Moore-type cyclization leading to arene chromium tricarbonyl 1,4-diradical intermediates and the isolation of indolines

Full text of DOI:10.1021/ja953619n

J. Am. Chem. Soc. 1996, 118, 1807-1808
1807
Scheme 1
Moore-Type Cyclization Leading to Arene
Chromium Tricarbonyl 1,4-Diradical Intermediates
and the Isolation of Indolines
Annette Rahm and William D. Wulff*
Department of Chemistry, Searle Chemistry Laboratory
The UniVersity of Chicago, Chicago, Illinois 60637
ReceiVed October 27, 1995
Compounds containing the 5-hydroxyindole unit are among
the most active compounds in the central nervous system.1 A
convergent approach to this unit is possible on paper from the
intramolecular benzannulation reaction of carbene complex 1
where both rings of the indoline unit are generated in a single
step. It has long been known that the reactions of aryl amino
carbene complexes with alkynes proceed to give five-membered-
ring annulated products.2 In contrast, it has recently been found
that alkenyl amino complexes react with alkynes to produce
six-membered-ring annulated products that contain a phenol
function.3 As a result of these observations, the intramolecular
benzannulation of vinyl amino carbene complexes of the type
1 (Scheme 1) promised to provide a new and straightforward
approach to the synthesis of 5-hydroxyindoles.3 However, we
have found that this will not be possible since, for example,
thermolysis of complex 1 (R2 ) H, R1 ) Ph) produces the
1-azabicyclooctane 3 rather than the 5-hydroxyindoline 2.4
It was reasoned that the failure of the thermolysis of complex
1 to give the indoline 2 was the result of the failure of a carbon
monoxide insertion to compete with a cyclization on chromium
to form a chromacyclohexadiene, which upon reductive elimina-
tion gives the observed five-membered ring. A solution to this
problem was envisioned upon consideration of the cycloaro-
matization of enynyl ketenes that has recently been developed
by Moore, Liebeskind, Nakatani, and Saito.5 This cyclization
gives phenols via a 1,4-diradical intermediate with one radical
center on the phenol oxygen and the other at a meta position
on the newly formed arene ring. As indicated in Scheme 2, it
should be possible to set up this reaction with a chromium
carbene complex if an alkynyl substituent is incorporated onto
the carbene complex. The thermolysis of complex 4 would be
expected to give an indoline product rather than the five-
membered-ring product analogous to 3 since that pathway would
require the cyclization of the intermediate 5 to give the species
6, which contains an allene in a six-membered ring. We report
here the success of this strategy for the synthesis of indolines
in a process that involves the first example of a cycloaromati-
zation reaction via 1,4-diradical intermediates where the newly
formed arene ring is generated in the coordination sphere of a
metal.6
Scheme 2
The amino-tethered bis-alkynyl carbene complexes were
prepared by aminolysis of the corresponding methoxyl com-
plexes 11 with 1-amino-3-pentyne and then, without isolation,
N-methylation to directly give the complexes 12 in good overall
yields.9 The thermolysis of the phenyl-substituted complex 12a
in the presence of 1,4-cyclohexadiene as a hydrogen source was
examined under a variety of conditions. We were delighted to
see that, as anticipated by the mechanism in Scheme 2, the
generation and cyclization of an enynyl ketene intermediate to
a 1,4-diradical intermediate did occur as evidenced by the
isolation of the indoline 13a (Scheme 3). However, the yields
(1) (a) Hugel, H. M.; Kennaway, D. J. Org. Prep. Proced. Int. 1995, 27,
1. (b) Levy, A. D.; van de Kar, L. D. Life Sci. 1992, 51, 83. (c) Peroutka,
S. J. Pharmacol. Toxicol. 1990, 67, 373. (d) Glennon, R. A. J. Med. Chem.
1987, 30, 1.
(2) (a) Yamashita, A. Tetrahedron Lett. 1986, 27, 5915. (b) For a list of
subsequent examples, see ref 3.
(3) Wulff, W. D.; Gilbert, A. M.; Hsung, R. P.; Rahm, A. J. Org. Chem.
1995, 60, 4566.
(7) Warner, B. P.; Millar, S. P.; Broene, R. D.; Buchwald, S. L. Science
1995, 269, 814.
(4) Rahm, A.; Wulff, W. D. Tetrahedron Lett. 1995, 36, 8753.
(5) (a) Foland, L. D.; Karlsson, J. O.; Perri, S. T.; Schwabe, R.; Xu, S.
L.; Patil, S.; Moore, H. W. J. Am. Chem. Soc. 1989, 111, 975. (b) Xia, H.;
Moore, H. W. J. Org. Chem. 1992, 57, 3765. (c) Sullivan, R. W.; Coghlan,
V. M.; Munk, S. A.; Reed, M. W.; Moore, H. W. J. Org. Chem. 1994, 59,
2276. (d) Liebeskind, L. S.; Foster, B. S. J. Am. Chem. Soc. 1990, 112,
8612. (e) Nakatani, K.; Isoe, S.; Maekawa, S.; Saito, I. Tetrahedron Lett.
1994, 35, 605. This reaction is isoelectronic with the cycloaromatization
of enynyl allenes that was originally reported by Myers: (f) Myers, A. G.;
Kuo, E. Y.; Finney, N. S. J. Am. Chem. Soc. 1989, 111, 8057.
(6) A recent report describes a Bergman-type cyclization with the metal
atom in a 10-membered ring containing an enediyne unit,7 and another
describes a Myers-type cyclization with an enyne-substituted vinylidene
complex.8
(8) Wang, Y.; Finn, M. G. J. Am. Chem. Soc. 1995, 117, 8045.
(9) The alkynyl (alkoxy) carbene complexes 11 were prepared by the
method of Fischer,10 and 1-amino-3-pentyne was isolated as its hydrochlo-
ride salt from a two-step sequence beginning with 4-hexynoic acid via the
acid chloride in 72% yield by a Curtius rearrangement by the procedure of
Na¨geli where trimethylsilyl azide is substituted for sodium azide.11 See
supporting information for details.
(10) Complexes 11 were prepared according to procedures found in the
following references, where in some cases methyl triflate was substituted
as the methylating agent: (a) Fischer, E. O.; Kreissl, R. R. J. Organomet.
Chem. 1972, 35, C47. (b) Chan, K. S.; Wulff, W. D. J. Am. Chem. Soc.
1986, 108, 5229.
(11) Mo¨ller, F. In Methoden der Organischen Chemie (Houben-Weyl);
Georg Thieme Verlag: Stuttgart, 1957; Vol. 11/1, p 865.
0002-7863/96/1518-1807$12.00/0 © 1996 American Chemical Society

1808 J. Am. Chem. Soc., Vol. 118, No. 7, 1996
Communications to the Editor
Scheme 3
Scheme 4
failed to cyclize. It was unexpected to find that the cyclized
products were isolated as metal-free compounds since (arene)-
chromium tricarbonyl complexes are almost always isolated in
cases where phenols are formed from the benzannulation of
alkenyl carbene complexes with alkynes and trapped in situ,
especially since this is also the case for intermolecular reactions
of amino (alkenyl) carbene complexes.3,12
Table 1
If the metal is lost from the hydroxyindoline product 10
because the in situ protection of the phenol function is too slow,
then, perhaps, it would be possible to prevent the loss of the
metal by employing a trapping agent for the diradical intermedi-
ate 9 that would lead directly to a compound with a protected
phenol function. Indeed, when the thermolysis of complex 12a
was carried out in the presence of triethylsilane, only the
silylated 5-hydroxyindoline chromium tricarbonyl complex 22a
was isolated (Scheme 4). The isolation of metal complex 22a
indicates that the cyclization of the enynyl ketene to the diradical
intermediate occurs in the coordination sphere of the metal.
Proof of this would require demonstrating that the metal is not
lost from the ketene complex 8 and then becomes recomplexed
to the indoline product after its formation. While this has not
been experimentally addressed here, it has been shown that the
formation of (phenol)chromium tricarbonyl complexes from the
benzannulation reaction of Fischer carbene complexes with
alkynes occurs with the formation of the arene ring in the
coordination sphere of the metal and without the loss of the
metal at any time during during the reaction.15 The thermolysis
of 12a in deuteriotriethylsilane gave the deuterated complex 23a,
which by deuterium NMR was found to have deuterium
incorporated exclusively at the C-7 position. However, 1H NMR
revealed that the extent of deuterium incorporation at C-7 was
only 25%, indicating that the solvent competes with the DSiEt3
for the C-7 radical center. None of the metal-free 5-hydroxy-
indoline 13a was observed, indicating that the oxygen radical
at C-6 is apparently selectively silylated.
carbene % yield
hydrogen
source (HS)
% yield
[12] [HS] of 14
R
complexa of 12
Ph
Ph
Ph
Ph
Ph
12a
12a
12a
12a
12a
12b
12c
12d
71 1,4-cyclohexadiene 0.005 0.5
43
34
63
49
53
71 1,4-cyclohexadiene 0.01
71 1,4-cyclohexadiene 0.01
71 1,4-cyclohexadiene 0.02
71 γ-terpinene
66 γ-terpinene
70 γ-terpinene
68 γ-terpinene
0.1
1.0
2.0
2.0
2.0
2.0
2.0
0.02
0.02
0.02
0.02
t-Bu
SiMe3
1-C6H9
31
NDb
41
a Complexes 12 were prepared as indicated in Scheme 3 and obtained
as only the E isomer, except for 12c, which was obtained as a 16:1
mixture of E and Z isomers; see ref 13. b Not detected.
for these cyclizations are low, giving a 25% yield of 13a under
the best conditions. The loss of the metal from the product is
not surprising given the known air sensitivity of phenol
chromium tricarbonyl complexes formed in the normal benz-
annulation reaction.12
In some instances it has been observed that the yields of
benzannulated products can be improved if the reaction is carried
out in the presence of electrophiles that are added to affect in
situ protection of the phenol function.12 As indicated by the
data in Table 1, the yields of the indoline products could be
greatly enhanced if the reaction was performed in the presence
of acetic anhydride and triethylamine. The optimal conditions
The new synthesis of 5-hydroxyindolines described herein
is made possible by a metal-mediated Moore-type cyclization
of an enynyl ketene complex and features the construction of
both rings of the indole nucleus in a single step.
o
were found to be 0.01 M in THF at 80 C with 100 equiv of
1,4-cyclohexadienone. Given the expense of the large excess
of 1,4-cyclohexadiene required, a switch was made in hydrogen
source to γ-terpinene, a naturally occurring 1,4-cyclohexadiene.
Several reactions were screened with γ-terpinene at 0.02 M,
and it was found that several different substituents on the alkynyl
group could be tolerated and only the silylated complex 12c
Acknowledgment. This work was supported by the National
Institutes of Health (GM 33589). The NMR instruments used were
funded in part by the NSF Chemical Instrumentation Program.
(12) (a) Chamberlin, S.; Wulff, W. D. J. Am. Chem. Soc. 1992, 114,
10667. (b) Chamberlin, S.; Wulff, W. D.; Bax, B. Tetrahedron 1993, 49,
5531.
(13) The carbene complexes 12 can exist as two diastereomers due to
hindered rotation about the nitrogen-carbene carbon bond. The stereo-
chemistry was assigned on the basis of the chemical shift of the methylene
and methyl groups attached to the nitrogen atom and the observation that
the closer a proton is to the metal center the greater the deshielding.14 See
supporting information for details.
Supporting Information Available: Experimental procedures and
spectral data for all new compounds (9 pages). This material is
contained in libraries on microfiche, immediately follows this article
in the microfilm version of the journal, can be ordered from the ACS,
and can be downloaded from the Internet; see any current masthead
page for ordering information and Internet access instructions.
JA953619N
(14) (a) Moser, E.; Fischer, E. O. J. Organomet. Chem. 1969, 16, 275.
(b) Fischer, E. O.; Leupold, M. Chem. Ber. 1972, 105, 599. (c) Anderson,
B. A.; Wulff, W. D.; Rahm, A. J. Am. Chem. Soc. 1993, 115, 4602.
(15) Do¨tz, K. H. Angew. Chem., Int. Ed. Engl. 1975, 14, 644.