycloalkyl, C3_20cycloalkoxy, aryl, aryloxy, heteroaryl and
heteroaryloxy, all of which are optionally substituted and one or more of the
carbons in C,_ZOalkyl, C,_20alkoxy, C2_20alkenyl, C3_20cycloalkyl, Cs_
20cycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally
replaced
with a heteroatom selected from 0, S, N, NR10 and NR'0R";
or
R' and R2 are linked to form an optionally substituted monocyclic or
polycyclic
ring system having 4 to 20 atoms including the carbonyl to which R' and R2
are bonded, and one or more of the carbons of the ring system is optionally
replaced with a heteroatom selected from 0, S, N, NR10 and NR'0R";
R3 to R' are independently selected from H, Cl_20alkyl, Cl_20alkoxy, C2_
2oalkenyl, C3_20cycloalkyl, C3_20cycloalkoxy, aryl, aryloxy, heteroaryl and
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heteroaryloxy, the latter 9 groups being optionally substituted and one or
more
of the carbons in Cl_20alkyl, Cl_20alkoxy, C2_20alkenyl, C3_20cycloalkyl, C3_
20cycloalkoxy, aryl, aryloxy, heteroaryl or heteroaryloxy is optionally
replaced
with a heteroatom selected from 0, S, N, NR10 and NR'0R";
R8 and R9 are independently selected from H, Cl_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 0 atoms to which R8
and R9 are bonded;
R10 and R" are independently selected from H, Cl_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 "Cl_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 "Cl_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,
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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.
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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,
lb and II include those in which R' and R2 are independently selected from Cl_
loalkyl, C2_,oalkenyl, aryl and heteroaryl, all of which are optionally
substituted.
In a further embodiment of the invention, R' and R2 in the compounds of the
formulae Ia, lb 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, lb and II include those in which R' 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 R' 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 heteroatom selected from 0, S, N, NR'o
and NR10R", in which Rl0 and R" are independently selected from H, Cl_
6alkyl and aryl. In a still further embodiment of the invention, R' and R2 in
the
compounds of the formulae Ia, lb 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 heteroatom selected from 0, S, and
NR10; in which R'0 is H or benzyl.
In an embodiment of the invention, the optional substituents on R' and
R2 in the compounds of the formulae Ia, lb and II are independently selected
from OH, halo, CN, NO2, phenyl, benzyl, OCi-6alkoxy, C1_6alkyl, C1_6alkenyl,
C,_6alkenyloxy, NH2, NH(C,_6alkyl), N(Cl_6alkyl)(C1_6alkyl), C(O)C,_6alkyl,
C(O)OC1_6alkyl, S02CI_6alkyl, SO2NH2, SO2NHC,-6aIkyl, and SC1-4alkyl. More
particularly, in another embodiment of the invention, the optional
substituents
on R' and R2 in the compounds of the formulae Ia, lb and II are independently
CA 02562661 2006-10-05
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selected from OH, F, Cl, Br, CN, NO2, phenyl and C1_4alkyl. Still more
particularly, the optional substituents on R' and R2 in the compounds of the
formulae Ia, lb and II further comprise at least one stereocenter.
It is an embodiment of the invention that R3 to R' in the compounds of
the formulae Ia, lb and III are independently selected from H, Cl_loalkyl, 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 C,_10alkyl, C3_locycloalkyl, aryl or heteroaryl is optionally
replaced
with a heteroatom selected from 0, S, N, NR10 and NR'0R" in which R'0 and
R" are independently selected from H and C1_6alkyl. In a particular
embodiment of the invention, R3 to R' in the compounds of the formulae Ia, lb
and III are independently selected from H and C1_6alkyl. In a more particular
embodiment of the invention, R3 to R' in the compounds of the formulae Ia, lb
and III are independently selected from H and methyl. Still further, in an
embodiment of the invention, the optional substituents on R3 and R' in the
compounds of the formulae Ia, lb and III are independently selected from OH,
halo, CN, NO2, phenyl, benzyl, OC1_6alkoxy, CI_6alkyl, Cl_6alkenyl, Cl_
6alkenyloxy, NH2, NH(Cl_6alkyl), N(Cl_6alkyl)(Cl_6alkyl), C(OP_6alkyl,
C(O)OC1-6alkyl, SO2C,-6aIkyl, SO2NH2, SO2NHC1_6alkyl, and SCI-4alkyl.
It is an embodiment of the invention that R8 and R9 in the compound of
the formula III are independently selected from H, C1_10alkyl, C3-
12cycIoalkyl,
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, R 8 and R9 in the compound of the formula I I I
are
linked to form an optionally substituted monocyclic or polycyclic ring system
having 5 to 12 atoms, including the B and 0 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
0 atoms to which R8 and R9 are bonded. It is an embodiment of the invention
CA 02562661 2006-10-05
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, OCj_
6alkoxy, C1_6alkyl, Cl_6alkenyl, Cl_6alkenyloxy, NH2, NH(Cl_6alkyl), N(Cj_
6alkyl)(C1_6alkyl), C(O)Cl_6alkyl, C(O)OC1_6alkyl, SO2C1_6alkyl, SO2NH2,
5 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
10 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, R12C00, R12S04 and BF4 in which R12 is selected from Cl_loalkyl, C3-
20cycloalkyl, aryl and heteroaryl, all of which are optionally substituted. In
an
embodiment of the invention, X is selected from Cl, Br, R12C00, R12SOa 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 are independently selected from
OH, halo, CN, NO2, phenyl, benzyl, OC1_6alkoxy, C1_6alkyl, C,_6alkenyl, C,_
6alkenyloxy, NH2, NH(C1_6alkyl), N(C,_6alkyl)(C,_6alkyl), C(O)C1_6alkyl,
C(O)OC1_6alkyl, SO2C,-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
CA 02562661 2006-10-05
11
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 Left., 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 lb (Scheme
I).
Rs
M
R3Y~1IXR7
4H
ONH3 NH R III R6 2N ~~ R2 Rs 1 R7 (or R6)
R'~R2 MeOH R'~R2 R'
R3 R4 4 R6 (or R')
II IV Ia (or 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.
CA 02562661 2006-10-05
12
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 (R'=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. 'H 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 CDCI3 (S 7.26). Carbon chemical shifts were
internally referenced to the deuterated solvent signals in CDCI3 (S 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
CA 02562661 2006-10-05
13
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 Et20 (15 mL). The desired amine was
then extracted with 1 N HCI (15 ml). The acidic aqueous extract was washed
with Et20 (3 x 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 x 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)
0 ~B(OH)2 Me NH2
~ 5e
Br I/ NH3 Br
la MeOH 6a
6a was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) 8 7.44
(2H, d, J = 8.5 Hz), 7.35 (2H, d, J = 8.5 Hz), 5.55 (1 H, dddd, J = 18.0, 9.5,
8.0,
7.0 Hz), 5.09 - 5.04 (2H, m), 2.53 (1 H, dd, J = 13.5, 7.0 Hz), 2.38 (1 H, dd,
J =
13.5, 8.0 Hz), 1.49 (2H, br s), 1.44 (3H, s); 13C NMR (CDCI3, 125 MHz) S
147.79, 133.89, 131.14, 127.26, 120.12, 118.81, 54.45, 49.64, 30.93; IR (film)
v, 3423, 1638 cm-'; HRMS (CI) m/z calcd. for CjjH15BrN (MH+) 240.0388,
found 240.0395.
(ii) 1,1-Diethylbut-3-enylamine (6b)
~ B(OH)2
Et2C=O
NH3 H2N
lb MeOH 6b
CA 02562661 2006-10-05
14
6b was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 5.77
(1 H, ddt, J = 16.0, 11.0, 7.5 Hz)), 5.04 (1 H, d, J = 11.0 Hz), 5.03 (1 H, 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 (CDCI3, 75 MHz) S 134.44, 117.69, 53.36,
43.85, 31.66, 7.70; IR (film) v 3420, 1636 cm '; HRMS (ESI) m/z calcd. for
C$H18N (MH+) 128.1439, found 128.1444.
(iii) 2-Amino-2-methylpent-4-en-1-ol (6c)
O ~B(OH)2 NH2
HO~ NH3 HO~.~'~/'~
1 c MeOH 6c
6c was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 5.79
(1 H, ddt, J = 16.5, 10.5, 7.5 Hz), 5.12 - 5.01 (2H, m), 3.30 (1 H, 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 (CDCI3, 75 MHz) S 133.77, 118.51, 68.07, 52.70, 44.28,
24.53; IR (film) v 3345, 3157, 1639 cm '; HRMS (CI) m/z calcd. for C6H14NO
(MH') 116.1075, found 116.1072.
(iv) 1-Benzyl-l-phenylbut-3-enylamine (6d)
O ~B(OH)2 Ph NH2
Ph Ph
Ph
NH3
id MeOH 6d
6d was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 7.38 -
7.08 (8H, m), 6.90 - 6.84 (2H, m), 5.53 (1 H, dddd, J = 17.0, 10.0, 8.5, 5.5
Hz),
5.15 - 5.00 (2H, m), 3.12 (1 H, d, J = 13.0 Hz), 2.97 (1 H, d, J = 13.0 Hz),
2.86
(1 H, dd, J = 13.5, 5.5 Hz), 2.44 (1 H, dd, J = 13.5, 8.5 Hz), 1.50 (2H, br
s); 13C
NMR (CDC13, 75 MHz) 8 146.52, 137.09, 134.08, 130.68, 128.07, 127.86,
CA 02562661 2006-10-05
126.46, 126.30, 126.19, 118.81, 57.97, 50.54, 47.62; I R(fi(m) v, 3401, 1677
cm-1; HRMS (ESI) m/z calcd. for C17H2ON (MH+) 238.1596, found 238.1585.
(v) 1-Methyl-1-(3-methylbutyl)but-3-enylamine (6e)
5
0 ~B(OH)2 Me NH2
~ie NH3 6e
MeOH
6e was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) 8 5.74
(1 H, ddt, J = 17.0, 10.0, 7.5 Hz), 5.05 - 4.93 (2H, m), 2.00 (2H, d, J = 7.5
Hz),
10 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 (CDCI3, 75 MHz) S 134.50, 117.77,
51.14, 47.15, 40.36, 32.82, 28.45, 27.71, 22.53; IR (film) p3385, 1636 cm-1;
HRMS (ESI) m/z calcd. for CioH22N (MH+) 156.1752, found 156.1745.
15 (vi) 1-Ethyl-1 -(4-Methoxyphenyl)but-3-enylamine (6f)
0 Et NH2
B(OH)2 j\
MeO c NH3 MeO ~
if MeOH 6f
6f was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) S 7.31
(2H, d, J = 9.0 Hz), 6.86 (2H, d, J = 9.0 Hz), 5.53 (1 H, 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 (1 H, dd, J = 13.5, 6.0 Hz), 2.36 (1 H, dd, J = 13.5, 8.5 Hz), 1.85 (1 H,
dq, J
= 14.0, 7.5 Hz), 1.66 (1 H, dq, J = 14.0, 7.5 Hz), 1.52 (2H, br s), 0.71 (3H,
t, J
= 7.5 Hz); 13C NMR (CDCI3, 75 MHz) S 157.72, 138.66, 134.32, 126.93,
118.34, 113.27, 57.06, 55.16, 48.37, 36.05, 8.04; IR (film) p3420, 1638, 1610,
CA 02562661 2006-10-05
16
1511, 1248 cm-'; HRMS (CI) m/z calcd. for C13H2ONO (MH+) 206.1545, found
206.1565.
(vii) 4-(1-Amino-1 -methylbut-3-enyl)benzonitrile (6g)
O Me NH2
B(OH)2
NC ~ ~~
J NH3 NCI /
1 g MeOH 6g
6g was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) S 7.57
(4H, apparent s), 5.55 - 5.40 (1 H, m), 5.07 - 4.97 (2H, m), 2.51 (1 H, dd, J
=
13.5, 6.5 Hz), 2.36 (1 H, dd, J = 13.5, 8.0 Hz), 1.46 (2H, br s), 1.43 (3H,
s); 13C
NMR (CDCI3, 75 MHz) 8 154.26, 133.32, 131.99, 126.36, 119.37, 119.03,
110.05, 54.94, 49.50, 30.85; IR (film) v3499, 2228, 1639 cm-1; HRMS (CI)
m/z calcd. for C12H15N2 (MH+) 187.1235, found 187.1235.
(viii) 1-Methyl-1-(4-nitrophenyl)but-3-enylamine (6h)
O Me NH2
I B(OH)2 ~
~
O2N / NH3 02N
1 h MeOH 6h
6h was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) S 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 (1 H, dd, J = 13.5, 8.0 Hz), 1.54 (2H, br s), 1.50
(3H, s);
13C NMR (CDCI3, 125 MHz) b 156.28, 146.47, 133.13, 126.45, 123.30,
119.43, 55.01, 49.55, 30.92; IR (film) v3375, 1639, 1526, 1351 cm-1; HRMS
(CI) m/z calcd. for C11H15N202 (MH+) 207.1134, found 207.1132.
CA 02562661 2006-10-05
17
(ix) 1-Methyl-1 E-styrylbut-3-enylamine (6i)
B(OH)2 I ~ \ \
O N\/\
NH3
1 i MeOH 6i
6i was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) 8 7.45 -
7.15 (5H, m), 6.46 (1 H, d, J = 16.0 Hz), 6.28 (1 H, d, J = 16.0 Hz), 5.87 -
5.72
(1 H, m), 5.18 - 5.05 (2H, m), 2.31 (1 H, dd, J = 16.5. 7.5 Hz), 2.23 (1 H,
dd, J =
16.5, 8.0 Hz), 1.41 (2H, br s), 1.27 (3H, s); 13C NMR (CDCI3, 75 MHz) S
138.42, 137.22, 133.95, 128.39, 128.27, 127.06, 126.14, 118.45, 52.96,
48.00, 28.57; IR (film) v 3545, 1638 cm"'; HRMS (CI) m/z calcd. for C13H18N
(MH+) 118.1439, found 118.1449.
(x) 9-Allyl-9H-fluoren-9-ylamine (6j)
O H2N
0::~O ~B(OH)2 NH3 _ \ I I/
1j MeOH 6j
6j was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) S 7.66
(2H, d, J = 7.5 Hz), 7.51 (2H, d, J = 7.0 Hz), 7.38 - 7.30 (4H, m), 5.57 (1 H,
ddt, J = 17.0, 10.0, 7.5 Hz), 5.01 (1 H, 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 (CDCI3, 125 MHz)
8 150.86, 139.28, 133.22, 128.00, 127.53, 123.26, 119.85, 118.60, 64.71,
45.46; IR (film) v3360, 1640 cm-'; HRMS (ESI) m/z calcd. for C16H16N (MH+)
222.1283, found 222.1278.
CA 02562661 2006-10-05
18
(xi) 4-Allyl-l-benzylpiperidin-4-ylamine (6k)
O H2N ~
B(OH)2
N NH3 N
Bn MeOH Bn
1k 6k
6k was isolated as a clear, colorless oil: 'H NMR (CDCI3, 300 MHz) 8 7.32 -
7.15 (5H, m), 5.81 (1 H, 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 (CDCI3, 75 MHz) S 138.43, 133.51, 128.88,
127.95, 126.69, 118.29, 63.08, 49.39, 48.67, 47.60, 37.83; IR (film) v3422,
1639 cm '; HRMS (ESI) m/z calcd. for C15H23N2 (MH+) 231.1861, found
231.1862.
(xii) 1-Phenyl-l-thiophen-2-ylbut-3-enylamine (61)
B(OH)2 H2N
O NH3 / I \
s MeOH
11 61
61 was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) 8 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 (1 H, d, J = 17.0, 1.5 Hz), 5.13 (1H, ddd, J = 10.0,
1.5, 1.0 Hz), 3.08 (1 H, dd, J = 14.0, 7.0 Hz), 3.01 (1 H, dd, J = 14.0, 7.5
Hz),
2.09 (2H, br s); 13C NMR (CDCI3, 75 MHz) 8 154.78, 147.10, 133.63, 128.15,
CA 02562661 2006-10-05
19
126.77, 126.50, 126.01, 124.22, 123.64, 119.55, 59.32, 49.15; IR (film)
v3410, 1639 cm-1; HRMS (CI) m/z calcd. for C14H16NS (MH+) 230.1003,
found 230.1017.
(xiii) 1-(1 H-Indol-3-yl)-1-methylbut-3-enylamine (6m)
O H2N Me
O~N ~ B(OH)2 ~ NH I I
H 3 N
MeOH H
1m 6m
6m was isolated as a clear, colorless oil: 'H NMR (CDCI3, 500 MHz) 8 8.03
(1 H, br s), 7.84 (1 H, d, J = 8.0 Hz), 7.37 (1 H, d, J = 8.0 Hz), 7.19 (1 H,
dt, J =
7.5, 1.0 Hz), 7.12 (1 H, dt, J = 7.5, 1.0 Hz), 7.07 (1 H, d, J = 2.5 Hz), 5.65
(1 H,
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 (1 H, dd, J = 13.5, 7.5 Hz), 2.63 (1 H, dd, J = 13.5, 7.5 Hz), 1.85
(2H,
br s), 1.61 (3H, s); 13C NMR (CDCI3, 75 MHz) 8 137.30, 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) v3205, 1639 cm-'.
(xiv) 1-Allyl-4-tert-butylcyclohexylamine (6n)
0 B(OH)2 NH2
/ ~
t Bu~ NH3 t-Bu
1 n MeOH 6n
6n was isolated as a clear, colorless oil (d.r. = 87:13). The diastereomeric
ratio was determined by'H NMR of the crude sample. Main diastereomer:'H
NMR (CDCI3, 300 MHz) 8 5.83 (1 H, 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),
CA 02562661 2006-10-05
0.90 - 0.83 (1H, m), 0.83 (9H, s); 13C NMR (CDCI3, 75 MHz) S 134.26,
117.87, 50.16, 49.94, 48.11, 38.43, 32.30, 27.50, 22.42; IR (film) v3368, 1638
cm-'; HRMS (CI) m/z calcd. for C13H26N (MH+) 196.2065, found 196.2068.The
stereochemistry of 6n (axial NH2) was confirmed by converting it
5 (allylbromide, iPr2NEt, CH2CI2; 49%) to the previously known compound N-
Allyl-l-Allyl-4-tert-butylcyclohexylamine (axial NHCH2CH=CH) [D. L. Wright, J.
P. Schulte, II and M. A. Page, Org. Left., 2000, 2, 1847].
(xv) 2-Allyl-bicyclo[2.2.1]hept-2-ylamine (6o)
B(OH)2
NH3
O MeOH NH2
1o 6o
6o was isolated as a clear, colorless oil (d.r. = 94:6). The diastereomeric
ratio
was determined by 'H NMR of the crude sample. Main diastereomer: 'H
NMR (CDCI3, 300 MHz) S 5.78 (1 H, 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 (1 H, d, J = 3.5 Hz), 1.78 (1 H, ddt,
J =
12.5, 9.0, 3.0 Hz), 1.60 - 1.42 (3H, m), 1.24 - 1.08 (6H, m), 0.82 (1 H, dd, J
=
12.5, 3.0 Hz); 13C NMR (CDCI3, 75 MHz) S 134.57, 117.95, 57.99, 47.41,
46.69, 46.48, 38.30, 37.54, 28.43, 22.92; IR (film) p3400, 1638 cm-1; HRMS
(CI) m/z calcd. for CjoH1$N (MH+) 152.1439, found 152.1435.
(xvi) 2-Amino-1,2-diphenylpent-4-en-1-ol (6p)
p B(OH)2 H2N
Ph'j~' Ph NH3 Ph~Ph
OH MeOH OH
ip 6p
CA 02562661 2006-10-05
21
6p was isolated as a clear, colorless crystalline solid. The diastereomeric
ratio (d.r. = 88:12) was determined by 'H NMR of the crude sample. Main
diastereomer: m.p. = 85-86 C (CH2CI2);'H NMR (CDCI3, 300 MHz) 8 7.30 -
7.06 (8H, m), 6.90 - 6.85 (2H, m), 5.56 - 5.40 (1 H, m), 5.12 (1 H, d, J =
17.0
Hz), 5.00 (1 H, d, J = 10.0 Hz), 4.74 (1 H, s), 2.95 (1 H, dd, J = 14.0, 5.5
Hz),
2.65 (1H, dd, J = 14.0, 9.0 Hz), 2.08 (3H, br s); 13C NMR (CDCI3, 75 MHz)
8142.54, 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) p3422, 1638 cm'; HRMS (CI) m/z
calcd. for C17H2ONO (MH+) 254.1545, found 254.1543.
(xvii) (1 S*,2R*,5R*)-2-Allyl-4,6,6-trimethylbicyclo[3. 1. 1 ]hept-3-en-2-
ylamine
(6q)
O B(OH)2 H2N
NH3
MeOH
1q 6q
6q was isolated as a clear, colorless oil (d.r. = 97:3). The diastereomeric
ratio
was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz)
S 5.85 (1 H, ddt, J = 17.5, 10.5, 7.5 Hz), 5.13 - 5.02 (3H, m), 2.36 (1 H, dt,
J =
9.0, 5.5 Hz), 2.20 (1 H, dd, J = 13.5, 7.0 Hz), 2.13 (1 H, 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 (CDCI3, 75 MHz) S 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)
v3410,
1713, 1681, 1623 cm-'; HRMS (ESI) m/z calcd. for C13H22N (MH+) 192.1752,
found 192.1756.
CA 02562661 2006-10-05
22
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. Heimchen, 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 (55%).
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), a,(3-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).
CA 02562661 2006-10-05
23
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 (ln-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 'H 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-l-(4-trifluoromethylphenyl)but-3-enylamine (4a)
0 B(OH)z J3~
Me F3C NH3 F3C Me
Me
OH 4a
4a was isolated as a clear, colorless oil (d.r. = 97:3). The diastereomeric
ratio
was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz)
S 7.60 (2H, d, J = 9.0 Hz), 7.56 (2H, d, J = 9.0 Hz), 5.66 - 5.53 (1 H, m),
5.10 -
5.00 (2H, m), 2.53 ('H, pentet, J = 7.0 Hz), 1.49 (2H, br s), 1.46 (3H, s),
0.91
(3H, d, J = 7.0 Hz); 13C NMR (CDCI3, 75 MHz) S 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) v3378, 1636 cm-1 ; HRMS (ESI) m/z
calcd. for C13H17F3N (MH+) 244.1313, found 244.1305.
CA 02562661 2006-10-05
24
(ii) (1 S*,2R*)-1,2-Dimethyl-l-(4-trifluoromethylphenyl)but-3-enylamine (4b)
j 0 H' ~ B(OH)2 H2N Me
7I/
F3C NH3 F3C Me
MeOH 4b
4b was isolated as a clear, colorless oil (d.r. = 96:4). The diastereomeric
ratio
was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz)
S 7.56 (4H, apparent s), 5.75 (1 H, ddd, J = 18.5, 10.5, 8.0 Hz), 5.13 - 5.03
(2H, m), 2.53 (1 H, pentet, J = 7.5 Hz), 1.58 (2H, br s), 1.43 (3H, s), 0.78
(3H,
d, J = 7.5 Hz); 13C NMR (CDCI3, 75 MHz) S 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) v3390, 1637 cm '; 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)
0
B(OH)2 H2N CONH2
I ~ C02Me H_ I \ _ \
/ NH3 / Me
MeOH 4c
4c was isolated as a clear, colorless, crystalline solid (d.r. = 97:3): m.p =
90
C (CH2CI2); 'H NMR (CDCI3, 300 MHz) S 7.65 - 7.58 (2H, m), 7.35 - 7.18
(4H, m), 6.20 (1 H, br s), 5.46 (1 H, ddd, J = 17.5, 10.0, 6.5 Hz), 5.05 -
4.95
(2H, m), 3.59 (1 H, pentet, J = 6.5 Hz), 1.59 (2H, br s), 1.08 (3H, d, J = 6.5
Hz); 13C NMR (CDCI3, 75 MHz) S 176.99, 141.60, 138.23, 128.16, 127.04,
125.64, 116.69, 65.54, 42.58, 12.27; IR (film) v3441, 3207, 1710, 1620, 1637
cm '; HRMS (CI) m/z calcd. for CjjH17N20 (MH+) 205.1341, found 205.1332.
CA 02562661 2006-10-05
(iv) (2S*,3R*)-2-Amino-3-methyl-2-phenylpent-4-enoic acid amide (4d)
0 H\ ~ /B(OH)2 H2N CONH2
C02Me 71/
NH3 / Me
MeOH 4d
5
4d was isolated as a clear, colorless, crystalline solid (d.r. = 96:4): m.p =
136
C (CH2CI2); 'H NMR (CDCI3, 500 MHz) 8 7.64 - 7.60 (2H, m), 7.35 - 7.24
(4H, m), 6.02 (1 H, ddd, J = 17.5, 10.5, 5.0 Hz), 5.59 (1 H, br s), 5.26 (1 H,
dt, J
= 10.5, 1.5 Hz), 5.17 (1 H, dt, J = 17.5, 1.5 Hz), 3.76 - 3.69 (1 H, m), 1.63
(2H,
10 br s), 0.73 (3H, d, J = 7.0 Hz); 13C NMR (CDCI3, 125 MHz) b 177.15, 141.16,
139.07, 128.24, 127.06, 125.54, 117.21, 65.47, 41.87, 10.97; IR (film) v3432,
3170, 1715, 1633 cm '; HRMS (CI) m/z calcd. for CjjH17N20 (MH+) 205.1341,
found 205.1337.
15 (v) (1S*,2S*)-1,2-Dimethyl-l-phenylbut-3-enylamine (4e)
0 B(OH)2 H2N Me
H~
I i NH3 IMe
MeOH 4e
4e was isolated as a clear, colorless oil (d.r. = 97:3). The diastereomeric
ratio
20 was determined by'H NMR of the crude sample. 'H NMR (CDCI3, 300 MHz)
S 7.42 - 7.10 (4H, m), 5.65 -5.55 (1 H, m), 4.96 - 5.02 (2H, m), 2.45 (1 H,
dq, J
= 7.0 Hz), 1.50 (2H, br s), 1.38 (3H, s), 0.83 (3H, d, J = 7.0 Hz); 13C NMR
(CDCI3, 75 MHz) S 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.,
25 2002, 67, 5359].
CA 02562661 2006-10-05
26
(vi) 2-Amino-2,3-dimethylpent-4-enoicacid amide (4f)
0 Y~B~OH~2 H2N CONH2
H _ ~~I
C02Me NH3
Me
if MeOH 4f
4f was isolated as a clear, colorless oil (d.r. = 60:40). The diastereomeric
ratio was determined by 'H NMR of the crude sample. Main diastereomer:'H
NMR (CDCI3, 300 MHz) S 7.41 (1H, br s), 5.95 - 5.60 (2H, m), 5.15 - 5.05
(2H, m), 2.81 (1 H, pentet, J = 6.5 Hz), 1.28 (3H, s), 1.26 (2H, br s), 0.99
(3H,
d, J = 6.5 Hz); 13C NMR (CDCI3, 75 MHz) S 180.06, 139.33, 116.28, 59.62,
43.29, 25.10, 11.88; IR (film) u3444, 3250, 1691, 1654, 1557 cm-1; HRMS
(CI) m/z calcd. for C7H14N20 (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 methylpyruvate (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 a-allylated amino acid derivatives.
CA 02562661 2006-10-05
27
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.
CA 02562661 2006-10-05
28
Table 1: Addition of allyl boron reagents (5) to N-unsubstituted ketimine
derived from la.
0 ~BR2 H2N Me
~ 5 (1.6 equiv.) ~
I/ NH3 (ca. 10 equiv.) Br I/
Br MeOH, rt, 16 h
1a 6a
Entry 5 Yield of 6a
(%)a
O
1 B (5a) 35
~_o
2 10 k (5b) 29
B_O
3 6(O'Pr)2 (5c) 43
4 0 70b'
i ~ ~ (sd)
BO
B(oH)2 (se) 79b
5
a Isolated yield after acid-base extraction. b
Anal sis (H NMR, 2.4,6-trimethylbenzene
standard) of the organic phase from the acid-base
work-up revealed <~% of the , correspondin
homoaIlylic alcohol- Isolated ield after aci -
base extraction and preparative W.
CA 02562661 2006-10-05
29
Table 2: Reaction of N-unsubstituted imines derived from ketones with
allylboronic acid (5e)a.
5e
'5~B(OH)2
O (1.6 equiv) H2N R2
R'R2 NH3 (10 equiv.) R1 " \
1 MeOH, rt, 16 h 6
Entry Ketone Yield
(%)b
1 Et2C=O (1 b) 73 (6b)
O
2 HOI-lk (I c) 80 (6c)
O
3 Ph'-APh (ld) 78 (6d)
O
4 (le) 85 (6e)
4- (1f) 72 (6f)
MeOC6H4C(O)CH2CH3
6 4-NCC6H4C(O)CH3 (lg) 80 (6g)
7 4-O2NC6H4C(O)CH3 (1h) 87 (6h)
O
8 Ph (11) 70 (61)c
O
9 0 0 (1J) 78 (6J)
0
(1 k) 92(6k)
N
Bn
11 s Ph (11) 75(61)
O
0
m) 80 (6m)
12 07N (l
H
Standard reaction conditions: A solution of the
ketone (0.5 mmol), ammonia (ca. 7N in MeOH
5 0.75 mL ca. 10 eguiv.) and alTylboronic acid (5ej
~2M in N~ebOH, 0.40 rnL, 0.80 mmol) was stirred for
6 h at rt. Isolated ield after acid-base extraction.
Isolated yield attyer acid-base extraction, and
preparative 1 LC.
CA 02562661 2006-10-05
Table 3: Reaction of N-unsubstituted imines derived from ketones with
allylboronic acid (5e) in which the ketones contain a pre-existing
stereocentre.
5e (1.6 equiv.) NH2
NH3, MeOH
t Bu \~~ ~
t-Bu16 h, rt
1n 6n
95%, d.r. = 87:13
5e (1.6 equiv.)
NH3, MeOH
(2)
16h,rt 0 NH2
1o 6o
91 %, d.r. = 94:6
O 5e (1.6 equiv.) H2N -//
~Ph NH3, MeOH ~e; Ph (3)
Ph 16 h, rt Ph/ \~
OH OH
1p 6p
81 %, d. r. = 88:12
NHz
5e (1.6 equiv.)
NH3, MeOH
16 h, rt (4)
lq 6q
84%, d.r. = 97:3
5
CA 02562661 2006-10-05
31
Table 4: Reaction of N-unsubstituted ketimines with (E)- and (Z)-crotylboronic
acid (7a/b)a
R3r B(OHh
(2.0equfv.)
)
O 7a: R3 = Me, R4 = H H2N R2
R, R2 7b:R3=H,R4=Me
NH3 (10 equiv.) Rg R
MeOH, rt, 24 h
1 4
Entry Crotyl Product Yield d.r.
reagent (%)"
H2N
1 7a F3CJ\ \ 80 (4a) 97:3
/ =
H2N
2 7b F3C I\ \ 73 (4b)' 96:4
/
3
e~z 3 7a 95 (4c) 97:
H2N CONH2
4 7b I\ \ 92 (4d)'" 96:4
H2N :
7a I\ _\ 50 (4e) 97:3
H2N CONHZ
6 7a 88 (41)' 60:40
Standard reaction conditions: ketone (0.5 mmol)- ammonia (ca. 7N in MeOH,,
0.75
5 mL, ca.,10 e uiv.) and crot~lboronic acid (7a(b) (2M 'n MeOH, 0;50 n~L, 1.00
mmol~
were stirred ~or 24 h at rt. Isolated yiela aTter acid-pase extraction.
Isolated yiel
after acio-base extraction, and preparative, TLC. ~Viethyl benzoylformate wa
em lo ea as the starting ketone and aminol sis oT the _ ester was observed.
Mepthy~pyruvate was empoyed as the startmg ketyone, and ammolysis of the ester
was
observed.
