An efficient three-component one-pot approach to the synthesis of 2,3,4,5-tetrahydro-1H-2-benzazepines by means of rhodium-catalyzed hydroaminomethylation

Article abstract of DOI:10.1021/ol702933g

We have developed a novel and efficient three-component one-pot, catalytic approach for the synthesis of 2,3,4,5-tetrahydro-1H-2-benzazepines, using a rhodium catalyst that does not require phosphine. The isolated yields are excellent and the protocol tol

Full text of DOI:10.1021/ol702933g

ORGANIC
LETTERS
2008
Vol. 10, No. 3
485-487
An Efficient Three-Component One-Pot
Approach to the Synthesis of
2,3,4,5-Tetrahydro-1H-2-benzazepines by
Means of Rhodium-Catalyzed
Hydroaminomethylation†
Tiago O. Vieira and Howard Alper*
Centre for Catalysis Research and InnoVation, Department of Chemistry, UniVersity of
Ottawa, 10 Marie Curie, Ottawa, Ontario, Canada K1N 6N5
howard.alper@uottawa.ca
Received December 4, 2007
ABSTRACT
We have developed a novel and efficient three-component one-pot, catalytic approach for the synthesis of 2,3,4,5-tetrahydro-1H-2-benzazepines,
using a rhodium catalyst that does not require phosphine. The isolated yields are excellent and the protocol tolerates anilines of diverse
basicity.
Significant efforts have been made to develop new methods
for the preparation of heterocyclic compounds.1 A particu-
larly interesting class of heterocycles are the seven-membered
ring benzazepines. The 2-benzazepine moiety constitutes the
core structure of a number of pharmacologically important
(4) (a) Johnson, R. E.; Busacca, C. A. Sterling drug, Inc., U.S. Patent
5,098,901; Chem. Abstr. 1992, 117, 7949j. (b) Fujisawa, Pharmaceutical
Co. Ltd., Japan; Chem. Abstr. 1991, 115, 158987e. (c) Croisier, P.;
Rodriguez, L. UCB S. A., Ger. Offen. 2,733,868 and 2,733,869; Chem.
Abstr. 1978, 88, 152455g and 152456h. (d) Meschino, J. A. McNeil
Laboratories, Inc., U.S. Patent 3,894,072; Chem. Abstr. 1975, 83, 114031e.
(e) Meschino, J. A. McNeil Laboratories, Inc., U.S. Patent 3,828,096; Chem.
Abstr. 1974, 81, 136001f. (f) Meschino, J. A. McNeil Laboratories, Inc.,
U.S. Patent 3,483,186; Chem. Abstr. 1970, 72, 121383x. (g) Fujimura, H.;
Hori, M. Takeda Chemical Industries, Ltd., U.S. Patent 3,409,607; Chem.
Abstr. 1969, 70, 77827c.
† In memoriam of Prof. Helena M. C. Ferraz (1948-2007).
(1) Gilchrist, T. L. In Heterocyclic Chemistry, 3rd ed.; Addison Wes-
ley: Essex, England, 1997; p 414.
(2) Kouznetsov, V.; Palma, A.; Ewert, C. Curr. Org. Chem. 2001, 5,
519.
(3) (a) Banwell, M. G.; Kokas, O. J.; Willis, A. C. Org. Lett. 2007, 9,
3503. (b) Mach, U. R.; Hackling, A. E.; Perachon, S.; Ferry, S.; Wermuth,
C. G.; Schwartz, J.-C.; Sokoloff, P.; Stark, H. ChemBioChem 2004, 5, 508.
(c) May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron Lett. 2003, 44,
1203. (d) Sha, C.-K.; Hong, A.-W.; Huang, C.-M. Org. Lett. 2001, 3, 2177.
(e) Guillou, C.; Beunard, J.-L.; Gras, E.; Thal, C. Angew. Chem., Int. Ed.
2001, 40, 4745. (f) Ollero, L.; Castedo, L.; Dom´ınguez, D. Tetrahedron
Lett. 1998, 39, 1413. (g) Jin, J.; Weinreb, S. M. J. Am. Chem. Soc. 1997,
119, 2050. (h) Clark, M. T.; Chang, J.; Navran, S. S.; Huzoor-Akbar;
Mukhopadhyay, A.; Amin, H.; Feller, D. R.; Miller, D. D. J. Med. Chem.
1986, 29, 181. (i) Holton, R. A.; Sibi, M. P.; Murphy, W. S. J. Am. Chem.
Soc. 1988, 110, 314. (j) Boente, J. M.; Castedo, L.; Cuadros, R.; Saa´, J.
M.; Suau, R.; Perales, A.; Mart´ınez-Ripoll, M.; Fayos, J. Tetrahedron Lett.
1983, 24, 2029. (k) Trybulski, E. J.; Fryer, R. I.; Reeder, E.; Walser, A.;
Blount, J. J. Med Chem. 1983, 26, 1596. (l) Trybulski, E. J.; Benjamin, L.;
Vitone, S.; Walser, A.; Fryer, R. I. J. Med. Chem. 1983, 26, 367.
(5) Feuston, B. P.; Culberson, J. C.; Duggan, M. E.; Hartman, G. D.;
Leu, C.-T.; Rodan, S. B. J. Med. Chem. 2002, 45, 5640.
(6) (a) Ferraccioli, R.; Carenzi, D.; Catellani, M. Tetrahedron Lett. 2004,
45, 6903. (b) Basavaiah, D.; Satyanarayana, T. Chem. Commun. 2004, 32.
(c) Nyerges, M.; Vira´nyi, A.; Pinte´r, A.; To¨ke, L. Tetrahedron Lett. 2003,
44, 793. (d) Kamimura, A.; Taguchi, Y.; Omata, Y.; Hagihara, M. J. Org.
Chem. 2003, 68, 4996. (e) Katritzky, A. R.; Maimait, R.; Xu, Y.-J.;
Akhmedova, R. G. Synthesis 2002, 601. (f) Martins, J. C.; Rompaey, K.
V.; Wittman, G.; To¨mbo¨ly, C.; To´th, G.; De Kimpe, N.; Tourwe´, D. J.
Org. Chem. 2001, 66, 2884. (g) Ga´mez-Montaa˜o, R.; Cha´vez, M. I.; Roussi,
G.; Cruz-Almanza, R. Tetrahedron Lett. 2001, 42, 9. (h) Griesbeck, A. G.;
Mauder, H. Angew. Chem., Int. Ed. Engl. 1992, 31, 73.
10.1021/ol702933g CCC: $40.75
© 2008 American Chemical Society
Published on Web 01/03/2008

compounds.2 Several members of this class have ex-
hibited hypotensive, analgesic, anticonvulsant, antiarrhy-
thimic activities, and have also proved to be useful for the
treatment of mental disorders and hypoxia.3,4 Quite
recently, 2-benzazepines were found to be antagonists
of Rvâ3 integrinsa receptor of glycoproteins assumed to
play a pivotal role in cell-cell adhesion, signaling, and
apoptosis.5 Therefore, the development of simple
and convenient procedures for the synthesis of such sub-
units is a challenging endeavor in synthetic organic chem-
istry.6
Carbonylation strategies to heterocycles have attracted
considerable attention in recent years, and several creative
applications have been described in the literature.7 Further-
more, as the hydroformylation reaction represents an indus-
trially applicable methodology, extension of this technique
toward multistep one-pot transformations is particularly
appealing. A powerful example is the hydroaminomethylation
reaction8san elegant and important industrial process for the
preparation of secondary and tertiary amines. This is a highly
atom economical process that consists of a tandem hydro-
formylation reaction followed by reductive amination.9,10
Thus, this catalytic reaction is consistent with the goals of
“green” chemistry.
Table 1. Screening for the Hydroaminomethylation of 1aa
entry
I (mol %)
CO/H2 (psi)
conv (%)
2a (%)
3 (%)
1
2
3
4
5
5.0
5.0
5.0
6.0
7.5
700/300
700/200
700/100
700/100
700/100
>98
>98
80
90
>98
80
90
>98
>98
>98
20
10
a All reactions were performed on a 0.5 mmol scale in 2.5 mL of toluene.
The percent conversion and the product ratio were determined by 1H NMR
on the crude product mixture.
Having found the optimum conditions, a number of
substrates were used, with different substitution patterns at
the nitrogen. The 2-benzazepines were isolated in excellent
yields (Scheme 2).
Inspired by our recent results concerning the synthesis of
1,2,3,4-tetrahydroquinolines,10a we wondered whether 2-ben-
zazepine motifs could be pursued through Rh-catalyzed
hydroaminomethylation (Scheme 1). Herein, we report a
Scheme 2. Hydroaminomethylation of a Series of
Isopropenylamines
Scheme 1. Envisioned Route for the Synthesis of
2-Benzazepines
The route presented in Scheme 1 begins and ends with
reductive amination. Although the protocol developed thus
far is very attractive, we were interested in determining
whether we could combine the preparation of the starting
materials and the hydroaminomethylation itself into a one-
pot sequential process. Thus, by mixing 2-isopropenylben-
zaldehyde, aniline, and the rhodium catalyst, under the
conditions previously optimized, we were gratified to isolate
2a in 90% yield. To contrast the two methods, the benza-
zepines 2b,c,e were also prepared, through the multicom-
ponent approach, and the high isolated yields were compa-
rable (Scheme 3).
noVel and efficient one-pot catalytic approach for the
synthesis of 2,3,4,5-tetrahydro-1H-2-benzazepines, using a
rhodium catalyst that does not require phosphine.
To check the feasibility of the proposed protocol, a
few experiments were performed using the amine 1a as
the substrate. At higher H2 pressures, hydrogenation of
the substrate occurred in up to 20% yield (Table 1, entry 1).
However, after optimization by use of a 7:1 ratio of
CO/H2, 2a could be obtained as the only product, al-
though using a higher catalyst concentration (Table 1, entry
5).
(7) Mihovilovic, M. D.; Stanetty, P. Angew. Chem., Int. Ed. 2007, 46,
3612.
Scheme 3. One-Pot Synthesis of 2-Benzazepines
(8) Reppe, W.; Vetter, H. Liebigs Ann. Chem. 1953, 582, 133.
(9) For reviews, see: (a) Eilbracht, P.; Schmidt, A. M. Top.
Organomet. Chem. 2006, 18, 65. (b) Beller, M.; Seayad, J.; Tillack, A.;
Jiao, H. Angew. Chem., Int. Ed. 2004, 43, 3368. (c) Eilbracht, P.;
Ba¨rfacker, L.; Buss, C.; Collmann, C.; Kitos-Rzychon, B. E.; Kranemann,
C. L.; Rische, T.; Roggenbuck, R.; Schmidt, A. Chem. ReV. 1999, 99,
3329.
486
Org. Lett., Vol. 10, No. 3, 2008

The hydroaminomethylation reaction is a well-known
protocol, and its mechanism has been previously established.9
However, for our three-component multistep approach, it is
not possible to be certain of the order of the events.
Intuitively, one would anticipate that the initial reductive
amination should happen first, and the hydroformylation of
a trisubstituted double bond should be the rate-determining
step. Some indication of this pathway comes from the use
of 4 as the reactant, which only formed the amine 5 in 90%
yield (eq 1). The reaction stopped after the first reductive
amination, and the hydroformylation could not take place,
probably due to steric hindrance.
Figure 1. Other 2-benzazepines prepared by the three-component
one-pot approach. All reactions were performed by using 0.50 mmol
each of aldehyde and aniline, 7.5 mol % of I, 2.5 mL of toluene,
under 800 psi CO/H2 (7:1), at 120 °C, for 48 h. Isolated yields are
shown.
The scope of the reaction was further investigated by the
preparation of several other 2-benzazepines, through this
multicomponent alternative method, in excellent yields
(Figure 1). The protocol proved to be general and highly
efficient for the diverse nature of benzaldehydes and anilines.
In conclusion, we have discovered a novel and highly atom
economical protocol for the one-pot synthesis of 2-benza-
zepines. Notable features include the following: (a) the air-
stable catalyst does not require added phosphine; (b) the ease
of access of substrates and; (c) the high product yields. This
strategy opens new opportunities for the synthesis of a wide
variety of 2-benzazepines, and to the possibility of building
libraries of pharmaceutically important moieties.
(10) For some examples, see: (a) Vieira, T. O.; Alper, H. Chem.
Commun. 2007, 2710. (b) Ahmed, M.; Buch, C.; Routaboul, L.; Jackstell,
R.; Klein, H.; Spannenberg, A.; Beller, M. Chem. Eur. J. 2007, 13, 1594.
(c) Klein, H.; Jackstell, R.; Kant, M.; Martin, A.; Beller, M. Chem. Eng.
Technol. 2007, 30, 721. (d) Chiou, W.-H.; Mizutani, N.; Ojima, I. J. Org.
Chem. 2007, 72, 1871. (e) Ahmed, M.; Bronger, R. P. J.; Jackstell, R.;
Kamer, P. C. J.; van Leeuwen, P. W. N. M.; Beller, M. Chem. Eur. J.
2006, 12, 8979. (f) Wang, Y. Y.; Luo, M. M.; Chen, H.; Li, X. J. Green
Chem. 2006, 8, 545. (g) Briggs, J. R.; Klosin, J.; Whiteker, G. T. Org.
Lett. 2005, 7, 4795. (h) Routaboul, L.; Buch, C.; Klein, H.; Jackstell, R.;
Beller, M. Tetrahedron Lett. 2005, 46, 7401. (i) Behr, A.; Roll, R. J. Mol.
Catal. A: Chem. 2005, 239, 180. (j) Schmidt, A.; Marchetti, M.; Eilbracht,
P. Tetrahedron 2004, 60, 11487. (k) Ahmed, M.; Seayad, A. M.; Jackstell,
R.; Beller, M. J. Am. Chem. Soc. 2003, 125, 10311. (l) Seayad, A. M.;
Selvakumar, K.; Ahmed, M.; Beller, M. Tetrahedron Lett. 2003, 44, 1679.
(m) Teuma, E.; Loy, M.; Le, Berre, C.; Etienne, M.; Daran, J.-C.; Kalck,
P. Organomethallics 2003, 22, 5261. (n) Lin, Y.-S.; El Ali, B.; Alper, H.
Tetrahedron Lett. 2001, 42, 2423. (o) Zimmermann, B.; Herwig, J.; Beller,
M Angew. Chem., Int. Ed. 1999, 38, 2372. (p) Rische, T.; Mu¨ller, K.-S.;
Eilbracht P. Tetrahedron 1999, 55, 9801. (q) Rische, T.; Eilbracht, P.
Tetrahedron 1999, 55, 1915. (r) Bergmann, D. J.; Campi, E. M.; Jackson,
W. R.; Patti, A. F. Chem. Commun. 1999, 1279. (s) Rische, T.; Kitsos-
Rzychon, B.; Eilbracht, P. Tetrahedron 1998, 54, 2723. (r) Rische, T.;
Eilbracht, P. Synthesis 1997, 1331.
Acknowledgment. We are indebted to SASOL Technol-
ogy and to the Natural Sciences and Engineering Research
Council of Canada for financial support of our research.
Supporting Information Available: Experimental pro-
cedures and full characterization of new compounds are
reported, as well as the NMR spectra for the precursor amines
and the 2-benzazepines prepared. This material is available
free of charge via the Internet at http://pubs.acs.org.
OL702933G
Org. Lett., Vol. 10, No. 3, 2008
487