CO-trapping reaction under thermolysis of alkoxyamines: Application to the synthesis of 3,4-cyclopenta-1-tetralones

Article abstract of DOI:10.1021/ol050951n

(Chemical Equation Presented) An efficient one-pot sequence comprising a PRE-mediated radical 5-exo-cyclization, a radical carbonylation, a nitroxide trapping reaction, and a subsequent acid-catalyzed Friedel-Craft-type acylation provides a new entry into

Full text of DOI:10.1021/ol050951n

ORGANIC
LETTERS
2
005
Vol. 7, No. 14
985-2988
CO-Trapping Reaction under
Thermolysis of Alkoxyamines:
Application to the Synthesis of
2
3,4-Cyclopenta-1-tetralones
†
†
†
,†
Yoshitaka Uenoyama, Masaaki Tsukida, Takashi Doi, Ilhyong Ryu,* and
Armido Studer*
,
‡
Department of Chemistry, Graduate School of Science, Osaka Prefecture UniVersity,
Sakai, Osaka 599-8531, Japan, and Organisch-Chemisches Institut, Westf a¨ lische
Wilhelms-UniVersit a¨ t M u¨ nster, Corrensstrasse 40, 48149 M u¨ nster, Germany
ryu@c.s.osakafu-u.ac.jp; studer@uni-muenster.de
Received April 28, 2005
ABSTRACT
An efficient one-pot sequence comprising a PRE-mediated radical 5-exo-cyclization, a radical carbonylation, a nitroxide trapping reaction, and
a subsequent acid-catalyzed Friedel
−Craft-type acylation provides a new entry into 3,4-cyclopenta-1-tetralones. Eight examples are presented.
3
Over the last few decades, radical chemistry has gained
increasing importance in synthetic organic chemistry. While
cesses such as living radical polymerizations. Using TEMPO
(2,2,6,6-tetramethylpiperidine-1-oxyl) and related nitroxides,
one of us has previously developed radical cyclization and
polymerization reactions which are controlled by the per-
1
nitroxides are known to efficiently trap radicals to give
alkoxyamines, thermally induced reverse homolysis of
activated alkoxyamines has recently been recognized as a
facile process for the clean generation of C-centered radicals.
This unique “go & return” propensity of alkoxyamines led
organic chemists to design radical reaction processes based
on key basic sequences, which involve (1) the homolysis of
alkoxyamines to give carbon radical/nitroxide pairs, (2)
radical reactions of the resulting carbon radicals, and (3)
recombination of the resulting radicals with nitroxides. In
this context, alkoxyamines have been used not only for basic
2
,4
sistent radical effect (PRE).
In this paper, we focus on the participation of carbon
monoxide in TEMPO-based radical cyclization chemistry.
5
(
2) (a) Studer, A. Angew. Chem., Int. Ed. 2000, 39, 1108. (b) Marque,
S.; Fischer, H.; Baier, E.; Studer, A. J. Org. Chem. 2001, 66, 1146. (c)
Molawi, K.; Schulte, T.; Siegenthaler, K. O.; Wetter, C.; Studer, A. Chem.
Eur. J. 2005, 11, 2335. (d) Studer, A.; Schulte, T. Chem. Rec. 2005, 5, 27.
Studer, A. Chem. Soc. ReV. 2004, 33, 267. Wetter, C.; Jantos, K.; Woithe,
K.; Studer, A. Org. Lett. 2003, 5, 2899. Wetter, C.; Studer, A. Chem.
Commun. 2004, 174. Teichert, A.; Jantos, K.; Harms, K.; Studer, A. Org.
Lett. 2004, 6, 3477. Herrera, A. J.; Studer, A. Synthesis 2005, 1389. Allen,
A. D.; Cheng, B.; Fenwick, M. H.; Givehchi, B.; Henry-Riyad, H.; Nikolaev,
V. A.; Shikhova, E. A.; Tahmassebi, D.; Tidwell, T. T. Wang, S. J. Org.
Chem. 2001, 66, 2611. Allen, A. D.; Fenwick, M. F.; Henry-Riyad, H.;
Tidwell T. T. J. Org. Chem. 2001, 66, 5759. Leroi, C.; Fenet, B.; Couturier,
J.-L.; Guerret, O.; Ciufolini, M. A. Org. Lett. 2003, 5, 1079.
(3) Solomon, D. H.; Rizzardo, E.; Cacioli, P. US Patent 4,581,429; P.
Eur. Pat. Appl. 135280; Chem. Abstr. 1985, 102, 221335q. Georges, M.
K.; Veregin, R. P. N.; Kazmaier, P. M.; Hamer, G. K. Macromolecules
1993, 26, 2987. Review: Hawker, C. J.; Bosman, A. W.; Harth, E. Chem.
ReV. 2001, 101, 3661.
2
organic transformations but also in iterative reaction pro-
†
Osaka Prefecture University.
Westf a¨ lische Wilhelms-Universit a¨ t M u¨ nster.
‡
(
1) For reviews on radical chemistry, see: (a) Renaud, P., Sibi, M. P.,
Eds. Radicals in Organic Synthesis; Wiley-VCH: Weinheim, Germany,
001; Vols. 1 and 2. (b) Curran, D. P.; Porter, N. A.; Giese, B.
2
Stereochemistry of Radical Reactions; VCH: Weinheim, 1996. (c) Moth-
erwell, W. B.; Crich, D. Free Radical Chain Reactions in Organic Synthesis;
Academic: London, 1992.
1
0.1021/ol050951n CCC: $30.25
© 2005 American Chemical Society
Published on Web 06/15/2005

Since the cyclopentane-fused tetralone framework represents
6
a key feature of hemigeran-type natural products, we
Table 1. Carbonylation of 1a under Thermal Conditions
hypothesized that a TEMPO-based radical cyclization-
carbonylation sequence would lead to a useful annulation
route for preparing such a tricyclic framework (Figure 1).
3
a(%)
4a(%)
(trans/cis)
a
b
b
entry 1a (M) time (h) 2a (%) (trans/cis)
1
2
3
4
5
0.01
0.01
0.01
0.05
0.05
12
20
12
12
20
7
7
8
24 (74:26)
trace
trace
trace
trace
14 (68:32)
46 (69:31)
45 (70:30)
41 (69:31)
45 (68:32)
c
trace
trace
Figure 1.
a
1
Except for entry 2, yields were determined by H NMR. Cis product
b
containing less than 5% of trans isomer was formed. Isolated yields. Cis/
trans ratios were determined by H NMR. CSA (10 mol %) was added.
1
c
We anticipated that the ultimately formed acyl-TEMPO
2b
would resist cleavage back to the acyl radical and TEMPO.
product in 14% yield. Probably, acid 4a derives from 3a by
hydrolysis. Interestingly, the tricyclic product 2a, the
We employed a two-step procedure comprising (1) a PRE-
mediated cyclization/carbonylation of 1-phenyl-substituted
8
targeted compound, was also identified, albeit in a low yield.
The addition of camphor sulfonic acid (CSA),2a which
promoted the thermal cyclization of 1a in the absence of
CO, failed to improve the yields of carbonylation products
in the present case (entry 3). After careful experimentation,
we found that the formation of carboxylic acid 4a as
predominant product could be attained at a higher substrate
concentration (0.05 M) (entries 4 and 5).
5
-hexenyloxyamines under thermolysis conditions and (2)
an intramolecular Friedel-Crafts-type acylation using Otera’s
conditions as outlined for the synthesis of 3,4-cyclopenta-
7
1-tetralones in Scheme 1.
Scheme 1. Carbonylation/Acylation Strategy for the
Construction of Hemigeran Skeletons
Since the C-O bond of acyl-TEMPO is stable toward
2
b
homolysis at the temperature employed, the predominant
formation of carboxylic acid 4a was somewhat surprising.
This led us to check the possibility of direct hydrolysis of
the initially formed acyl-TEMPO 3a by t-BuOH under the
reaction conditions. Indeed, heating of 3a in t-BuOH at 130
°
C for 12 h provided 4a in 94% yield (Scheme 2, eq 1). The
mechanism for the hydrolysis is currently not understood.
After confirming that carboxylic acid 4a is most likely
obtained via an initially formed acyl-TEMPO 3a in situ, we
next examined the conversion of 3a and 4a to the desired
benzo fused ketone 2a. To cyclize carboxylic acid 4a to
tricyclic ketone 2a, we tested Otera’s intramolecular Friedel-
Crafts procedure, which involves treatment of the acid with
(
4) (a) Daikh, B. E.; Finke, R. G. J. Am. Chem. Soc. 1992, 114, 2938.
b) Fischer, H. J. Am. Chem. Soc. 1986, 108, 3925. (c) Kothe, T.; Marque,
S.; Martschke, R.; Popov, M.; Fischer, H. J. Chem. Soc., Perkin Trans. 2
998, 1553. (d) Review: Fischer, H. Chem. ReV. 2001, 101, 3581.
5) For reviews on radical carbonylations, see: (a) Ryu, I.; Sonoda, N.
(
1
(
Angew. Chem., Int. Ed. Engl. 1996, 35, 1050. (b) Ryu, I.; Sonoda, N.;
Curran, D. P. Chem. ReV. 1996, 96, 177. (c) Ryu, I. Chem. Soc. ReV. 2001,
3
0, 16. Also see a review on acyl radicals: (d) Chatgilialoglu, C.; Crich,
D.; Komatsu, M.; Ryu, I. Chem. ReV. 1999, 99, 1991.
(6) (a) Wellington, K. D.; Cambie, R. C.; Rutledge, P. S.; Bergquist, P.
R. J. Nat. Prod. 2000, 63, 79. (b) Nicolaou, K. C.; Gray, J.; Tae, J. Angew.
Chem., Int. Ed. 2001, 40, 3675. (c) Nicolaou, K. C.; Gray, J.; Tae, J. Angew.
Chem., Int. Ed. 2001, 40, 3679. (d) Clive, D. L. J.; Wang, J. Angew. Chem.,
Int. Ed. 2003, 42, 3406.
We examined the reaction of 1-phenyl-substituted 5-hex-
enyloxyamine 1a under various conditions. When a solution
of alkoxyamine 1a (0.01 M) in t-BuOH was heated at 130
C for 12 h under CO pressure (85 atm), the envisaged acyl-
TEMPO product 3a was formed in 24% yield (Table 1, entry
). Unexpectedly, carboxylic acid 4a was found as side
(
7) Otera, J.; Orita, A. Jpn. Kokai Tokkyo Koho 2000, 2000-351741.
(8) The acid may be formed from the corresponding tert-butyl ester via
°
thermal fragmentation. The tert-butyl ester can be formed from acyl-TEMPO
a via thermal ketene formation and subsequent trapping of the ketene with
t-BuOH.
3
1
2986
Org. Lett., Vol. 7, No. 14, 2005

Scheme 2. Hydrolysis and Friedel-Crafts Acylation
Table 2. Synthesis of 3,4-Cyclopenta-1-tetralones 2 from
Alkoxyamines 1 and CO
c
7
trifluoromethanesulfonic acid (CF
3
SO
3
H). To our delight,
the desired tetralone derivative 2a was obtained in 82% yield
eq 2). Moreover, we found that treatment of TEMPO-
derivative 3a with CF SO H under the same conditions also
(
3
3
gave tricyclic compound 2a in 71% (eq 3).
With these results in hand, we examined a sequential
process comprising the carbonylation of alkoxyamines under
thermal conditions and a subsequent acid promoted cycliza-
tion reaction. Table 2 summarizes the synthesis of substituted
3,4-cyclopenta-1-tetralones realized when the sequential
procedure was used.
In the first example, after the consecutive reaction,
chromatographic separation gave the desired product 2a in
51% yield. The substrate 1b, containing an allyl ether moiety
also gave the corresponding tetralone derivative bearing a
fused THF ring (entry 2, 55%). We also tested substrates
1c-e containing methyl substituents at the phenyl ring. The
corresponding cyclopentane-fused tetralone derivatives 2c-e
were formed in similar yields (entries 3-5). On the other
hand, in the case of substrate 1f, containing a fluorine atom
at the para position, the acid-promoted cyclization was
sluggish, requiring an overnight reaction to reach completion
(entry 6). A product having a spiro ring was also synthesized
using the two step protocol (entry 8). All the tetralones
prepared were obtained as trans/cis mixture of isomers. The
diastereoisomeric ratio was readily determined by H NMR
spectroscopy.9
a
Friedel-Crafts acylation was conducted over 20 h. b Radical carbo-
nylation was performed in 1 h. c Conditions: (1) CO (75-80 atm), 130
C, 20 h; (2) CF3SO3H, 50 °C, 2 h.
1
°
The radical cyclization/carbonylations described above
require 20 h for completion. We have recently shown that
the size of the substituents at the nitroxide moiety heavily
influences the reactivity of the alkoxyamines. With steri-
cally hindered nitroxides highly efficient PRE-mediated
processes can be achieved. Therefore, we also tested the
reaction of tetraethyl-substituted analogue 1i (entry 9).
Indeed, the first cyclization/carbonylation reaction was
completed within 1 h. Subsequent acid treatment provided
cyclopentane-fused tetralone 2a in 48% yield. Compared with
the analogous TEMPO-mediated process, the reaction time
could be shortened; however, a nearly identical yield was
obtained.
2c
In summary, the trapping of CO in the thermolysis of
5-alkenyloxyamines represents a new route for tin free radical
carbonylation. The carbonylated products can be converted
to 3,4-cyclopentatetralones by subsequent treatment with
(
9) The unusual trans selectivity for the radical 5-exo cyclization was
previously observed for similar PRE-mediated alkoxyamine isomerizations,
see ref 2a. This is probably due to the reversibility of the 5-exo cyclization;
see: Walling, C.; Cioffari, A. J. Am. Chem. Soc. 1972, 94, 6064.
Org. Lett., Vol. 7, No. 14, 2005
2987

trifluoromethane sulfonic acid. Three consecutive C-C-
bond-forming processes are achieved in a one-pot procedure.
We are currently exploring some additional efficient
alkoxyamine systems that may also be useful in carbonylation
reactions and related applications. These studies are currently
underway.
for continuous support. I.R. acknowledges a Grant-in-Aid
for Scientific Research on Priority Areas (A) “Reaction
Control of Dynamic Complexes” from the Monbukagakusho,
Japan, for financial support of this work.
Supporting Information Available: Experimental pro-
cedures and analytical data of all new tetralones. This
material is available free of charge via the Internet at
http://pubs.acs.org.
Acknowledgment. We thank Kian Molawi and Birgit
Janza for their help in the preparation of starting materials.
The Fonds der Chemischen Industrie is acknowledged (A.S.)
OL050951N
2988
Org. Lett., Vol. 7, No. 14, 2005