A titanium-catalyzed three-component coupling to generate α,β-unsaturated β-iminoamines

Article abstract of DOI:10.1021/ja0284714

The three-component coupling of an amine, alkyne, and isonitrile is facilitated by a titanium complex bearing the N,N-di(pyrrolyl-α-methyl)-N-methylamine (dpma) ligand. From this methodology, α,β-unsaturated β-iminoamines are generated regioselectively with many substrates and are available on multigram scales. Copyright

Full text of DOI:10.1021/ja0284714

Published on Web 02/12/2003
A Titanium-Catalyzed Three-Component Coupling To Generate
r,â-Unsaturated â-Iminoamines
Changsheng Cao, Yanhui Shi, and Aaron L. Odom*
Department of Chemistry, Michigan State UniVersity, East Lansing, Michigan 48824
Received September 9, 2002 ; E-mail: odom@cem.msu.edu
Table 1. Examples of Ti(NMe2)2(dpma) (1)-Catalyzed
Three-Component Couplings
Titanium-mediated hydroamination of alkynes by primary amines
has drawn a great deal of recent interest.1 The reactions are often
rapid, regioselective, and utilize inexpensive catalysts. We have
been exploring methodologies to expand the scope of titanium
hydroamination catalysis to generate products outside of imines
and recently published catalysts effective for the 1,1-disubstituted-
hydrazine hydroamination of alkynes, which provides hydrazones
and substituted indoles.2 Continuing in this area, we sought to
identify reactions where three molecules are coupled in a single
synthetic step.3 In this report, we demonstrate that titanium catalysts
are effective for three-component couplings to form R,â-unsaturated
â-iminoamines.
The synthesis of pyrrolyl complex Ti(NMe2)2(dpma) (1), where
dpma is N,N-di(pyrrolyl-R-methyl)-N-methylamine, is shown in eq
1.4 The H2dpma ligand is prepared in a single, high-yielding step
(70-80%) by a Mannich reaction between pyrrole, methylamine
hydrochloride, and formaldehyde.4b Complex 1 is available in near
quantitative yield by treatment of commercially available Ti(NMe2)4
with H2dpma. To avoid isolation of the air-sensitive complex, 1
can be generated in situ with comparable catalytic activity. Catalyst
1 has a relatively broad scope and is applicable for hydroamination
of terminal and internal alkynes by alkyl and arylamines.5
Scheme 1
a R ) 1,1,3,3-tetramethylbutane. b Reactions were carried out at 100 °C
in toluene with 10 mol % 1 and are complete in <48 h. Products were
isolated on multigram scales by column chromatography. c Cy ) cyclohexyl.
d 13% yield of N,N′-phenyl-tert-butylformamidine was isolated. e 15% yield
of N,N′-phenyl-tert-butylformamidine was isolated.
byproduct was produced in sufficient quantities for isolation. Other
reactions had smaller quantities of formamidine observable by GC.
In most cases, 1.1 or 1.2 equiv of isonitrile was employed to
compensate for formamidine generation. Other byproducts for the
reactions are sometimes present in trace quantities; studies are
underway aimed at isolation and structural characterization of these
minor products. The desired compounds were purified and isolated
on multigram scales by column chromatography. The products have
multiple tautomers accessible. For most entries, the more stable
tautomer, as determined by NMR spectroscopy, is shown. Entry
5b is apparently a tautomeric mixture in solution.
A generalized reaction is shown in Scheme 1. The major product
for the substrates shown is due to three-component coupling. Two
byproducts that have been identified from reaction mixtures are
the N,N′-disubstituted-formamidine from reaction of isonitrile with
the primary amine, a reaction catalyzed by several metal com-
plexes.6 In some cases, the imine product from simple alkyne
hydroamination is observed. However, with the substrates inves-
tigated thus far, the imine is generated in only trace quantities as
analyzed by GC-FID of crude reaction mixtures.
With 1 as catalyst, the syntheses were successful with arylamines,
alkylamines, terminal alkynes, and internal alkynes with isonitriles
bearing a quaternary alkyl group. Reactions with phenyl isonitrile
Some representative examples of three-component coupling
reactions are given in Table 1. For entries 1 and 3, the formamidine
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J. AM. CHEM. SOC. 2003, 125, 2880-2881
10.1021/ja0284714 CCC: $25.00 © 2003 American Chemical Society

C O M M U N I C A T I O N S
pyridones.10 We are currently exploring other catalysts, the scope
of this new transformation, and potential one-pot generation of
heterocycles from the product 1-azabutadienes.
Scheme 2
Acknowledgment. The authors appreciate the financial support
of the Petroleum Research Fund, Department of Energy Defense
Programs, and Michigan State University. A.L.O. is an Office of
Naval Research Young Investigator. The authors thank Babak
Borhan for many helpful discussions.
Supporting Information Available: Syntheses and characterization
data for products in Table 1 (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
and cyclohexyl isonitrile have not yielded three-component coupling
products under the same conditions. Alternative conditions, cata-
lysts, and isonitriles are under exploration to further expand the
scope of the reaction.
A couple of control experiments are worthy of note. First, the
three components do not react in the absence of catalyst, even to
form the observed byproducts of the catalysis. Second, treatment
of isolated imine with isonitrile in the presence of catalyst does
not result in the generation of the three-component coupling product.
Consequently, the reaction is not simply hydroamination followed
by a catalyzed reaction with an isonitrile. Apparently, the isonitrile
must be present during the C-N bond forming process to yield
the R,â-unsaturated â-iminoamines.
We propose the catalysis involves the reaction of isonitrile with
an intermediate in hydroamination (Scheme 2). From the established
mechanism for titanium hydroamination,7 a titanium imido complex
can react reversibly with an alkyne to form a metalloazacyclobutene.
Because imine does not generate a three-component coupling
product under the reaction conditions (vide supra), we propose that
the isonitrile insertion occurs prior to protonolysis of the metal-
loazacyclobutene. Consequently, 1,1-insertion of an isonitrile into
a Ti-C bond, which is usually favorable and reversible, generates
a new C-C bond and an iminoacyl complex. Protonolysis of an
iminoacyl-amido intermediate by amine would generate the ob-
served three-component coupling product.
References
(1) (a) Johnson, J. S.; Bergman, R. G. J. Am. Chem. Soc. 2001, 123, 2923-
2924. (b) Siebeneicher, H.; Doye, S. J. Prakt. Chem./Chem.-Ztg. 2000,
342, 102-106. (c) Haak, E.; Bytschkov, I.; Doye, S. Angew. Chem., Int.
Ed. 1999, 38, 3389-3391. (d) Bytschkov, I.; Doye, S. Eur. J. Org. Chem.
2001, 4411-4418. (e) Shi, Y.; Ciszewski, J. T.; Odom, A. L. Organo-
metallics 2001, 20, 3967-3969. (f) Ong, T.-G.; Yap, G. P. A.; Richeson,
D. S. Organometallics 2002, 21, 2839-2841. (g) Ackermann, L.;
Bergman, R. G. Org. Lett. 2002, 4, 1475-1478. (h) Doye, S.; Sibeneicher,
H. Eur. J. Org. Chem. 2002, 1213-1220. (i) Heutling, A.; Doye, S. J.
Org. Chem. 2002, 67, 1961-1964. (j) Haak, E.; Bytschkov, I.; Doye, S.
Eur. J. Org. Chem. 2002, 457-463. (k) Tillack, A.; Castro, I. G.; Hartung,
C. G.; Beller, M. Angew. Chem., Int. Ed. 2002, 41, 2541-2543. (l) Hill,
J. E.; Profilet, R. D.; Fanwick, P. E.; Rothwell, I. P. Angew. Chem., Int.
Ed. Engl. 1990, 29, 664-665.
(2) Cao, C.; Shi, Y.; Odom, A. L. Org. Lett. 2002, 4, 2853-2856.
(3) For recent articles on multicomponent couplings, see: (a) Schreiber, S.
L. Science 2000, 287, 1964-1969. (b) Spring, D. R.; Krishnan, S.;
Blackwell, H. E.; Schreiber, S. L. J. Am. Chem. Soc. 2002, 124, 1354-
1363. (c) Ding, S.; Gray, N. S.; Wu, X.; Ding, Q.; Schultz, P. G. J. Am.
Chem. Soc. 2002, 124, 1594-1596. (d) Hsieh-Wilson, L. C.; Xiang, X.-
D.; Schultz, P. G. Acc. Chem. Res. 1996, 29, 164-170. (e) Do¨mling, A.;
Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168-3210. (f) Bienayme´, H.;
Hulme, C.; Oddon, G.; Schmitt, P. Chem.-Eur. J. 2000, 6, 3321-3329.
For some examples of transition metal-catalyzed three-component cou-
plings, see: (g) Muraoka, T.; Kamiy, S.; Matsuda, I.; Itoh, K. Chem.
Commun. 2002, 1284-1285 and references therein.
(4) (a) Harris, S. A.; Ciszewski, J. T.; Odom, A. L. Inorg. Chem. 2001, 40,
1987-1988. (b) Li, Y.; Turnas, A.; Ciszewski, J. T.; Odom, A. L. Inorg.
Chem. 2002, 41, 6298.
(5) (a) Cao, C.; Ciszewski, J. T.; Odom, A. L. Organometallics 2001, 20,
5011-5013. (b) Cao, C.; Ciszewski, J. T.; Odom, A. L. Organometallics
2002, 21, 5148.
(6) For examples, see: (a) Davis, T. L.; Yelland, W. E. J. Am. Chem. Soc.
1937, 59, 1998-1999. (b) Saegusa, T.; Murase, I.; Ito, Y. J. Org. Chem.
1971, 36, 2876-2880. (c) Bestchart, C.; Hegedus, L. S. J. Am. Chem.
Soc. 1992, 114, 4, 5010-5017.
(7) For mechanistic studies on group 4 metal-catalyzed hydroamination, see:
(a) Straub, B. F.; Bergman, R. G. Angew. Chem., Int. Ed. 2001, 40, 4632-
4635. (b) Sweeney, Z. K.; Salsman, J. L.; Anderson, R. A.; Bergman, R.
G. Angew. Chem., Int. Ed. 2000, 39, 2339-2343. (c) Polse, J. L.;
Anderson, R. A.; Bergman, R. G. J. Am. Chem. Soc. 1998, 120, 13405-
13414. (d) Baranger, A. M.; Walsh, P. J.; Bergman, R. G. J. Am. Chem.
Soc. 1993, 115, 2753-2763. (e) Walsh, P. J.; Baranger, A. M.; Bergman,
R. G. J. Am. Chem. Soc. 1992, 114, 1708-1719. (f) Pohlki, F.; Doye, S.
Angew. Chem., Int. Ed. 2001, 40, 2305-2308.
(8) For recent examples of transition metal â-diketiminate chemistry, see:
(a) Kakaliou, L.; Scanlon, W. J.; Qian, B.; Baek, S. W.; Smith, M. R.,
III; Motry, D. H. Inorg. Chem. 1999, 38, 5964-5977. (b) Fekl, U.;
Goldberg, K. I. J. Am. Chem. Soc. 2002, 124, 6804-6805. (c) Spencer,
D. J. E.; Aboelella, N. W.; Reynolds, A. M.; Holland, P. L.; Tolman, W.
B. J. Am. Chem. Soc. 2002, 124, 2108-2109. (d) Smith, J. M.; Lachicotte,
R. J.; Pittard, K. A.; Cundari, T. R.; Lukat-Rodgers, G.; Rodgers, K. R.;
Holland, P. L. J. Am. Chem. Soc. 2001, 123, 9222-9223. (e) Dai, X.;
Warren, T. H. Chem. Commun. 2001, 1998-1999. For a recent review:
(f) Bourget-Merle, L.; Lappert, M. F.; Severn, J. R. Chem. ReV. 2002,
102, 3031.
Regioselectivities in the three-component coupling reactions
using 1 as catalyst have been similar to results expected from
hydroamination. For example, hydroamination of 1-hexyne by
cyclohexylamine gives a 1.6:1 mixture of Markovnikov:anti-
Markovnikov products.5 Three-component coupling between 1-hex-
yne, cyclohexylamine, and tert-butylisonitrile (entry 5, Table 1)
results in a 1.2:1 mixture of separable regioisomers. Similarly,
cyclohexylamine hydroamination of phenylacetylene with 1 as
catalyst provides a 1:6 Markovnikov:anti-Markovnikov isomer
ratio.5b Consistent with this, the major isomer generated during the
three-component coupling has the nitrogen bearing the cyclohexyl
group â to the phenyl group (entry 6, Table 1). The regioisomer
with the phenyl R to the nitrogen bearing the cyclohexyl group
was observed by GC/FID, ratio of 1:8, but was not isolated.
The products generated during these catalyses are reminiscent
of â-diketimines, which in deprotonated form are common ligands
for both early and late transition metals.8 This titanium catalysis
allows access to highly unsymmetrical derivatives in a single
synthetic step. In addition, 1-azabutadienes can be used in Diels-
Alder reactions to form heterocycles.9 For example, R,â-unsaturated
â-iminoamines react with ketenes to produce 3,4-dihydro-2-
(9) Boger, D. L.; Weinreb, S. N. Hetero Diels-Alder Methodology in Organic
Synthesis, Academic Press: San Diego, 1987.
(10) For a leading example, see: Brady, W. T.; Shieh, C. H. J. Org. Chem.
1983, 48, 2499-2502.
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