Synthesis of five-, six-, and seven-membered ring lactams by Cp*Rh complex-catalyzed oxidative N-heterocyclization of amino alcohols

Article abstract of DOI:10.1021/ol0489954

A new effective catalytic system consisting of [Cp*RhCl ₂]₂/K₂CO₃ (Cp* = pentamethylcyclopentadienyl) for the lactamization of amino alcohols has been developed. As an example, the reaction of 3-(2-aminophenyl)-1-propanol in the presence of [Cp*RhCl₂]₂ (5.0% Rh) and K ₂CO₃ (10%) in acetone gives 3,4-dihydro-2(1H)-quinolinone in an isolated yield of 80%. A variety of five-, six-, and seven-membered benzo-fused lactams are synthesized by this catalytic system.

Full text of DOI:10.1021/ol0489954

ORGANIC
LETTERS
2004
Vol. 6, No. 16
2785-2788
Synthesis of Five-, Six-, and
Seven-Membered Ring Lactams by
Cp*Rh Complex-Catalyzed Oxidative
N-Heterocyclization of Amino Alcohols
Ken-ichi Fujita,* Yoshinori Takahashi, Maki Owaki, Kazunari Yamamoto, and
Ryohei Yamaguchi*
Graduate School of Human and EnVironmental Studies, Kyoto UniVersity,
Kyoto 606-8501, Japan
fujitak@kagaku.mbox.media.kyoto-u.ac.jp
Received June 1, 2004
ABSTRACT
A new effective catalytic system consisting of [Cp*RhCl2]2/K2CO (Cp* ) pentamethylcyclopentadienyl) for the lactamization of amino alcohols
3
has been developed. As an example, the reaction of 3-(2-aminophenyl)-1-propanol in the presence of [Cp*RhCl2]2 (5.0% Rh) and K2CO (10%)
3
in acetone gives 3,4-dihydro-2(1H)-quinolinone in an isolated yield of 80%. A variety of five-, six-, and seven-membered benzo-fused lactams
are synthesized by this catalytic system.
The benzo-fused lactam skeleton is an important element in
a number of pharmacologically and biologically active
compounds. Particularly, oxindole, dihydroquinolinone, and
tetrahydrobenzazepinone derivatives are found in many
natural products, marketed drugs, and drug candidates.1 In
this context, it is quite important to develop an efficient
method for the synthesis of these compounds. Although a
number of noncatalyzed,2 transition metal-catalyzed,3,4 pho-
tochemical,5 and radical-mediated6 reactions for the synthesis
of oxindoles have been developed, there have been only a
few examples of simple and efficient catalytic synthesis of
tetrahydroquinolinones and tetrahydrobenzazepinones.7
We are currently studying the catalytic activity of group
9 metals bearing pentamethylcyclopentadienyl (Cp*) ligands
toward hydrogen-transfer reactions8,9 and have reported
intramolecular N-alkylation of amino alcohols catalyzed by
a Cp*Ir complex (eq 1, left arrow).8b During the investigation
(3) Palladium-catalyzed reactions: (a) Hennessy, E. J.; Buchwald, S. L.
J. Am. Chem. Soc. 2003, 125, 12084. (b) Culkin, D. A.; Hartwig, J. F. Acc.
Chem. Res. 2003, 36, 234. (c) Zhang, T. Y.; Zhang, H. Tetrahedron Lett.
2002, 43, 193. (d) Lee, S.; Hartwig, J. F. J. Org. Chem. 2001, 66, 3402. (e)
Ashimori, A.; Bachand, B.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc.
1998, 120, 6477. (f) Ashimori, A.; Bachand, B.; Calter, M. A.; Govek, S.
P.; Overman, L. E.; Poon, D. J. J. Am. Chem. Soc. 1998, 120, 6488. (g)
Shaughnessy, K. H.; Hamann, B. C.; Hartwig, J. F. J. Org. Chem. 1998,
63, 6546.
(4) Rhodium-catalyzed reactions: (a) Hirao, K.; Morii, N.; Joh, T.;
Takahashi, S. Tetrahedron Lett. 1995, 36, 6243. (b) Brown, D. S.; Elliott,
M. C.; Moody, C. J.; Mowlem, T. J.; Marino, J. P., Jr.; Padwa, A. J. Org.
Chem. 1994, 59, 2447. (c) Doyle, M. P.; Shanklin, M. S.; Pho, H. Q.;
Mahapatro, S. N. J. Org. Chem. 1988, 53, 1017.
(5) Goehring, R. R.; Sachdeva, Y. P.; Pisipati, J. S.; Sleevi, M. C.; Wolfe,
J. F. J. Am. Chem. Soc. 1985, 107, 435.
(6) (a) Jones, K.; McCarthy, C. Tetrahedron Lett. 1989, 30, 2657. (b)
Bowman, W. R.; Heaney, H.; Jordan, B. M. Tetrahedron Lett. 1988, 29,
6657.
(7) (a) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35. (b) Wolfe,
J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52, 7525. (c) Ali,
B. E.; Okuro, K.; Vasapollo, G.; Alper, H. J. Am. Chem. Soc. 1996, 118,
4264. (d) Jones, K.; Wilkinson, J.; Ewin, R. Tetrahedron Lett. 1994, 35,
7673.
(1) (a) Marti, C.; Carreira, E. M. Eur. J. Org. Chem. 2003, 2209. (b)
Oshiro, Y.; Sakurai, Y.; Sato, S.; Kurahashi, N.; Tanaka, T.; Kikuchi, T.;
Tottori, K.; Uwahodo, Y.; Miwa, T.; Nishi, T. J. Med. Chem. 2000, 43,
177. (c) Zhao, H.; Thurkauf, A.; Braun, J.; Brodbeck, R.; Kieltyka, A.
Bioorg. Med. Chem. Lett. 2000, 10, 2119. (d) Tamura, S. Y.; Goldman, E.
A.; Bergum, P. W.; Semple, J. E. Bioorg. Med. Chem. Lett. 1999, 9, 2573.
(e) Murakami, Y.; Hara, H.; Okada, T.; Hashizume, H.; Kii, M.; Ishihara,
Y.; Ishikawa, M.; Shimamura, M.; Mihara, S.; Kato, G.; Hanasaki, K.;
Hagishita, S.; Fujimoto, M. J. Med. Chem. 1999, 42, 2621. (f) Jossang, A.;
Jossang, P.; Hadi, H. A.; Se´venet, T.; Bodo, B. J. Org. Chem. 1991, 56,
6527. (g) Wiseman, E. H.; Chiaini, J.; McManus, J. M. J. Med. Chem.
1973, 16, 131.
(2) Beckett, A. H.; Daisley, R. W.; Walker, J. Tetrahedron 1968, 24,
6093 and references therein.
10.1021/ol0489954 CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/07/2004

Table 1. Synthesis of 3,4-Dihydro-2(1H)-quinolinone (2a)
from 3-(2-Aminophenyl)-1-propanol (1a) under Various
Catalytic Conditionsa
Table 2. Synthesis of Various Six- and Seven-Membered
Benzo-Fused Lactams from Amino Alcohols Catalyzed by the
[Cp*RhCl2]2/K2CO3 Systema
entry
catalyst
base
yieldb (%)
1
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
Cp*Rh(OAc)2‚H2O
RhCl(PPh3)3
[RhCl(CO)2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
Na2CO3
Et3N
81
62
72
f
28
43
0
2c
3d
4e
5
6
7
8
9
46
0
a Reaction was carried out in a heavy-walled glass reactor at 100 °C for
20 h with 1a (0.50 mmol), catalyst (5.0% Rh), and base (10%) in acetone
(12.5 mL). b Determined by GC. c Reaction temperature was 80 °C.
d Amount of acetone was 6.3 mL. e Reaction was carried out in toluene
(12.5 mL) instead of acetone. f 1,2,3,4-Tetrahydroquinoline (32%) was
isolated in addition to a small amount of 2a (ca. 5%).
on this reaction in further detail, we found that intramolecular
lactamization proceeded instead of N-alkylation when the
reaction was carried out with Cp*Rh catalyst in acetone (eq
1, right arrow). This result prompted us to develop this
catalytic lactamization system into the synthesis of a variety
of benzo-fused lactams. To the best of our knowledge, there
has been only one report on the transformation of amino
alcohols to lactams by the transition metal-catalyzed hydro-
gen transfer reactions.10 In this paper, we report a new and
efficient method for the synthesis of five-, six-, and seven-
membered benzo-fused lactams catalyzed by a Cp*Rh
complex.
a Reaction was carried out in a heavy-walled glass reactor at 100 °C for
20 h with amino alcohol (0.50 mmol), [Cp*RhCl2]2 (5.0% Rh), and K2CO3
(10%) in acetone (12.5 mL). b Isolated yield. c Reaction time was 30 h.
d [Cp*RhCl2]2 (9.8% Rh) was used as a catalyst. e [Cp*RhCl2]2 (10.5% Rh)
was used as a catalyst.
acetone (12.5 mL), 3,4-dihydro-2(1H)-quinolinone (2a) was
formed in 81% yield (entry 1). In this reaction, lactamization
proceeded selectively; other products such as 1,2,3,4-
tetrahydroquinoline or quinoline were not detected. A lower
reaction temperature (80 °C) resulted in a lower yield of 2a
(entry 2). When the amount of acetone was reduced to 6.3
mL, the yield of 2a slightly decreased (entry 3). When the
reaction was performed in toluene as a solvent instead of
acetone, 1,2,3,4-tetrahydroquinoline was formed in 32% yield
in addition to a very small amount of 2a (ca. 5%)(entry 4).
These results clearly indicate that acetone plays a key role
as a hydrogen acceptor. Other rhodium catalysts, Cp*Rh-
(OAc)2‚H2O, RhCl(PPh3)3, and [RhCl(CO)2]2, showed lower
activity than [Cp*RhCl2]2 (entries 5-7).11 The yield of 2a
considerably decreased when the reaction was performed in
the presence of Na2CO3 or triethylamine as a base instead
of K2CO3 (entries 8 and 9).
First, we investigated oxidative N-heterocyclization of
3-(2-aminophenyl)-1-propanol (1a) under various conditions.
The reactions were performed in the presence of several
rhodium complexes and bases in acetone as a solvent. The
results are summarized in Table 1. When the reaction was
performed at 100 °C for 20 h in the presence of [Cp*RhCl2]2
(0.0125 mmol, 5.0% Rh) and K2CO3 (0.050 mmol, 10%) in
(8) (a) Fujita, K.; Furukawa, S.; Yamaguchi, R. J. Organomet. Chem.
2002, 649, 289. (b) Fujita, K.; Yamamoto, K.; Yamaguchi, R. Org. Lett.
2002, 4, 2691. (c) Fujita, K.; Owaki, M.; Yamaguchi, R. Chem. Commun.
2002, 2964. (d) Fujita, K.; Li, Z.; Ozeki, N.; Yamaguchi, R. Tetrahedron
Lett. 2003, 44, 2687. (e) Hanasaka, F.; Fujita, K.; Yamaguchi, R.
Organometallics 2004, 23, 1490. (f) Fujita, K.; Kitatsuji, C.; Furukawa,
S.; Yamaguchi, R. Tetrahedron Lett. 2004, 45, 3215.
(9) Some other groups have reported hydrogen-transfer reductive ami-
nation reactions catalyzed by group 9 metal (Rh, Ir) complexes bearing a
Cp* ligand. (a) Kadyrov, R.; Riermeier, T. H. Angew. Chem., Int. Ed. 2003,
42, 5472. (b) Kitamura, M.; Lee, D.; Hayashi, S.; Tanaka, S.; Yoshimura,
M. J. Org. Chem. 2002, 67, 8685. (c) Ogo, S.; Makihara, N.; Kaneko, Y.;
Watanabe, Y. Organometallics 2001, 20, 4903.
On the basis of these results, we next examined the
synthesis of various six- and seven-membered benzo-fused
lactams under the optimized conditions. The results are
summarized in Table 2. 3-(2-Aminophenyl)propanols (1b-
2786
Org. Lett., Vol. 6, No. 16, 2004

Scheme 1
g) bearing a substituent on the aromatic ring were converted
moderate (63%) even with a higher catalyst loading (9.8%
Rh) (entry 6). It should be noted that the present catalytic
system was applicable to the synthesis of 1,3,4,5-tetrahydro-
2H-1-benzazepin-2-one (2h) using 4-(2-aminophenyl)-1-
butanol (1h) as a starting material (entry 8).
into the corresponding 3,4-dihydro-2(1H)-quinolinones (2b-
g) in moderate to excellent yields, respectively (entries 2-7).
With substrates bearing an electron-withdrawing substituent
(Cl, CO2Me, and COMe), the yields of the products were
excellent (entries 2-4). In the case of the substrate 1e bearing
a CN substituent, the yield of the product 2e was relatively
low (71%) even with a longer reaction time (30 h), which is
possibly due to the deactivation of the catalyst by the
coordination of CN substituent to the rhodium center (entry
5). In the case of the substrate 1f bearing the electron-
donating OMe substituent, the yield of the product 2f was
Synthesis of five-membered benzo-fused lactams (oxin-
doles) was also examined. The results are summarized in
Table 3. 2-Aminophenethyl alcohols (3a-d) bearing a
substituent on the aromatic ring, the methylene chain, and
the nitrogen atom were converted into the corresponding
oxindoles (4a-d) in moderate to high yields, respectively.
In contrast to the synthesis of dihydroquinolinones and
tetrahydrobenzazepinone, the synthesis of oxindoles could
be carried out at a lower temperature (acetone reflux) with
a lower catalyst loading (3.0% Rh). Reaction of 2-ami-
nophenethyl alcohol (3a) in the presence of [Cp*RhCl2]2
(3.0% Rh) and K2CO3 (10%) in acetone (20 mL) under reflux
for 8 h gave oxindole (4a) in 74% yield (entry 1). In this
reaction, a small amount of indole (10%) was also formed.
Reaction of 2-(2-aminophenyl)-1-propanol (3b) gave 3-me-
thyloxindole (4b) in good yield (80%) (entry 2). Oxindoles
bearing a substituent at the aromatic ring or the nitrogen atom
could be also synthesized; however, the yields were relatively
low (entries 3 and 4).
Table 3. Synthesis of Oxindoles from Amino Alcohols
Catalyzed by the [Cp*RhCl2]2/K2CO3 Systema
Although the mechanism for the present reaction is not
completely clear yet, a possible one is shown in Scheme 1.12
The first step of the reaction would involve the coordination
of amino alcohol to the rhodium center to give an intermedi-
ate A. Then, â-hydrogen elimination would occur to give
(10) Ruthenium-catalyzed oxidative N-heterocyclizations of amino al-
cohols to lactams have been reported. In these reactions, a higher reaction
temperature (140 °C) and addition of excess benzalacetone as a hydrogen
acceptor are required, and applicable amino alcohols are highly restricted.
Naota, T.; Murahashi, S.-I. Synlett 1991, 693.
(11) Reaction of 1a (0.50 mmol) at 100 °C for 20 h in the presence of
[Cp*IrCl2]2 (0.0127 mmol, 5.1% Ir) and K2CO3 (0.050 mmol, 10%) in
acetone (12.5 mL) gave 2a in 59% yield.
a Reaction was carried under reflux for 8 h with amino alcohol (1.0
mmol), [Cp*RhCl2]2, and K2CO3 (10%) in acetone (20 mL). b Isolated yield.
c Reaction was carried out in 0.50 mmol scale. d Reaction time was 20 h.
Org. Lett., Vol. 6, No. 16, 2004
2787

an amino-aldehyde B and a rhodium hydride species C (step
a). Insertion of acetone into the rhodium-hydride bond in
C would occur to give a rhodium isopropoxide species D
(step b), which is subject to the alkoxy exchange reaction
with amino alcohol to regenerate A (step c). Concurrently,
the intermediate B would undergo condensation to give a
cyclic hemiaminal E (step d). Oxidation of E by the rhodium
catalyst via â-hydrogen elimination would give the lactam
product F (steps e and f). Thus, the Cp*Rh catalyst could
play a dual role in both dehydrogenations of the alcohol as
well as the hemiaminal.
ring lactams from amino alcohols catalyzed by a Cp*Rh
complex. It should be noted that selective synthesis of
N-alkylated or lactamized product from the same starting
materials (amino alcohols) can be achieved by altering the
catalytic systems (Cp*Rh in acetone or Cp*Ir in toluene8b).
Investigations in further detail about the differences of
catalytic activities of Cp*Rh and Cp*Ir complexes are now
in progress, which we will disclose in due course.
Acknowledgment. This work was supported by Grant-
in-Aid for Scientific Research from the Japan Society for
the Promotion of Science (No. 14550806).
In summary, we have shown a new efficient catalytic
system for the synthesis of five-, six-, and seven-membered
Supporting Information Available: Full experimental
details and characterization data. This material is available
free of charge via the Internet at http://pubs.acs.org.
(12) First step in this mechanism is similar to that we have proposed for
the intramolecular cyclization of amino alcohols catalyzed by a Cp*Ir
complex (ref 8b). We are currently investigating in detail the differences
in catalytic activities between Cp*Rh and Cp*Ir complexes, which will be
disclosed in due course.
OL0489954
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Org. Lett., Vol. 6, No. 16, 2004