Thiol-catalyzed acyl radical cyclization of alkenals

Article abstract of DOI:10.1021/jo048275a

(Chemical Equation Presented) Thiol-catalyzed direct generation of acyl radicals and their intramolecular addition to olefins of alkenals gave 2-substituted five- and six-membered cyclic ketones in reasonably good yields. The combination of odorless tert-dodecanthiol and AIBN or V-40 was the initiator of choice among surveyed radical generators for the cyclization of alkenals. Aldehydes having electron-deficient olefins cyclized more easily than those having unactivated olefins.

Full text of DOI:10.1021/jo048275a

SCHEME 1. Cyclization of ω-Oxo-alkenoate 1a in
an Anionic (Path A) and a Radical (Path B) Mode
Thiol-Catalyzed Acyl Radical Cyclization of
Alkenals
Kazuya Yoshikai, Tomoharu Hayama,
Katsumi Nishimura, Ken-ichi Yamada, and
Kiyoshi Tomioka*
Graduate School of Pharmaceutical Sciences, Kyoto
University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan
tomioka@pharm.kyoto-u.ac.jp
Received September 30, 2004
TABLE 1. The Radical Cyclization Reaction of 1a with
Various Thiols Initiated by AIBN
entry
thiol/RSH
time (h)
yield (%)a
1b
2
Bn
4
6
63 (18)
16 (76)
74 (16)
44 (53)
2 (96)
89 (<3)
trace (98)
20 (17)
Ph
3
t-Bu
6
4
2,4,6-(Me)3C6H2CH2
Ph3C
6
6
19
22
23
5
6b
7b
8
t-C12H25
none
Thiol-catalyzed direct generation of acyl radicals and their
intramolecular addition to olefins of alkenals gave 2-sub-
stituted five- and six-membered cyclic ketones in reasonably
good yields. The combination of odorless tert-dodecanthiol
and AIBN or V-40 was the initiator of choice among surveyed
radical generators for the cyclization of alkenals. Aldehydes
having electron-deficient olefins cyclized more easily than
those having unactivated olefins.
NHPIc
a The numbers in parentheses are the recovery yields of 1a. b In
refluxing benzene (1 M). c N-Hydroxyphthalimide (NHPI) was used
instead of a thiol.
droxy-â′-thioalkanoate 3 in 95% yield (Scheme 1, path
A). We then expected that the chemistry of S-centered
radical 4 might enable the same transformation with a
catalytic amount of an initiator.4 However, the reaction
of 1a with phenylmethanethiol (1.2 equiv) and AIBN (0.6
equiv) in refluxing toluene did not give the expected
product 3 but ketoester 5a in 74% yield (Scheme 1, path
B). The reaction seemed to proceed via acyl radical
intermediate 6.5,6 This type of cyclization has been
achieved with acyl radicals7 generated by a homolytic
cleavage of C-S,8 C-Se,9 and other carbon-heteroatom
bonds10 and by coupling of carbon-centered radicals with
Development of atom economical transformation is an
important strategy in synthetic organic chemistry.1
A
good example of an atom economical transformation is
an addition reaction, in which all elements in the starting
substrates remain in the products. Herein, we describe
the formation of various 2-substituted cyclic ketones via
thiol-catalyzed addition reactions of acyl radicals to
internal olefins.
We have already reported cyclization reactions of
ω-oxo-R,â-unsaturated esters through a tandem conju-
gate addition-intramolecular aldol reaction initiated by
lithium thiolate.2,3 The reaction of 1a with lithium phen-
ylmethanethiolate 2 gave stereoselectively cyclic â-hy-
(4) A dramatic inversion of cis/trans selectivity in a cyclization
reaction was observed by changing an ionic reaction to a radical one:
Denes, F.; Chemla, F.; Normant, J. F. Angew. Chem., Int. Ed. 2003,
42, 4043-4046.
(5) An intermolecular acyl radical reaction was reported: Dang, H.-
S.; Roberts, B. P. J. Chem. Soc., Perkin Trans. 1 1998, 67-75.
(6) For a review of acyl radicals: Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991-2069.
(7) For polarity reversal catalysis of hydrogen atom abstraction:
Roberts, B. P. Chem. Soc. Rev. 1999, 28, 25-35.
(8) (a) Ozaki, S.; Adachi, M.; Sekiya, S.; Kamikawa, R. J. Org. Chem.
2003, 68, 4586-4589. (b) Crich, D.; Hao, X. J. Org. Chem. 1997, 62,
5982-5988. (c) Delduc, P.; Tailhan, C.; Zard, S. Z. J. Chem. Soc., Chem.
Commun. 1988, 308-310.
(9) (a) Evans, P. A.; Roseman, J. D. J. Org. Chem. 1996, 61,
2252-2253. (b) Boger, D. L.; Mathvink, R. J. J. Org. Chem. 1992, 57,
1429-1443. (c) Schwartz, C. E.; Curran, D. P. J. Am. Chem. Soc. 1990,
112, 9272-9284. (d) Bachi, M. D.; Denenmark, D. Heterocycles 1989,
28, 583-588. (e) Bachi, M. D.; Bosch, E. Tetrahedron Lett. 1986, 27,
641-644.
(1) Trost, B. M. Science 1991, 254, 1471-1477.
(2) (a) Ono, M.; Nishimura, K.; Tsubouchi, H.; Nagaoka, Y.; Tomioka,
K. J. Org. Chem. 2001, 66, 8199-8203. (b) Ono, M.; Nishimura, K.;
Nagaoka, Y.; Tomioka, K. Tetrahedron Lett. 1999, 40, 6979-6982.
(3) Our previous studies on the catalytic asymmetric Michael
reaction of thiols: (a) Nishimura, K.; Tsubouchi, H.; Ono, M.; Hayama,
T.; Nagaoka, Y.; Tomioka, K. Tetrahedron Lett. 2003, 44, 2323-2326.
(b) Nishimura, K.; Tomioka, K. Yakugaku Zasshi 2003, 123, 9-18. (c)
Nishimura, K.; Tomioka, K. J. Org. Chem. 2002, 67, 431-434. (d)
Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K. Angew. Chem., Int.
Ed. 2001, 40, 440-442. (e) Tomioka, K.; Okuda, M.; Nishimura, K.;
Manabe, S.; Kanai, M.; Nagaoka, Y.; Koga, K. Tetrahedron Lett. 1998,
39, 2141-2144. (f) Nishimura, K.; Ono, M.; Nagaoka, Y.; Tomioka, K.
J. Am. Chem. Soc. 1997, 119, 12974-12975. (g) Tomioka, K. Synthesis
1990, 541-549.
10.1021/jo048275a CCC: $30.25 © 2005 American Chemical Society
Published on Web 12/15/2004
J. Org. Chem. 2005, 70, 681-683
681

TABLE 2. The Acyl Radical Cyclization Reaction of 1, Using tert-Dodecanethiol and AIBN or V-40a
a In toluene or PhCl, V-40 was used as an initiator, whereas AIBN was used in benzene. b The numbers in parentheses are the recovery
yields of 1. c In 1 M solution. d Cis:trans ) 5:6. e With 1.5 equiv of the initiator. f With 3.0 equiv of the thiol. g At 100 °C. h With 0.6 equiv
of V-40. i V-40 was added in two portions (0.3 equiv each). j Cis:trans ) 2:3.
carbon monooxide.11 However, there is no example of this
cyclization12,13 through direct generation of acyl radicals
from formyl alkenoates.14,15
2). Bulkier 2-methyl-2-propanethiol improved the yield
to 74% (entry 3), but the results with 2,4,6-trimethyl-
phenylmethanethiol and triphenylmethanethiol were less
satisfactory (entries 4 and 5). Finally, bulky tert-dode-
canethiol,5 which has a much higher boiling point
(227-248 °C) than the reaction temperature, gave the
best result to provide 5a in 89% yield (entry 6). Without
thiols and under thoroughly deoxygenated conditions no
reaction proceeded and 1a was recovered in high yield
(entry 7).17 With N-hydroxyphthalimide (NHPI)14a,b in-
stead of a thiol, the yield of 5a was poor (entry 8). It is
also important to note that bulky and stench-free18 thiols
prevent formation of hemithioacetals with the aldehyde
We first examined the reaction of ω-oxo-alkenoate 1a
in benzene or toluene (1 M) with several thiols using
AIBN (0.3 equiv) as a radical initiator (Table 1). The
reaction with a catalytic amount of phenylmethanethiol
gave 5a in 63% yield (entry 1). The use of benzenethiol
reduced the yield to 16% probably because phenylthiyl
radical is too stable (bond dissociation energy (BDE) in
kJ/mol: RS-H ) 366, PhS-H ) 349, Ac-H ) 374)16 to
abstract hydrogen from the formyl group efficiently (entry
(10) (a) Bath, S.; Laso, N. M.; Lopez-Ruiz, H.; Quinclet-Sire, B.; Zard,
S. Z. Chem. Commun. 2003, 204-205. (b) Crich, D.; Chen, C.; Hwang,
J.-T.; Yuan, H.; Papadatos, A.; Walter, R. I. J. Am. Chem. Soc. 1994,
116, 8937-8951. (c) Coveney, D. J.; Patel, V. F.; Pattenden, G.;
Thompson, D. M. J. Chem. Soc., Perkin Trans. 1 1990, 2721-2728.
(d) Curran, D. P.; Liu, H. J. Org. Chem. 1991, 56, 3463-3465. (e)
Cekovic, Z. Tetrahedron Lett. 1972, 13, 749-752.
(14) Direct generation of an acyl radical and its intermolecular
addition to an olefin: (a) Tsujimoto, S.; Sakaguchi, S.; Ishii, Y.
Tetrahedron Lett. 2003, 44, 5601-5604. (b) Tsujimoto, S.; Iwahama,
T.; Sakaguchi, S.; Ishii, Y. Chem. Commun. 2001, 2352-2353. (c)
Gottschalk, P.; Neckers, D. C. J. Org. Chem. 1985, 50, 3498-3502.
See also ref 4.
(11) Ryu, I.; Kusano, K.; Hasegawa, M.; Kambe, N.; Sonoda, N. J.
Chem. Soc., Chem. Commun. 1991, 1018-1019.
(15) A similar cyclization of dithioalkyl radicals: Nishida, A.;
Kawahara, N.; Nishida, M.; Yonemitsu, O. Tetrahedron 1996, 52,
9713-9734.
(12) A chiral carbene-catalyzed cyclization of this type: (a) Kerr,
M. S.; Rovis, T. Synlett 2003, 1934-1936. (b) Kerr, M. S.; Read de
Alaniz, J.; Rovis, T. J. Am. Chem. Soc. 2002, 124, 10298-10299.
(13) Rhodium-catalyzed asymmetric intramolecular 5-endo hydroa-
cylation of alkenals: Tanaka, M.; Imai, M.; Fujio, M.; Sakamoto, E.;
Takahashi, M.; Eto-Kato, Y.; Wu, X. M.; Funakoshi, K.; Sakai, K.;
Suemune, H. J. Org. Chem. 2000, 65, 5806-5816.
(16) Luo, Y.-R. Handbook of Bond Dissociation Energies in Organic
Compounds; CRC Press: Boca Raton, FL, 2002.
(17) Under the standard argon atmosphere carboxylic acids were
obtained along with 5a in poor yield.
(18) Nishide, K.; Patra, P. K.; Matoba, M.; Shanmugasundaram, K.;
Node, M. Green Chem. 2004, 6, 142-146.
682 J. Org. Chem., Vol. 70, No. 2, 2005

SCHEME 2. Plausible Radical Chain Mechanism
for the Cyclization Reaction
thiol 8 to give thiyl radical 9. Hydrogen abstraction from
1a by 9 produces acyl radical 6 which cyclizes to give 10.22
Hydrogen exchange with thiol 8 gives product 5a and
thiyl radical 9 to propagate the chain reaction.
Table 2 shows that the stability of cyclized radical
intermediate 10 strongly influences the yields of the
products. Thus, alkenes 1a-e and 1j having good radical
stabilizing substituents (BDE in kJ/mol: R-C-H of ethyl
propanoate ) 400, t-Bu-H ) 400)16 gave the products
in better yields (entries 1-5 and 10) than 1f-h, which
give less stable primary or secondary alkyl radicals (BDE
in kJ/mol: Et-H ) 421, iPr-H ) 411) as intermediates
(entries 6-8). The hydrogen abstraction from thiol 8 by
more stable benzylic radical (BDE in kJ/mol: R-C-H of
PhPr ) 366) is probably so slow that the reaction of 1i is
less efficient (entry 9).
In conclusion, we have developed a thiol-catalyzed
intramolecular addition reaction of a formyl group to an
olefin to give a variety of 2-substituted cyclic ketones in
reasonably good yields. Because the aldehyde hydrogen
atom is transferred to the product via a thiol, this
reaction is quite atom economical.
as well as conjugate addition to the R,â-unsaturated
ester. Dimethylzinc or triethylborane-initiated radical
reaction19 was not applicable in this thiol-catalyzed acyl
radical cyclization.20
Full conversion of 1a was achieved when the reaction
was conducted in refluxing chlorobenzene (bp 132 °C) to
give 5a in 90% yield (Table 2, entry 1). At higher
temperature, 1,1′-azobis(cyclohexanecarbonitrile) (V-40),
which has a much longer half-life (2 h/100 °C) than AIBN
(7 min/100 °C),21 was the initiator of choice. Other
formylalkenoates also underwent this cyclization reac-
tion. Six-membered cyclic alkanoates 5b and 5c were
obtained from 1b and 1c in 85% and 78% yield, respec-
tively (entries 2 and 3). Formation of benzene-fused rings
was also possible to give 5d and 5e from 1d and 1e in
73% and 76% yield, respectively (entries 4 and 5). In
contrast to the brilliant, carbene-catalyzed cyclization
reactions,12 an electron-withdrawing methoxycarbonyl
group is not essensial for the cyclization reaction to
proceed. Mono-, di- and trialkyl-substituted alkenes 1f-j
can be utilized as an acyl radical acceptor to give the
corresponding cyclized products in good yields (entries
6-10). It is noteworthy that a relatively high concentra-
tion for an intramolecular reaction (1-0.1 M) is ap-
plicable to obtain the products in good yields without
formation of any byproducts from an intermolecular
reaction.
Experimental Section
The General Procedure for Cyclization of Alkenal
(Table 2, Entry 2). Methyl (2-oxocyclohexane)acetate (5b):
V-40 (37 mg, 0.15 mmol) was added to a solution of alkenal 1b
(85 mg, 0.50 mmol) and tert-dodecanethiol (30 mg, 0.15 mmol)
in dry toluene (5 mL). The solution was degassed three times
by the freeze-thaw procedure. The mixture was then refluxed
under argon atmosphere for 19 h. The crude reaction mixture
was directly purified by silica gel column chromatography
(hexane/ether 4/1) to give cyclic ketone 5b (73 mg, 85%)23 as a
colorless oil.
Acknowledgment. This research was partially sup-
ported by the 21st Century COE (Center of excellence)
Program Knowledge Information Infrastructure for
Genome Science and a Grant-in-Aid for Scientific Re-
search from the Ministry of Education, Culture, Sports,
Science and Technology, Japan.
Supporting Information Available: The preparation
methods of alkenals 1 and the characterization data of new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
The reaction seems to proceed through a radical chain
process shown in Scheme 2.5 The thermal decomposition
of AIBN initiates the reaction by the formation of
cyanoalkyl radical 7, which abstracts a hydrogen from
JO048275A
(19) (a) Yamamoto, Y.; Maekawa, M.; Yamada, K.; Tomioka, K.
Tetrahedron 2005, 61, 379-384. (b) Yamada, K.; Yamamoto, Y.;
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Yamada, K.; Yamamoto, Y.; Maekawa, M.; Chen, J.; Tomioka, K.
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Form Carbon-Carbon Bonds. In Organic Reactions; Adams, R., Blatt,
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Niemann C., Eds.; Willey & Sons: New York, 1963; Vol. 13, pp 113-
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abstraction by thiyl radicals and their reaction with a disulfide:
Nambu, H.; Hata, K.; Matsugi, M.; Kita, Y. Chem. Commun. 2002,
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