Two novel domino reactions triggered by thiyl-radical addition to vinylcyclopropyl oxime ether

Article abstract of DOI:10.1021/ol900604a

Two domino reactions of vinylcyclopropyl oxime ethers involving (i) thiyl radical addition, ring-opening, and hydroxylation reactions and (ii) thiyl radical addition, ring-opening, and aldol-type reactions were developed.

Full text of DOI:10.1021/ol900604a

ORGANIC
LETTERS
2009
Vol. 11, No. 12
2651-2654
Two Novel Domino Reactions Triggered
by Thiyl-Radical Addition to
Vinylcyclopropyl Oxime Ether
Habibur Rahaman, Masafumi Ueda, Okiko Miyata, and Takeaki Naito*
Kobe Pharmaceutical UniVersity, 4-19-1, Motoyamakita, Higashinada,
Kobe 658-8558, Japan
taknaito@kobepharma-u.ac.jp
Received April 3, 2009
ABSTRACT
Two domino reactions of vinylcyclopropyl oxime ethers involving (i) thiyl radical addition, ring-opening, and hydroxylation reactions and (ii)
thiyl radical addition, ring-opening, and aldol-type reactions were developed.
The classical thiol-olefin co-oxygenation reaction, tradition-
ally called hydroxysulfenylation, is an instrumental step in
the multistep synthesis of functionalized cyclic peroxide.
Hydroxysulfenylation is one of the interesting modes of
reactions in organic synthesis that leads to the production
of many functionalized products.1 A diverse array of
hydroxysulfenylations including the electron-rich or electron-
deficient alkenes as radical acceptors has been documented.2
The ring-opening hydroxysulfenylation reaction is poorly
understood. Feldman and Parvez have widened the scope of
the thiol-olefin co-oxygenation reaction on vinylcyclopropyl
derivatives and opened avenues to the synthesis of sulfur-
free five-membered cyclic peroxides.3 On the other hand,
the multicomponent reaction involving the domino process
is an important field of research and attracts great interest
and use in organic syntheses. A handful of examples on the
thiophenol-catalyzed domino reaction leading to the produc-
tion of the cyclopentane derivatives have been reported.4
However, the domino reaction involving a multiprocess
leading to the formation of the carbon-sulfur and carbon-
carbon bond is restricted. Recently, we have published two
(1) (a) Beckwith, A. L. J.; Wagner, R. D. J. Am. Chem. Soc. 1979, 101,
7099. (b) Iriuchijima, S.; Maniwa, K.; Sakakibara, T.; Tsuchihashi, G. J.
Org. Chem. 1974, 39, 1170. (c) LeBel, N. A.; Czaja, R. F.; DeBoer, A. J.
Org. Chem. 1969, 34, 3112. (d) Ito, O. In S-Centered Radicals; Alfassi,
Z. B., Ed.; Wiley: Chichester, 1999 193. (e) Korshin, E. E.; Hoos, R.;
Szpilman, A. M.; Konstantinovski, L.; Posner, G. H.; Bachi, M. D.
Tetrahedron 2002, 58, 2449. (f) Kim, J.; Li, H. B.; Rosenthal, A. S.; Sang,
D.; Shapiro, T. A.; Bachi, M. D.; Posner, G. H. Tetrahedron 2006, 62,
4120. (g) Griesbaum, K. Angew. Chem., Int. Ed. Engl. 1970, 9, 273. (h)
Bertrand, M. P.; Ferreri, C. In Radicals in Organic Synthesis; Renaud, P.,
Sibi, M. P., Eds.; Wiley-VCH: Weinheim, 2001; p 485.
(3) (a) Feldman, K. S.; Simpson, R. E.; Parvez, M. J. Am. Chem. Soc.
1986, 108, 1328. (b) Feldman, K. S.; Simpson, R. E. J. Am. Chem. Soc.
1989, 111, 4878. (c) Feldman, K. S.; Simpson, R. E. Tetrahedron Lett.
1989, 30, 6985.
(2) (a) O’Neill, P. M.; Mukhtar, A.; Ward, S. A.; Bickley, J. F.; Davies,
J.; Bachi, M. D.; Stocks, P. A. Org. Lett. 2004, 6, 3035. (b) O’Neill, P. M.;
Verissimo, E.; Ward, S. A.; Davies, J.; Korshin, E. E.; Araujo, N.; Pugh,
M. D.; Cristiano, M. L. S.; Stocks, P. A.; Bachi, M. D. Bioorg. Med. Chem.
Lett. 2006, 16, 2991. (c) Baucherel, X.; Uziel, J.; Juge, S. J. Org. Chem.
2001, 66, 4504. (d) Ueda, M.; Miyabe, H.; Shimizu, H.; Sugino, H.; Miyata,
O.; Naito, T. Angew. Chem., Int. Ed. 2008, 47, 5600.
(4) (a) Feldman, K. S.; Romanelli, A. L.; Ruckle, R. E., Jr.; Miller, R. F.
J. Am. Chem. Soc. 1988, 110, 3300. (b) Feldman, K. S.; Berven, H. M.;
Weinreb, P. H. J. Am. Chem. Soc. 1993, 115, 11364. (c) Miura, K.; Fugami,
K.; Oshima, K.; Utimoto, K. Tetrahedron Lett. 1988, 29, 1543–1988; 29,
5135. (d) Kim, S.; Lee, S. Tetrahedron Lett. 1991, 32, 6575. (e) Huval,
C. C.; Singleton, D. A. J. Org. Chem. 1994, 59, 2020. (f) Singleton, D. A.;
Church, K. M. J. Org. Chem. 1990, 55, 4780.
10.1021/ol900604a CCC: $40.75
Published on Web 05/19/2009
 2009 American Chemical Society

separate reports on hydroxysulfenylation and the domino
radical-addition-aldol-type reaction on the R,ꢀ-unsaturated
oxime ethers.2d,5
Table 1. Hydroxysulfenylation of Vinylcyclopropyl Oxime
Ether 1
In this paper, we initially aimed to develop the thiyl radical
addition and hydroxylation reaction on the vinylcyclopropyl
oxime ether 1 to produce the R-hydroxy oxime ethers 2
which are crucial synthetic precursors to 1,2-amino alcohols
abundantly found in many naturally occurring compounds.6a
The oxime ethers 2 are also suitable intermediates for the
synthesis of unnatural amino acids, ꢀ-blockers, and
antibiotics.6b-d Our second goal was to develop a novel
domino process for the synthesis of ꢀ-hydroxy oxime ethers
3. These oxime ethers are 1,3-amino alcohol precursors found
in many molecules of pharmaceutical and biological interest
and constituents of several antibiotics7 and other biologically
active natural products (Scheme 1).8
Et3Ba
entry substrate
thiol (equiv)
PhSH 4a (4)
PhSH 4a (4)
PhSH 4a (3)
PhSH 4a (3.5)
PhSH 4a (3.5)
p-Cl-C6H4SH 4b (3.5)
p-MeO-C6H4SH 4c (3.5)
p-Cl-C6H4SH 4b (3.5)
p-MeO-C6H4SH 4c (3.5)
p-Cl-C6H4SH 4b (3.5)
PhSSPh 5 (3.5)
(equiv) 2a-cb(%)
1
2
3
4
5
6
7
8
1E
1E
1E
1E
1E
1E
1E
1Z
1.5
1
1
2a (70)
2a (72)
2a (68)c
2a (76)
2a (78)
2b (88)
2c (84)
2b (87)
2c (82)
2b (86)
n.d.
1
0.5
0.5
0.5
0.5
0.5
0.5
0.5
9
1Z
10
11
1E/Z
1E
Scheme 1
a A 1.04 M hexane solution was used. b Isolated yield. c Starting material
(15%) was recovered.
entries 1-5). After several sets of reactions were screened, the
use of 0.5 equiv of triethylborane was found to deliver good
yields from the reaction (Table 1, entry 5). Substituted thiophe-
nols carrying either electron-donating or -withdrawing groups
on a benzene ring also worked well under our reaction
conditions (Table 1, entries 6 and 7). High yields and the best
results were observed when 3.5 equiv of p-chlorothiophenol
4b was used (Table 1, entry 6). E-Selectivity was found
throughout the screening of the reaction irrespective of the
configuration of the oxime ether 1 (Table 1, entries 8 and 9). A
mixture of E/Z isomers 1 led to the formation of E-oxime ether
2 in good yields (Table 1, entry 10). The hydroxysulfenylation
product 2 was not found when diphenyl disulfide 5 was used
as a thiyl radical source (Table 1, entry 11).
Initially, the possibility of thiyl radical addition to the
olefin part, ring-opening of cyclopropane in the vinylcyclo-
propyl oxime ether 1, and subsequent trapping of the
intermediate radical by molecular oxygen was explored. The
exposure of E-oxime ether 1 to thiophenol 4a in the presence
of triethylborane under an oxygen atmosphere did success-
fully provide the desired ring-opened hydroxysulfenylation
product 2a with a yield of 78% (Table 1, entry 5). Under a
similar set of reaction conditions, the corresponding Z-isomer
1 with p-chlorothiophenol also provided the identical E-
oxime ether 2b with a yield of 87% (Table 1, entry 8).
Scheme 2
.
Thiol Radical-Addition Reaction of Vinylcyclopropyl
Derivatives
The amount of thiophenol and triethylborane used has an
impact on the chemical efficiency and yield of the reaction
products. To achieve good conversion and yield, more than 3
equiv of thiophenol was necessary for this reaction (Table 1,
(5) (a) Ueda, M.; Miyabe, H.; Sugino, H.; Miyata, O.; Naito, T. Angew.
Chem., Int. Ed. 2005, 44, 6190. (b) For our reviews on radical reactions of
imines, see: (c) Miyabe, H.; Ueda, M.; Naito, T. Synlett 2004, 1140. (d)
Naito, T. Heterocycles 1999, 50, 505.
(6) (a) Bergemier, S. C. Tetrahedron 2000, 56, 2561. (b) Yadav, J. S.;
Reddy, A. R.; Narsaiah, A. V.; Reddy, B. V. S. J. Mol. Catal. A 2007, 261,
207. (c) Corey, E. J.; Zhang, F. Angew. Chem., Int. Ed. 1999, 38, 1931. (d)
Bose, D. S.; Narsaiah, A. V. Bioorg. Med. Chem. 2005, 3, 627.
(7) (a) Weinreb, S. M.; Melnick, M. J. Org. Chem. 1988, 53, 850. (b)
Ohno, M.; Wang, Y.; Izawa, T.; Kobayashi, S. J. Am. Chem. Soc. 1982,
104, 6465.
(8) (a) Wovkulich, P. M.; Uskokovic, M. R. J. Am. Chem. Soc. 1981,
103, 3956. (b) Jager, V.; Muller, I. Tetrahedron Lett. 1982, 23, 4777. (c)
Shono, T.; Matsumura, Y.; Tsubata, K.; Uchida, K. J. Org. Chem. 1996,
51, 2590. (d) Tufariello, J. J.; Puglis, J. M. Tetrahedron Lett. 1986, 27,
1265. (e) Vaultier, M.; Tirel, P. J.; Carrie, R. Tetrahedron Lett. 1989, 30,
1947.
In order to reveal the reaction route of our domino
hydroxysulfenylation reaction, additional reactions were
2652
Org. Lett., Vol. 11, No. 12, 2009

carried out (Scheme 2). In the absence of sufficient amounts
of oxygen, the reaction of the oxime ether 1 did not give
hydroxy sulfide 2a but hydrolyzed aldehyde 6. However, in
the presence of sufficient amounts of oxygen, vinylcyclo-
propylaldehyde 7 and ester 8 gave the corresponding thiol
addition and ring-opened products 6 and 9, respectively
(Scheme 2). The formation of the Michael-type of adducts
6 and 9 demonstrated that the oxime ether group is very
important for our domino type of hydroxylation reaction.
Next, we explored the possibility of the thiyl radical
addition to 1 and subsequent ionic trapping of the N-boryl
enamine intermediate C by a suitable eletrophile for the
development of a new domino reaction triggered by thiyl
radical addition (Table 2). The domino thiyl radical addition
Table 2. Thiol Radical-Addition and Aldol-Type Reaction of
Oxime Ether 1
1
The H NMR spectra of the reaction mixture of 1 with
thiophenol and triethylborane in CD2Cl2 under nitrogen
atmosphere exhibited a doublet signal (J ) 13.5 Hz) at δ
6.66 ppm due to the R-proton of the enamine. According to
our previous report,5a this observation suggests the formation
of E-boryl enamine C (Scheme 3). Considering the results,
Scheme 3. Reaction Mechanism
a A 1.04 M hexane solution (1 equiv) was used. b A 1.07 M hexane
solution (1 equiv) was used. c Thiophenol (3.5 equiv) was used. d Aldehyde
(1 equiv) was used. e 12a-g were obtained as the E-isomer only;
diastereomeric ratios were 9:1-7:3. f Isolated yield. g A mixture of E/Z
isomers was used.
(i) involving the significance of the oxime ether group, (ii)
characterization of the E-boryl enamine intermediate C, and
(iii) feasible formation of aldehyde 6 in the absence of
sufficient amounts of oxygen, the proposed reaction route
for the domino hydroxysulfenylation reaction is presented
in Scheme 3.
and aldol-type reaction of E-vinyl oxime ether 1 was first
tested with p-methoxythiophenol 4c as a thiyl radical
precursor and p-chlorobenzaldehyde 11a as an electrophile,
respectively, in the presence of triethylborane. To achieve
good conversion and yield of the domino product, the
systematic study on the reaction conditions involving the ratio
of the substrate, electrophile, and other reagents was
investigated. The ꢀ-hydroxy oxime ether 12a was isolated
with a yield of 82% and good diastereoselectivity when 3.5
equiv of p-methoxythiophenol 4c, 1 equiv of p-chloroben-
zaldehyde 11a, 1 equiv of triethylborane, and 1 equiv of
trimethylaluminum were employed under an inert atmosphere
(Table 2, entry 1). Encouraged by our expected domino
reaction of 1, we surveyed the scope of using different
thiophenols and aldehydes. Substituents on the thiophenol
ring with both electron-withdrawing and electron-donating
groups proved to be tolerated (Table 2, entries 1-5 and 7),
and simple thiophenol 4a was also effective (Table 2, entry
6). As an electrophile, p-methoxy- and o-methoxybenzalde-
hydes 11b,c and 2-furfural 11d worked effectively and were
found to be good trapping agents (Table 2, entries 4, 5, and
7, respectively). In related reactions, formaldehyde did not
work well but cyclohexylaldehyde 11e gave the same type
of ꢀ-hydroxy oxime ether 12g in good yields.
Triethylborane is known to immediately react with thiophe-
nol to give diethyl phenylthioborane 10 and ethane gas.2d,9
Homolytic cleavage of the B-S bond by molecular oxygen
at the boron atom generates the thiyl radical,10 which reacts
with vinylcyclopropyl oxime ether 1 to produce the homoal-
lylic carbon-centered radical A. Radical A is not very stable,
but more stable aminyl radical B is captured by triethylborane
to afford the E-boryl enamine intermediate C, which can
undergo an ene-type reaction with oxygen to form intermedi-
ate D. The peroxide D will be readily reduced by thiophenol
to give the final alcohol 2a accompanying the formation of
the diphenyl disulfide 5. However, hydroxysulfenylation of
1 with diphenyl disulfide 5 did not proceed (Table 1, entry
11), which excluded the regeneration of the thiyl radical from
5 in the reaction mechanism.
(9) Triethylborane immediately reacts with RSH to give RSBEt2; see:
Gilman, H.; Nelson, J. F. J. Am. Chem. Soc. 1937, 59, 935
.
(10) (a) Ichinose, Y.; Wakamatsu, K.; Nozaki, K.; Birbaum, J. L.;
Oshima, K.; Utimoto, K. Chem. Lett. 1987, 1647. (b) Masuda, Y.; Hoshi,
M.; Nunokawa, Y.; Arase, A. J. Chem. Soc., Chem. Commun. 1991, 1444.
Org. Lett., Vol. 11, No. 12, 2009
2653

The erythro-configuration of the major isomer 12b was
determined by the formation of its cyclic cis-acetonide
derivative 13 of the corresponding reduced 1,3-amino alcohol
(Scheme 4).11 According to our previous report on the
between the sulfide chain substituent and aryl group of the
aldehyde 11 is minimized.
As reported in Houk’s study on the aldol reaction of an
enamine with acetaldehyde, an axial or equatorial methyl
group on acetaldehyde is predicted to be almost equal in
energy, and thus, it is not unusual to find an axial Ar2 group
in the transition state.12
Scheme 4. Preparation of Cyclic Acetonide Derivative
In conclusion, we have succeeded in two domino reactions
of vinylcyclopropyl oxime ethers involving thiyl radical
addition-ring-opening reaction-hydroxylation and thiyl
radical addition-ring-opening-aldol-type reactions. Both
domino reactions construct highly functionalized acyclic
ε-thio-δ,γ-unsaturated-R-hydroxy oxime ethers and ε-thio-
δ,γ-unsaturated-ꢀ-hydroxymethyl oxime ethers, which are
versatile intermediates in organic synthesis and play an
important role in biological and chemical processes.13
Additionally, the success of our multicomponent reaction
with vinylcyclopropyl oxime ether provided the impetus to
develop the allyl sulfide containing 1,3-amino alcohol
compounds in a single operation.
domino hydroxysulfenylation reaction, the reaction is be-
lieved to proceed via the formation of an E-boryl enamine
intermediate C5a and subsequent trapping by the aldehyde
11 to afford the desired compound 12. The preferential
erythro-selectivity of the aldol-type reaction can be explained
by invoking a six-membered-ring transition state E as shown
Acknowledgment. We acknowledge the support of the
research grants-in-aid for Scientific Research (B) (to T.N.)
and C (to O.M.) from the Japan Society for the Promotion
of Science (JSPS) and Scientific Research on Priority Areas
(A) (to T.N.) from the Ministry of Education, Culture, Sports
and Technology. H.R. thanks the JSPS for a research grant
and financial assistance.
Scheme 5
.
Possible Transition State of the Domino Aldol-Type
Reaction
Supporting Information Available: Experimental pro-
1
cedures, characterization data, and copies of H NMR and
13C NMR spectra for selected compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
OL900604A
(11) See the Supporting Information for the reduction and acetonide
formation. The cis-configuration of the cyclic acetonide 13 was deduced
by NMR coupling constant and the NOESY.
(12) Bahmanyar, S.; Houk, K. N. J. Am. Chem. Soc. 2001, 123, 11273.
(13) (a) Cremlyn, R. J. An Introduction to Organo-Sulfur Chemistry;
Wiley & Sons: New York, 1996. (b) Recently, one invention relates that
allyl sulfide with another composition was used in an effective amount of
formulation, including emulsion, to repel blood-feeding ectoparasitic
arthropods. See Int. Patent No. PCT/CA2008/000591.
in Scheme 5. The E-boryl enamine C reacts with the Me3Al-
activated aldehyde in such a fashion that steric repulsion
2654
Org. Lett., Vol. 11, No. 12, 2009