Title: Iminoamines and preparation thereof
Abstract: A process is described for producing one or more substituted iminoamines, in particular .beta.-unsaturated .beta.-iminoamines, in a single reaction comprising reacting one or more primary amines, alkynes, and isonitriles in the presence of a transition metal catalytic complex, preferably a titanium metal catalytic complex such as (N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium (Ti(NMe.sub.2).sub.2 (dpma)), under reaction conditions effective for 3-component coupling of the primary amines, alkynes, and isonitriles to produce one or more of the substituted iminoamines.
Patent Number: 6,861,559 Issued on 03/01/2005 to Odom
| Inventors:
|
Odom; Aaron L. (Lansing, MI)
|
| Assignee:
|
Board of Trustees of Michigan State University (East Lansing, MI)
|
| Appl. No.:
|
315269 |
| Filed:
|
December 10, 2002 |
| Current U.S. Class: |
564/272; 273/275; 273/277; 273/279; 556/51 |
| Intern'l Class: |
C07F 007//28; C07C 249//02; C07C 251//12; C07C 251//14; C07C 251//16 |
| Field of Search: |
564/272,273,275,277,279
556/51
|
References Cited [Referenced By]
Other References
Database CAPLUS on STN, Acc. No. 1979:134301, Alvager et al., Advances in
Experimental Medicine and Biology (1978), 97 (Pharmacol. Intervention
Aging Process), p. 293-6 (abstract).*
Becker et al. , Journal of Organic Chemistry (1969), 34(12), p. 4162-4.*
Database CAPLUS on STN, Acc. No. 1968;38739, Feldmann et al., Zeitschrift
fuer Naturforschung, Teil B: Anorganische Chemie, Organische Chemie,
Biochemie, Biophysik, Biologie (1967), 22(7), p. 722-31 (abstract).*
Database CAPLUS on STN, Acc. No. 1982:122764, Lloyd et al., Journal of
Chemical Research, Synopses (1981), 11, p. 356 7 (abstract).*
Schrieber, Science 287: 1964-1969 (2000.
Spring et al., J. Am. Chem. Soc. 124: 1354-1363 (2002).
Ding et al., J. Am. Chem. Soc. 124: 1594-1596 (2002).
Hsieh-Wilson et al., Acc. Chem. Res. 29: 164-170 (1996).
Johnson and Bergman, J. Am. Chem. Soc. 123: 2923-2924 (2001).
Siebeneicher and Doye, J. Prakt. Chem. Ztg. 341: 102-106 (2000).
Haak et al., Angew. Chem. Int. Ed. 38: 3389-3391 (1999).
Bytschkov and Doye, Eur. J. Org. Chem. 4411-4418 (2001).
Shi et al., Organometallics 21: 3967-3969 (2001).
Ong et al., Organometallics 21: 2839-2841 (2002).
Ackermann and Bergman, Org. Lett. 4: 1475-1478 (2002).
Doye and Siebeneicher, Eur. J. Org. Chem. 1231-1240 (2002).
Heutling and Doye, J. Org. Chem. 67: 1961-1964 (2002).
Haak et al., Eur. J. Org. Chem. 457-463 (2002).
Cao et al., Org. Lett. 4: 2853-2866 (2002).
Davis and Yelland, J. Am. Chem. Soc. 59: 1998-1999 (1937).
Saegusa et al., J. Org. Chem. 36: 2876-2880 (1971).
Bestchart and Hegedus, J. Am. Chem. Soc. 114: 5010-5017 (1992).
Harris et al., In Inorg. Che. 40: 1987-1988 (2001).
Straub and Bergman, Angew. Che. Int. Ed. 40: 4632-4635 (2001).
Walsh et al., J. Am. Chem. Soc. 114: 1708-1719 (1992).
Sweeney et al., Agnew. Chem. Int. Ed. 39: 2339-2343 (2000).
Polse et al., J. Cm. Chem. Soc. 120: 13405-13414 (1998).
Baranger et al., J. Cm. Chem. Soc. 115: 2753-2763 (1993).
Pohlki and Doye, Agnew. Chem. Int. Ed. 40: 2305-2308 (2001).
Tillack et al., Agnew. Chem. Int. Ed. 41: 2541-2543 (2002).
Raines and Kovacs, J. Heterocyclic Chem. 7: 233 (1970).
Cao et al., Organometallics 20: 5011-5013 (2001).
Kakaliou et al., Inorg. Chem. 38: 5964-5977 (1999).
Fekl and Goldberg, J. Am. Chem. Soc. 124: 6804-6805 (2002).
Spencer et al., J. Am. Chem. Soc. 124: 2108-2109 (2002).
Smith et al., J. Am. Chem. Soc. 123: 9222-9223 (2002).
Dai and Warren, Chem. Commun. 1998-1999 (2002).
Bourget-Merle et al., Chem. Rev. 102: 3031-3066 (2002).
Brady and Shieh, J. Org. Chem. 48: 2499-2502 (1983).
|
Primary Examiner: Davis; Brian
Attorney, Agent or Firm: McLeod; Ian C.
Claims
I claim:
1. A process for producing a substituted .alpha.,.beta.-unsaturated
.beta.-iminoamine which comprises:
reacting a primary amine, an alkyne, and an isonitrile in the presence of a
catalytic complex comprising a transition metal selected from the group
consisting of titanium, zirconium, hafnium, and unnilquadium and a
chelating ligand in a solvent which does not interfere with the reaction
for coupling the nitrogen of the primary amine to a first carbon of the
triple carbon-carbon bond of the alkyne and coupling the nitrile carbon of
the isonitrile to the second carbon of the triple carbon-carbon bond of
the alkyne to produce the substituted iminoamine.
2. The process of claim 1 wherein the primary amine is selected from the
group consisting of aryl amines, cyclic amines, alkylamines, substituted
aryl amines, substituted cyclic amines, substituted alkylamines, and
combinations thereof.
3. The process of claim 1 wherein the alkyne is selected from the group of
consisting of terminal alkynes, internal alkynes, substituted terminal
alkynes, substituted internal alkynes, and combinations thereof.
4. The process of claim 1 wherein the isonitrile is selected from the group
consisting of alkyl isonitriles, aryl nitriles, substituted alkyl
isonitriles, substituted aryl nitriles, and combinations thereof.
5. The process of claim 1 wherein the ligand is selected from the group
consisting of cyclopentadienyl, thiolate, pyrrolyl, amido, guandininate,
and derivatives thereof.
6. The process of claim 1 wherein the ligand is a chelating pyrrolyl-based
ligand selected from the group consisting of
N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine (dpma),
5,5-dimethyl-dipyrrolylmethane) (dmpm), 5,5-dipropyl-dipyrrolylmethane
(dppm), 5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(mnpm), and derivatives thereof.
7. The process of claim 1 wherein the catalytic complex is selected from
the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
8. The process of claim 1 wherein the catalytic complex is anchored to a
surface of a substrate.
9. The process of claim 8 wherein the substrate is glass or a polymer.
10. The process of claim 8 wherein the substrate is selected from the group
consisting of norbornene, polystyrene, and derivatives thereof.
11. The process of any one of claim 8, 9, or 10 wherein the catalytic
complex is selected from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
12. A process for producing a substituted .alpha.,.beta.-unsaturated
.beta.-iminoamine which comprises:
reacting a primary amine, an alkyne, and an isonitrile in the presence of a
catalytic complex comprising titanium and a chelating ligand in a solvent
which does not interfere with the reaction for coupling the nitrogen of
the primary amine to a first carbon of the triple carbon-carbon bond of
the alkyne and coupling nitrile carbon of the isonitrile to the second
carbon of the triple carbon-carbon bond of the alkyne to produce the
substituted .alpha.,.beta.-unsaturated .beta.-iminoamine.
13. The process of claim 12 wherein the primary amine is selected from the
group consisting of aryl amines, cyclic amines, alkylamines, substituted
aryl amines, substituted cyclic amines, substituted alkylamines, and
combinations thereof.
14. The process of claim 12 wherein the alkyne is selected from the group
of consisting of terminal alkynes, internal alkynes, substituted terminal
alkynes, substituted internal alkynes, and combinations thereof.
15. The process of claim 12 wherein the isonitrile is selected from the
group consisting of alkyl isonitriles, aryl nitriles, substituted alkyl
isonitriles, substituted aryl nitriles, and combinations thereof.
16. The process of claim 12 wherein the ligand is selected from the group
consisting of cyclopentadienyl, thiolate, pyrrolyl, amido, guandininate,
and derivatives thereof.
17. The process of claim 13 wherein the ligand is a chelating
pyrrolyl-based ligand selected from the group consisting of
N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine (dpma),
5,5-dimethyl-dipyrrolylmethane) (dmpm), 5,5-dipropyl-dipyrrolylmethane
(dppm), 5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(mnpm), and derivatives thereof.
18. The process of claim 12 wherein the catalytic complex is selected from
the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
19. The process of claim 12 wherein the catalytic complex is anchored to a
surface of a substrate.
20. The process of claim 19 wherein the substrate is glass or a polymer.
21. The process of claim 19 wherein the substrate is selected from the
group consisting of norbornene, polystyrene, and derivatives thereof.
22. The process of any one of claim 19, 20, or 21 wherein the catalytic
complex is selected from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
23. A process for producing a library of substituted
.alpha.,.beta.-unsaturated .beta.-iminoamines which comprises:
reacting one or more primary amines, one or more alkynes, and one or more
isonitriles in the presence of a catalytic complex comprising a transition
metal selected from the group consisting of titanium, zirconium, hafnium,
and unnilquadium and a chelating ligand in a solvent which does not
interfere with the reaction for coupling the nitrogen of the primary amine
to a first carbon of the triple carbon-carbon bond of the alkyne and
coupling nitrile carbon of the isonitrile to the second carbon of the
triple carbon-carbon bond of the alkyne to produce the library of
substituted iminoamines.
24. The process of claim 23 wherein the primary amines are selected from
the group consisting of aryl amines, cyclic amines, alkylamines,
substituted aryl amines, substituted cyclic amines, substituted
alkylamines, and combinations thereof.
25. The process of claim 23 wherein the alkynes are selected from the group
of consisting of terminal alkynes, internal alkynes, substituted terminal
alkynes, substituted internal alkynes, and combinations thereof.
26. The process of claim 23 wherein the substituted isonitriles are
selected from the group consisting of alkyl isonitriles, aryl nitriles,
substituted alkyl isonitriles, substituted aryl nitriles, and combinations
thereof.
27. The process of claim 23 wherein the ligand is selected from the group
consisting of cyclopentadienyl, thiolate, pyrrolyl, amido, guandininate,
and derivatives thereof.
28. The process of claim 23 wherein the ligand is a chelating
pyrrolyl-based ligand selected from the group consisting of
N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine (dpma),
5,5-dimethyl-dipyrrolylmethane) (dmpm), 5,5-dipropyl-dipyrrolylmethane
(dppm), 5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(mnpm), and derivatives thereof.
29. The process of claim 23 wherein the catalytic complex is selected from
the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
30. The process of claim 23 wherein the catalytic complex is anchored to a
surface of a substrate.
31. The process of claim 30 wherein the substrate is glass or a polymer.
32. The process of claim 30 wherein the substrate is selected from the
group consisting of norbornene, polystyrene, and derivatives thereof.
33. The process of any one of claim 30, 31, or 32 wherein the catalytic
complex is selected from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
34. A process for producing a substituted .alpha.,.beta.-unsaturated
.beta.-iminoamine which comprises:
reacting a primary amine, an alkyne, and an isonitrile in the presence of a
catalytic complex comprising a transition metal selected from the group
consisting of titanium, zirconium, hafnium, and unnilquadium and a
chelating ligand selected from the group consisting of cyclopentadienyl,
thiolate, pyrrolyl, amido, guandininate, and derivatives thereof in a
solvent which does not interfere with the reaction for coupling the
nitrogen of the primary amine to a first carbon of the triple
carbon-carbon bond of the alkyne and coupling nitrile carbon of the
isonitrile to the second carbon of the triple carbon-carbon bond of the
alkyne to produce the substituted .alpha.,.beta.-unsaturated
.beta.-iminoamine.
35. The process of claim 34 wherein the primary amine is selected from the
group consisting of aryl amines, cyclic amines, alkylamines, substituted
aryl amines, substituted cyclic amines, substituted alkylamines, and
combinations thereof.
36. The process of claim 34 wherein the alkyne is selected from the group
of consisting of terminal alkynes, internal alkynes, substituted terminal
alkynes, substituted internal alkynes, and combinations thereof.
37. The process of claim 34 wherein the isonitrile is selected from the
group consisting of alkyl isonitriles, aryl nitriles, substituted alkyl
isonitriles, substituted aryl nitriles, and combinations thereof.
38. The process of claim 34 wherein the ligand is a chelating
pyrrolyl-based ligand selected from the group consisting of
N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine (dpma),
5,5-dimethyl-dipyrrolylmethane) (dmpm), 5,5-dipropyl-dipyrrolylmethane
(dppm), 5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(mnpm), and derivatives thereof.
39. The process of claim 34 wherein the catalytic complex is selected from
the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm))
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
40. The process of claim 34 wherein the catalytic complex is anchored to a
surface of a substrate.
41. The process of claim 40 wherein the substrate is glass or a polymer.
42. The process of claim 40 wherein the substrate is selected from the
group consisting of norbornene, polystyrene, and derivatives thereof.
43. The process of any one of claim 40, 41, or 42 wherein the catalytic
complex is selected from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
44. A process for producing a substituted .alpha.,.beta.-unsaturated
.beta.-iminoamine which comprises:
reacting a primary amine, an alkyne, and an isonitrile in the presence of a
catalytic complex comprising a transition metal selected from the group
consisting of titanium, zirconium, hafnium, and unnilquadium and a
chelating ligand anchored to the surface of a substrate in a solvent which
does not interfere with the reaction for coupling the nitrogen of the
primary amine to a first carbon of the triple carbon-carbon bond of the
alkyne and coupling nitrile carbon of the isonitrile to the second carbon
of the triple carbon-carbon bond of the alkyne to produce the substituted
.alpha.,.beta.-unsaturated .beta.-iminoamine.
45. The process of claim 44 wherein the primary amine is selected from the
group consisting of aryl amines, cyclic amines, alkylamines, substituted
aryl amines, substituted cyclic amines, substituted alkylamines, and
combinations thereof.
46. The process of claim 44 wherein the alkyne is selected from the group
of consisting of terminal alkynes, internal alkynes, substituted terminal
alkynes, substituted internal alkynes, and combinations thereof.
47. The process of claim 44 wherein the isonitrile is selected from the
group consisting of alkyl isonitriles, aryl nitriles, substituted alkyl
isonitriles, substituted aryl nitriles, and combinations thereof.
48. The process of claim 44 wherein the ligand is selected from the group
consisting of cyclopentadienyl, thiolate, pyrrolyl, amido, guandininate,
and derivatives thereof.
49. The process of claim 44 wherein the ligand is a chelating
pyrrolyl-based ligand selected from the group consisting of
N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine (dpma),
5,5-dimethyl-dipyrrolylmethane) (dmpm), 5,5-dipropyl-dipyrrolylmethane
(dppm), 5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(mnpm), and derivatives thereof.
50. The process of claim 44 wherein the catalytic complex is selected from
the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
51. The process of claim 44 wherein the substrate is glass or a polymer.
52. The process of claim 51 wherein the substrate is selected from the
group consisting of norbornene, polystyrene, and derivatives thereof.
53. The process of claim 51 or 52 wherein the catalytic complex is selected
from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
54. A compound which is
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)).
55. A compound which is bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)).
56. A compound selected from the group consisting of
##STR24##
wherein Ph is phenyl, Me is methyl, Cy is cyclohexyl, Bu.sup.t is t-butyl,
and Bu.sup.n is n-butyl wherein R is selected from the group consisting of
linear or branched alkyl and cycloalkyl.
Description
CROSS-REFERENCE TO RELATED APPLICATION
Not applicable.
STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT
Not applicable.
REFERENCE TO A "COMPUTER LISTING APPENDIX SUBMITTED ON A COMPACT DISC"
Not Applicable.
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a process for producing one or more
substituted iminoamines, in particular .beta.-unsaturated
.beta.-iminoamines, in a single reaction comprising reacting one or more
primary amines, alkynes, and isonitriles in the presence of a transition
metal catalytic complex, preferably a titanium metal catalytic complex
such as (N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)), under reaction conditions effective for
3-component coupling of the primary amines, alkynes, and isonitriles to
produce one or more of the substituted iminoamines.
(2) Description of Related Art
One of the goals of methodology development in organic chemistry is to
maximize the molecular complexity of the products which can be obtained in
a single synthetic step (See Corey and Cheng, In The Logic of Chemical
Synthesis, John Wiley & Sons; New York, (1995)). Coupling simple molecules
in a predictable fashion is one means of achieving this goal, and the
potential utility of the reaction is greatly increased if three or more
molecules can be combined in a single synthetic step. For a brief overview
of combinatorial chemistry see Beck-Sickinger and Weber, In Combinatorial
Strategies in Biology and Chemistry, John Wiley & Sons; West Sussex,
England, (2000). For recent articles on diversity-oriented synthesis see
Schrieber, Science 287: 1964-1969 (2000); Spring et al., J. Am. Chem. Soc.
124: 1354-1363 (2002); Ding et al., J. Am. Chem. Soc. 124: 1594-1596
(2002); and Hsieh-Wilson et al., Acc. Chem. Res. 29: 164-170 (1996).
Recently, there has been considerable interest in intermolecular
hydroamination of alkynes by primary amines using catalysts incorporating
rhodium (Hartung et al., J. Org. Chem. 66: 6339-6343 (2001)), palladium
(Kadota et al., J. Org. Chem. 64: 4570-4571 (1999); Yamamoto and
Radhakrishnan, Chem. Soc. Rev. 28: 199-207 (1999)), ruthenium (Tokunaga et
al., Chem. Int. Ed. 38: 3222-3225 (1999)), lanthanides Li and Marks, J.
Am. Chem. Soc. 120: 1757-1771 (1998); Li and Marks, Organometallics 15:
3770-3772 (1996)), actinides (Straub et al., Organometallics 20: 5017-5035
(2001); Haskel et al., Organometallics 15: 3773-3775 (1996); Straub et
al., J. Chem. Soc. Dalton Trans. 2541-2546 (1996)), and titanium (Johnson
and Bergman, J. Am. Chem. Soc. 123: 2923-2924 (2001); Siebeneicher and
Doye, J. Prakt. Chem. Chem. Ztg. 341: 102-106 (2000); Haak et al., Angew.
Chem. Int. Ed. 38: 3389-3391 (1999); Bytschkov and Doye, Eur. J. Org.
Chem. 4411-4418 (2001); Shi et al., Organometallics 21: 3967-3969 (2001);
Ong et al., Organometallics 21: 2839-2841 (2002); Ackermann and Bergman,
Org. Lett. 4: 1475-1478 (2002); Doye and Sibeneicher, Eur. J. Org. Chem.
1231-1220 (2002); Heutling and Doye, J. Org. Chem. 67: 1961-1964 (2002);
and Haak et al., Eur. J. Org. Chem. 457-463 (2002)). Of particular
interest has been the hydroamination of alkynes by primary amines using
catalysts incorporating titanium. The titanium-catalyzed hydroamination
reactions are often rapid, regioselective, and utilize inexpensive
catalysts. More recently, the scope of titanium catalysis was expanded to
produce products outside of imines using a variety of titanium catalysts
for 1,1-disubstitued-hydrazine hydroamination of alkynes, which generates
hydrazones and substituted indoles (Cao et al., Org. Lett. 4: 2853-2866
(2002)(web published on Jul. 26, 2002).
A single-step process for the coupling of three simple molecules via
transition metal catalysis such as titanium catalysis to produce highly
substituted iminoamines would be particularly desirable because such a
process would provide a rapid and inexpensive means for producing useful
iminoamine-based pharmaceutical chemicals. The process would also enable
large libraries of iminoamine-based products to be constructed from
relatively few starting materials which can be screened for useful
pharmaceutical chemicals. The present invention provides a process for
coupling three molecules to produce highly substituted iminoamines in a
single step.
SUMMARY OF THE INVENTION
The present invention provides a process for producing one or more
substituted iminoamines, in particular .beta.-unsaturated
.beta.-iminoamines, in a single reaction comprising reacting one or more
primary amines, alkynes, and isonitriles in the presence of a transition
metal catalytic complex, preferably a titanium metal catalytic complex
such as (N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)), under reaction conditions effective for
3-component coupling of the primary amines, alkynes, and isonitriles to
produce one or more of the substituted iminoamines.
Therefore, the present invention provides a process for producing a
substituted iminoamine which comprises reacting a primary amine, an
alkyne, and an isonitrile in the presence of a catalytic complex
comprising a transition metal and a ligand under reaction conditions
effective for coupling the nitrogen of the primary amine to a first carbon
of the triple carbon-carbon bond of the alkyne and coupling the nitrile
carbon of the isonitrile to the second carbon of the triple carbon-carbon
bond of the alkyne to produce the substituted iminoamine.
The present invention further provides a process for producing a
substituted .alpha.,.beta.-unsaturated .beta.-iminoamine which comprises
reacting a primary amine, an alkyne, and an isonitrile in the presence of
a catalytic complex comprising a transition metal and a ligand under
reaction conditions effective for coupling the nitrogen of the primary
amine to a first carbon of the triple carbon-carbon bond of the alkyne and
coupling nitrile carbon of the isonitrile to the second carbon of the
triple carbon-carbon bond of the alkyne to produce the substituted
.alpha.,.beta.-unsaturated .beta.-iminoamine.
The present invention further provides a process for producing a library of
substituted iminoamines which comprises reacting one or more primary
amines, one or more alkynes, and one or more isonitriles in the presence
of a catalytic complex comprising a transition metal and a ligand under
reaction conditions effective for coupling the nitrogen of the primary
amine to a first carbon of the triple carbon-carbon bond of the alkyne and
coupling nitrile carbon of the isonitrile to the second carbon of the
triple carbon-carbon bond of the alkyne to produce the library of
substituted iminoamines.
In any one of the above processes, the primary amine is selected from the
group consisting of aryl amines, cyclic amines, alkylamines, substituted
aryl amines, substituted cyclic amines, substituted alkylamines, and
combinations thereof; the alkyne is selected from the group of consisting
of terminal alkynes, internal alkynes, substituted terminal alkynes,
substituted internal alkynes, and combinations thereof; and, the
isonitrile is selected from the group consisting of alkyl isonitriles,
aryl nitrites, substituted alkyl isonitriles, substituted aryl nitrites,
and combinations thereof.
In a preferred embodiment of any one of the above processes, the transition
metal comprising the catalytic complex is selected from the group
consisting of titanium, zirconium, hafnium, and unnilquadium, most
preferably, titanium.
In a preferred embodiment of any one of the above processes, the ligand
comprising the catalytic complex is selected from the group consisting of
cyclopentadienyl, thiolate, pyrrolyl, amido, guandininate, and derivatives
thereof. Preferably, the ligand is a chelating pyrrolyl-based ligand
selected from the group consisting of
N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine (dpma),
5,5-dimethyl-dipyrrolylmethane) (dmpm), 5,5-dipropyl-dipyrrolylmethane
(dppm), 5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(mnpm), and derivatives thereof.
In a preferred embodiment of any one of the above processes, the catalytic
complex is selected from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
In a further embodiment of any one of the above processes, the catalytic
complex is anchored to a surface of a substrate, particularly, a substrate
which is glass or a polymer. Examples of suitable substrates include, but
are not limited to, a substrate is selected from the group consisting of
norbornene, polystyrene, and derivatives thereof. Preferably, catalytic
complex anchored to the substrate is selected from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
In a further embodiment, the present invention provides a process for
producing a substituted .alpha.,.beta.-unsaturated .beta.-iminoamine which
comprises reacting a primary amine, an alkyne, and an isonitrile in the
presence of a catalytic complex comprising a transition metal and a ligand
selected from the group consisting of cyclopentadienyl, thiolate,
pyrrolyl, amido, guandininate, and derivatives thereof under reaction
conditions effective for coupling the nitrogen of the primary amine to a
first carbon of the triple carbon-carbon bond of the alkyne and coupling
nitrile carbon of the isonitrile to the second carbon of the triple
carbon-carbon bond of the alkyne to produce the substituted
.alpha.,.beta.-unsaturated .beta.-iminoamine.
In the above process, the primary amine is selected from the group
consisting of aryl amines, cyclic amines, alkylamines, substituted aryl
amines, substituted cyclic amines, substituted alkylamines, and
combinations thereof; the alkyne is selected from the group of consisting
of terminal alkynes, internal alkynes, substituted terminal alkynes,
substituted internal alkynes, and combinations thereof; and, the
isonitrile is selected from the group consisting of alkyl isonitriles,
aryl nitrites, substituted alkyl isonitriles, substituted aryl nitrites,
and combinations thereof.
In a preferred embodiment of the above process, the transition metal
comprising the catalytic complex is selected from the group consisting of
titanium, zirconium, hafnium, and unnilquadium, most preferably, titanium.
In a preferred embodiment of the above process, the ligand comprising the
catalytic complex is a chelating pyrrolyl-based ligand selected from the
group consisting of N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine (dpma),
5,5-dimethyl-dipyrrolylmethane) (dmpm), 5,5-dipropyl-dipyrrolylmethane
(dppm), 5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(mnpm), and derivatives thereof.
In a preferred embodiment of the above process, the catalytic complex is
selected from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
In a further embodiment of the above process, the catalytic complex is
anchored to a surface of a substrate, particularly, a substrate which is
glass or a polymer. Examples of suitable substrates include, but are not
limited to, a substrate is selected from the group consisting of
norbornene, polystyrene, and derivatives thereof. Preferably, catalytic
complex anchored to the substrate is selected from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
In further embodiment, the present invention provides a process for
producing a substituted .alpha.,.beta.-unsaturated .beta.-iminoamine which
comprises reacting a primary amine, an alkyne, and an isonitrile in the
presence of a catalytic complex comprising a transition metal and a ligand
anchored to the surface of a substrate under reaction conditions effective
for coupling the nitrogen of the primary amine to a first carbon of the
triple carbon-carbon bond of the alkyne and coupling nitrile carbon of the
isonitrile to the second carbon of the triple carbon-carbon bond of the
alkyne to produce the substituted .alpha.,.beta.-unsaturated
.beta.-iminoamine.
In the above process, the primary amine is selected from the group
consisting of aryl amines, cyclic amines, alkylamines, substituted aryl
amines, substituted cyclic amines, substituted alkylamines, and
combinations thereof; the alkyne is selected from the group of consisting
of terminal alkynes, internal alkynes, substituted terminal alkynes,
substituted internal alkynes, and combinations thereof; and, the
isonitrile is selected from the group consisting of alkyl isonitriles,
aryl nitrites, substituted alkyl isonitriles, substituted aryl nitrites,
and combinations thereof.
In a preferred embodiment of the above process, the transition metal
comprising the catalytic complex is selected from the group consisting of
titanium, zirconium, hafnium, and unnilquadium, most preferably, titanium.
In a preferred embodiment of the above process, the ligand comprising the
catalytic complex is selected from the group consisting of
cyclopentadienyl, thiolate, pyrrolyl, amido, guandininate, and derivatives
thereof. Preferably, the ligand is a chelating pyrrolyl-based ligand
selected from the group consisting of
N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine (dpma),
5,5-dimethyl-dipyrrolylmethane) (dmpm), 5,5-dipropyl-dipyrrolylmethane
(dppm), 5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(mnpm), and derivatives thereof.
In a preferred embodiment of the above process, the catalytic complex is
selected from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
In a further embodiment of the above process, the catalytic complex is
anchored to a surface of a substrate selected from the group consisting of
norbornene, polystyrene, and derivatives thereof. Preferably, catalytic
complex anchored to the substrate is selected from the group consisting of
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof.
The present invention further provides a compound which is
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)) or bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)).
The present invention further provides a compound selected from the group
consisting of
##STR1##
wherein Ph is phenyl, Me is methyl, Cy is cyclohexyl, Bu.sup.t is t-butyl,
and Bu.sup.n is n-butyl.
The present invention further provides a substituted iminoamine which has
the formula
##STR2##
wherein each R is independently selected from the group consisting of
hydrogen, methyl, alkyl, cycloalky, aryl, alkenyl, arylalkyl, alkylaryl,
arylalkenyl, alkenylaryl linear or branched, combinations thereof, and
substituted derivatives thereof.
OBJECTS
It is an object of the present invention to provide a transition
metal-catalyzed process for producing substituted iminoamine compounds.
It is a further object of the present invention to provide a transition
metal-catalyzed process for coupling three reactants to produce the
substituted iminoamine compounds
It is an object further still of the present invention to provide a
transition metal-catalyzed process for coupling three reactants to produce
.alpha.,.beta.-unsaturated .beta.-iminoamine derivatives.
It is an object further still of the present invention to provide a
transition metal-catalyzed process for coupling three reactants to produce
diimino-1,3-propandione derivatives.
These and other objects of the present invention will become increasingly
apparent with reference to the following drawings and preferred
embodiments.
DETAILED DESCRIPTION OF THE INVENTION
All patents, patent applications, government publications, government
regulations, and literature references cited in this specification are
hereby incorporated herein by reference in their entirety. In case of
conflict, the present description, including definitions, will control.
The present invention has provided a solution to the problem of providing a
general and efficient process for maximizing the molecular products that
can be obtained in a single synthetic step. It has been discovered that
transition metal catalysis, titanium catalysis in particular, can be used
in a process to couple one or more primary amine, isonitriles, and alkyne
reactants to form highly substituted iminoamine products, which are
substituted .alpha.,.beta.-unsaturated .beta.-iminoamines or
diimino-1,3-propandione derivatives. Thus, the process provides for the
synthesis of substituted iminoamine products with the general structure of
##STR3##
wherein each R is independently selected from the group consisting of
hydrogen, methyl, alkyl, cycloalkyl, aryl, alkenyl, arylalkyl, alkylaryl,
arylalkenyl, alkenylaryl linear or branched, combinations thereof, and
substituted derivatives thereof.
The reaction is illustrated in Scheme 1 wherein each R of the primary
amine, alkyne, and isonitrile reactants is as above and the solvent is any
solvent which does not interfere with formation of the substituted
iminoamine.
##STR4##
As shown in Scheme 1, the process couples one or more primary amine,
alkyne, and isonitrile reactants in the presence of a transition metal
catalytic complex to produce one or more iminoamines as the major product.
The preferred primary amine reactants include, but are not limited to,
substituted or unsubstituted alkyl amines, aryl amines (including
heteroaromatic, polyaromatic, and heteropolyaromatic hydrocarbon amines),
cyclic amines (including heterocyclic, polycyclic, and heteropolycyclic
amines), or combinations thereof. The preferred alkynes include, but are
not limited to, substituted and unsubstituted terminal alkynes, internal
alkynes, or combinations thereof (including cyclic, heterocyclic,
polycyclic, and heteropolycyclic alkynes). The preferred isonitriles
include, but are not limited to, substituted or unsubstituted alkyl
isonitriles, aryl isonitriles (including heteroaromatic, polyaromatic, and
heteropolyaromatic hydrocarbon isonitriles), cyclic isonitriles (including
heterocyclic, polycyclic, and heteropolycyclic isonitriles) and
combinations thereof. The term "substituted" when referring to the primary
amines, alkynes, and isonitriles means that the R groups of the primary
amines, alkynes, and isonitriles as shown in Scheme 1 include N, O, Cl,
Br, B, and the like. When referring to the iminoamine product, the term
"substituted" refers to the iminoamine as shown above and in Scheme 1.
Preferably, the reactants are mixed together before adding to the solvent
containing the catalytic complex or mixed together in the solvent before
adding the catalytic complex.
The identified minor products (by-products) of the process include
disubstituted formamidine produced from the reaction of the isonitrile
with the primary amine and substituted imine produced by simple alkyne
hydroamination. The production of disubstituted formamidine can be
catalyzed by several metal catalytic complexes (For example, see Davis and
Yelland, J. Am. Chem. Soc. 59: 1998-1999 (1937); Saegusa et al., J. Org.
Chem. 36: 2876-2880 (1971); and Bestchart and Hegedus, J. Am. Chem. Soc.
114: 5010-5017 (1992)). In general, the disubstituted formamidine is
produced in yields less than 15% and the substituted imine is produced in
only trace amounts.
The transition metal comprising the catalytic complex is coupled to a
ligand. Preferably, the transition metal is a Group-4 transition metal
such as titanium, zirconium, hafnium, unnilquadium, or the like. Most
preferably the transition metal is titanium. The transition metal can be
coupled to a ligand such as cyclopentadienyl, thiolate, pyrrolyl, amido,
guandininate, and derivatives thereof. A preferred ligand is a chelating
pyrrolyl-based ligand.
In a preferred embodiment, the catalytic complex is a titanium catalytic
complex which comprises a chelating pyrrolyl-based ligand. Examples of
chelating pyrrolyl-based ligands include, but are not limited to, of
N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine (dpma),
5,5-dimethyl-dipyrrolylmethane) (dmpm), 5,5-dipropyl-dipyrrolylmethane
(dppm), 5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(mnpm), and derivatives thereof. Chelation allows the synthesis of stable
catalytic complexes with an .eta..sup.1 -coordination of the pyrrolyl
substituents on the titanium as opposed to an .eta..sup.5 -coordination.
The catalysts produced using chelating pyrrolyl-based ligands have high
Lewis acidity. In a most preferred embodiment, the titanium catalytic
complex is
bis(dimethylamido)(N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine)titanium
(Ti(NMe.sub.2).sub.2 (dpma)),
(bis(dimethylamido)(5,5-dipropyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dppm)),
bis(dimethylamido)(5,5-dimethyl-dipyrrolylmethane)titanium
(Ti(NMe.sub.2).sub.2 (dmpm)), bis(dimethylamido)
5-methyl-5-ethylene-bicyclo[2.1.1]hept-2-ene-dipyrrolylmethane
(Ti(NMe.sub.2).sub.2 (mnpm)), and derivatives thereof. The structure of
Ti(NMe.sub.2).sub.2 (dpma) was reported by Harris et al. in Inorg. Chem.
40: 1987-1988 (2001) and has the structure shown below.
##STR5##
Examples of other catalytic complexes include, but are not limited to,
cyclopentadienyltitanium-imido complexes and zirconium bisamides such as
CpTi.dbd.NR(NHR) and Cp.sub.2 Zr(NHR).sub.2, respectively, wherein Cp is
cyclopentadienyl and R is 2,6-Me.sub.2 C.sub.6 H.sub.3 or methyl, alkyl,
aryl, amide, or derivatives thereof (Straub and Bergman, Angew. Chem. Int.
Ed. 40: 4632-4635 (2001); Walsh et al. J. Am. Chem. Soc. 114: 1708-1719
(1992)); enantiopure zirconocene imido complexes such as
(ebthi)(L)Zr.dbd.NR wherein ebthi is bis(tetrahydroindenyl)ethane, L is
tetrahydrofuran, and R is methyl, alkyl, aryl, amide, or derivatives
thereof (Sweeney et al., Agnew. Chem. Int. Ed. 39: 2339-2343 (2000));
base-free titanocene imido complexes such as Cp*.sub.2 Ti.dbd.NPh wherein
Cp* is pentamethylcyclopentadienyl and Ph is phenyl (Polse et al., J. Am.
Chem. Soc. 120: 13405-13414 (1998)); imidozirconium complexes such as
Cp.sub.2 Zr.dbd.NAr (Baranger et al., J. Am. Chem. Soc. 115: 2753-2763
(1993)); dimethyltitanocene complexes such as Cp.sub.2 TiMe.sub.2 (Pohlki
and Doye, Agnew. Chem. Int. Ed. 40: 2305-2308 (2001); Ti(Me.sub.2).sub.4
(Shi et al., Organometal. 20: 3967-3969 (2001); guanidinate-supported
metal imido complexes such as {(Me.sub.2 N)C(N.sup.i Pr).sub.2 }.sub.2
TiNAr and {(Me.sub.2 N)C(N.sup.i Pr).sub.2 }.sub.2 ZrNAr (Ong et al.,
Organometal. 21-2839-2841 (2002)); tetrakisamido titanium complexes
(Ackermann and Bergman, Org. Letts. 4: 1475-1478 (2002); and, titanocene
alkyne complexes such as Cp.sub.2 Ti(.eta..sup.2 -Me.sub.3
SiC.ident.CSiMe.sub.3) and CP.sub.2 Ti(.eta..sup.2 -Me.sub.3
SiC.ident.CSiPh) (Tillack et al., Agnew. Chem. Int. Ed. 41: 2541-2543
(2002).
While the solvent can be any solvent which does not interfere with the
3-component coupling process, a preferred solvent is an aprotic solvent
including, but not limited to, aromatic hydrocarbons such as toluene and
xylene, chlorinated aromatic hydrocarbons such as dichlorobenzene, and
ethers such as tetrahydrofuran. The amount of solvent can be any amount
but preferably an amount sufficient to solubilize, at least in part, the
reactants. A suitable quantity of solvent ranges from about 1 to about 100
grams of solvent per gram of reactants. Other quantities of solvent may
also be suitable depending on the particular reaction conditions and by
one skilled in the art.
The 3-component coupling process can be performed in a vessel open to air
or in a vessel in which the air has been removed. In cases where the air
is removed, the reaction mixture can be purged of air with a non-reactive
gas such as nitrogen, helium, or argon. Thus, the 3-component coupling
process can be performed under anaerobic conditions. The 3-component
coupling process conditions can include any operable conditions which
yield the desired coupled products. For example, the preferred temperature
can be a temperature from ambient (about 22.degree. C.) to about
200.degree. C., preferably at about 100.degree. C. The 3-component
coupling process can be performed at atmospheric pressure or at a pressure
lesser or greater than atmospheric pressure. The 3-component coupling
process is performed for a time sufficient to convert a substantial amount
of the reactants into the desired coupled product. In general, the
reaction time for producing a desired coupled product ranges from about 24
to 48 hours. The coupled products produced in a 3-component coupling
reaction can include at least 50% or greater of one regioisomer.
In a preferred 3-component coupling process, the catalytic complex is
selected from the group consisting of Ti(NMe.sub.2).sub.2 (dpma),
Ti(NMe.sub.2).sub.2 (dmpm), Ti(NMe.sub.2).sub.2 (dppm), and
Ti(NMe.sub.2).sub.2 (mnpm). Preferably, the catalytic complex is provided
in the reaction at about 10 mol % in an organic solvent which preferably
is toluene, and the reaction is performed at about 100.degree. C. The
preferred 3-component coupling process is illustrated in Examples 2 to 10.
The 3-component coupling process can be performed in any conventional
reactor designed for catalytic processes. Continuous, semi-continuous, and
batch reactors can be used. If the catalyst is substantially dissolved in
the reaction mixture as in homogeneous processes, then batch reactors,
including stirred tank and pressurized autoclaves can be used. In a
typical reaction, the reactants and catalyst are mixed in a solvent and
the reaction performed in a batch reactor at a temperature and pressure
effective for 3-component coupling.
Catalytic complexes containing dipyrrolylmethane ligands can be tethered to
surfaces such as norbornene, polystyrene, glass, or other polymers in
several different ways. If the catalyst is anchored to a support and is
substantially in a heterogeneous phase, then fixed-bed and fluidized bed
reactors can be used. For example, a titanium-dipyrrolylmethane derivative
with a norbornene tethered to the 5-position is co-polymerized with
norbornene to give a copolymer with the catalytic complex attached.
The 3-component coupling process can include one each of a particular
substituted or unsubstituted primary amine, alkyne, and isonitrile to
produce a particular species of coupled product. Alternatively, the
3-component coupling process can include any number of substituted or
unsubstituted primary amines, any number of substituted or unsubstituted
alkynes, and any number of substituted or unsubstituted isonitriles to
produce a library containing a plurality of coupled products.
The coupled products can be isolated by conventional means known to those
skilled in the art, including for example, chromatography, distillation,
crystallization, and sublimation. The yield of major and minor products
will depend on the particular catalytic complexes, reactants, solvent, and
process conditions used. Typically, the product yields are in terms of
mole percentage of product recovered.
The inexpensive, readily-available or synthesizable transition metal
catalytic complexes, such as the titanium catalytic complexes, catalyze a
3-component coupling of an isonitrile, an amine, and alkyne. The reaction
products produced are often diimino-1,3-propanedione derivatives. Highly
unsymmetrical compounds are produced, often with high regioselectivity.
The products are also ligands which are often used for both early and late
transition metals. Complexes of these ligands can be olefin polymerization
catalysts. The products are also useful as starting materials for a
variety of common organic transformations which can lead to production of
important compounds for pharmaceutical or other applications. Because many
of the diimino-1,3-propanedione derivatives can be prepared from
relatively few starting materials using combinatorial methods, the
titanium catalysts and process of the present invention are of particular
interest to those interested in olefin polymerization and pharmaceuticals.
The 3-component coupling process of the present invention provides several
advantages over the processes of the prior art. First, the reaction
couples three simple starting materials in a single step. The advantage is
that using combinatorial methodologies, relatively few starting materials
can be combined to produce a large library of compounds for testing in
specific applications.
Second, the coupled products are highly unsymmetrical and a single reaction
often yields only a single isomer of coupled product. This advantage
avoids the time and expense of purifying various isomers of a particular
coupled product.
Third, the 3-component coupling process enables coupled products to be
produced which are inaccessible using prior art processes. For example,
diimines of 2-mesityl-2,4-pentandione cannot be prepared using prior art
condensation methods. However, regiochemical data indicates that
functional derivatives of those diimines should be accessible using the
3-component coupling process disclosed herein.
The following examples are intended to promote a further understanding of
the present invention.
EXAMPLE 1
This example shows the synthesis of the titanium catalytic complex,
titanium pyrroyl complex Ti(NMe.sub.2).sub.2 (dpma), wherein dpma is
N,N-di(pyrrolyl-.alpha.-methyl)-N-methylamine. The H.sub.2 dpma ligand was
prepared in a single, high-yielding step (70-80%) by Mannich reaction
between pyrrole, methylamine hydrochloride, and formaldehyde in a
modification of the process in Raines and Kovacs, J. Heterocyclic Chem. 7:
233 (1970) as described in Harris et al., Inorg. Chem. 40: 1987-1988
(2001). Synthesis of the Ti(NMe.sub.2).sub.2 (dpma) is shown in Equation
1.
##STR6##
The Ti(NMe.sub.2).sub.2 (dpma) was prepared in near quantitative yield by
treatment of commercially available Ti(NMe.sub.2).sub.4 with the H.sub.2
dpma as described below.
Briefly, Ti(NMe.sub.2).sub.4 (1.098 g, 3.1704 mmol) was dissolved in
Et.sub.2 O (10 mL) and chilled to -35.degree. C. A 5 mL solution of
H.sub.2 dpma (0.600 g, 3.1704 mmol) in Et.sub.2 O was added dropwise.
After 30 minutes, the volatiles were removed and a yellow powder remained.
X-ray quality crystals were obtained from pentane/Et.sub.2 O at
-35.degree. C. in 97.1% yield (0.955 g). .sup.1 H NMR (300 MHz,
CDCl.sub.3): .delta.6.89(m, 2H), 6.07(m, 2H), 5.90(m, 2H) 4.03 (d, J=14
Hz, 2H), 3.75 (d, J=14 Hz, 2H), 3.30 (s, 12H), 2.49 (s, 3H). .sup.13 C NMR
(CDCl.sub.3): .delta.137.40, 126.64, 107.62, 102.54, 57.90, 47.18, 45.90,
42.82. MS (70 eV): m/z(%) 323.4(0.18)[M.sup.+ ]. Elemental Anal. Calc. For
C.sub.15 H.sub.25 N.sub.5 Ti: C, 55.73; H, 7.80; N, 21.66. Found: C,
55.64; H, 7.52; N, 21.38.
To avoid isolation of the air-sensitive complex, Ti(NMe.sub.2).sub.2 (dpma)
can be readily produced in situ with comparable catalytic activity.
Ti(NMe.sub.2).sub.2 (dpma) has a relatively broad scope and is applicable
for hydroamination of terminal and internal alkynes by alkyl and aryl
amines (Cao et al., Organometallics 20: 5011-5013 (2001)). A competing
reaction leading to oligomerization of terminal alkynes is only observed
when the alkyne has appreciable acidity, for example, phenylacetylene.
EXAMPLE 2
This example shows that Ti(NMe.sub.2).sub.2 (dpma) catalyzes the
3-component coupling of isonitriles, primary amines, and alkynes to
produce highly substituted iminoamines in a single step reaction. The
generalized reaction was as shown in Scheme 1 wherein the solvent was
toluene.
The major products for the majority of the substrates used were due to
3-component coupling. Two by-products that had been identified from the
reaction mixtures were N,N'-disubstituted-formamidine from the reaction of
isonitrile with the primary amine and substituted imines. The
disubstituted formamidines were the most common by-product and were found
in the largest quantities for reactions involving internal alkynes. In
some cases, the substituted imines from simple alkyne hydroamination were
also observed. However, with the substrates investigated so far, the imine
by-product was produced in only trace quantities as analyzed by GC-FID of
crude reaction mixtures. The desired product was isolated by
chromatography on silica gel.
Some representative examples of 3-component coupling reactions are given in
Table 1. The listing of substrates in Table 1 includes alkyl amines, aryl
amines, terminal alkynes, internal alkynes, alkyl isonitriles, and aryl
nitrites. In a couple of cases, the formamidine by-products were produced
in sufficient quantities to allow isolation (by-product 1a), and in those
cases the yields for the formamidine by-products are provided. Other
reactions had smaller quantities of formamidine observable by GC. In most
cases, 1.1 or 1.2 equivalents of isonitrile was used to compensate for
formamidine production. Other by-products for the reactions were sometimes
present (not shown). Because these by-products can be useful, studies are
underway which are aimed at isolation and structural characterization of
the by-products.
TABLE 1
Amine Alkyne Isonitrile.sup.a Product.sup.b (% yield) By-product
(% yield)
PhNH.sub.2 Bu.sup.n --.ident.--H C.ident.N--Bu.sup.t ##STR7##
##STR8##
PhNH.sub.2 Bu.sup.n --.ident.--H C.ident.N--R ##STR9## --
PhNH.sub.2 Ph--.ident.--Me C.ident.N--Bu.sup.t ##STR10##
##STR11##
PhNH.sub.2 Ph--.ident.--Me C.ident.N--R ##STR12## --
CyNH.sub.2.sup.c Bu.sup.n --.ident.--H C.ident.N--Bu.sup.t ##STR13##
--
CyNH.sub.2.sup.c Ph--.ident.--H C.ident.N--R ##STR14## --
.sup.a R = 1,1,3,3-tetramethylbutane
.sup.b Reactions were carried out at 100.degree. C. in toluene with 10 mol
% Ti(NMe.sub.2).sub.2 (dpma). The products were isolated on multigram
scales by chromatography.
.sup.c Cy = cyclohexyl
Reaction conditions and analyses for the products are provided in Examples
6-10.
The desired compounds were purified and isolated on multigram scales by
column chromatography. The products have multiple tautomers accessible.
For most of the reactions, the more stable tautomer, as determined by NMR
spectroscopy, is shown. Product 5b appears to be a tautomeric mixture in
solution.
With Ti(NMe.sub.2).sub.2 (dpma) as the catalyst, the synthesis was
successful with aryl amines, alkyl amines, terminal alkynes, and internal
alkynes with isonitriles bearing a quarternary alkyl group. Reactions with
phenyl isonitrile and cyclohexyl isonitrile have not yielded 3-component
coupling products under the same conditions. Alternative reaction
conditions, catalysts, and the like, are under exploration with the
substrates.
A couple of control experiments were performed which provided the following
information. First, the three components did not react in the absence of
the catalyst, even to form the observed by-products of the catalytic
reaction. Second, treatment of isolated imine with isonitrile in the
presence of the catalyst did not result in the production of the
3-component coupling product. Therefore, the reaction was not merely
hydroamination followed by catalyzed reaction with an isonitrile. The
isonitrile must be present during the C--N bonding forming reaction to
yield the substituted .alpha.,.beta.-unsaturated .beta.-iminoamine
products.
In light of the above, the 3-component coupling reaction most likely
operates as follows. The catalysis involves the selective reaction of the
isonitrile with an intermediate in the hydroamination catalysis.
Schematically, the product would be produced from 1,1-insertion of the
isonitrile into the metalloazacyclobutane intermediate formed on (2+2)
cycloaddition of alkyne to a titanium terminal imido. For mechanistic
studies on Group-4 metal catalyzed hydroamination see Straub and Bergman,
Angew. Chem. Int. Ed. 40: 4632-4635 (2001); Sweeney et al., Angew. Chem.
Int. Ed. 39: 2339-2343 (2000); Polse et al., J. Am. Chem. Soc. 120:
13405-13414 (1998); Baranger et al., J. Am. Chem. Soc. 115: 2753-2761
(1993); Walsh
