Atom-transfer radical addition of α-iodo esters to 1-alkynyl sulfldes

Article abstract of DOI:10.1246/cl.2009.462

Atom-transfer radical addition of α-iodo esters to 1-alkynyl sulfides is described. The products, 2-alkoxycarbonylmethyl-l-iodo-1-alkenyl sulfldes, can be converted into γ-keto esters. Copyright

Full text of DOI:10.1246/cl.2009.462

462
Chemistry Letters Vol.38, No.5 (2009)
Atom-transfer Radical Addition of ꢀ-Iodo Esters to 1-Alkynyl Sulfides
Junichi Imoto, Akinori Sato, Hideki Yorimitsu,ꢀ and Koichiro Oshimaꢀ
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510
(Received March 2, 2009; CL-090213; E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp,
oshima@orgrxn.mbox.media.kyoto-u.ac.jp)
nC11H23
I
Atom-transfer radical addition of ꢀ-iodo esters to 1-alkynyl
sulfides is described. The products, 2-alkoxycarbonylmethyl-1-
iodo-1-alkenyl sulfides, can be converted into ꢁ-keto esters.
O
nC11H23
CO2
A
EtO
O
R1 C C SR2
I
heat
EtO
1
2a
1-Alkynyl sulfides can be good precursors to synthesize var-
ious organosulfur compounds.1 For example, Diels–Alder reac-
tions of 1-alkynyl sulfides with conjugated dienes giving cyclic
alkenyl sulfides have been reported.1c On the other hand, there
are few reports of radical reactions using 1-alkynyl sulfides as
substrates,2 although radical addition would be a powerful meth-
od to prepare synthetically useful vinyl sulfides. Here we report
atom-transfer radical addition of ꢀ-iodo esters to 1-alkynyl sul-
fides.
R1
DLP
O
R1
SR2
I
SR2
O
EtO
B
2a
R1
SR2
EtO
3
O
EtO
B'
Treatment of butyl 1-octynyl sulfide (1a) with ethyl iodo-
acetate (2a) in the presence of a catalytic amount of dilauroyl
peroxide (DLP) in boiling benzene afforded the corresponding
adduct 3aa in 71% yield (Table 1, Entry 1).3,4 Although the ster-
eoisomeric ratio was close to 1:1, the reaction proceeded with
perfect regioselectivity. Alkynyl sulfides bearing a base-sensi-
tive siloxy moiety or an acid-sensitive THP moiety underwent
the radical addition without affecting the protective groups (En-
tries 2 and 3). Replacement of the butylsulfanyl group of 1a by
methylsulfanyl or phenylsulfanyl group did not affect the reac-
tivity (Entries 4 and 5). A secondary alkyl-substituted alkynyl
sulfide 1f was also applicable to the reaction, albeit the stereo-
selectivity was still low (Entry 6). Unfortunately, an aryl-substi-
tuted alkynyl sulfide, butyl phenylethynyl sulfide (1g), was not
suitable for the reaction because of the formation of a mixture
of regio- and stereoisomers.
Scheme 1.
thermally generated from DLP with release of CO2, would ab-
stract iodine from 2a to provide carbon-centered radical A.6 Be-
cause carbonylmethyl radicals are electron-deficient, radical A
would react smoothly with 1-alkynyl sulfide 1, an electron-rich
alkyne, to furnish the vinyl radical B. At this stage, the new car-
bon–carbon bond is formed regioselectively at the ꢂ-position of
the sulfur atom, at which higher electron-density resides due to
the resonance effect of the sulfur atom. The E/Z isomerization
between vinyl radicals B and B0 is fast. In addition, the sizes
of R1 and the ethoxycarbonylmethyl group are comparable.
Hence, both stereoisomers would react with 2a. Iodine-transfer
from 2a to the vinyl radicals would afford product 3 and regen-
erate radical A to complete the radical chain.
Next, we examined the scope of alkyl halides (Table 2).
Benzyl iodoacetate (2b) and tert-butyl iodoacetate (2c) also add-
ed to 1a to give the corresponding adducts, 3ab and 3ac in good
yields (Entries 1 and 2). Iodoacetonitrile (2d) also underwent the
addition reaction (Entry 3). However, radical addition of ꢀ-
iodoacetophenone (2e), N,N-diethyliodoacetamide (2f), or dieth-
yl bromomalonate (2g) to 1a resulted in failure, suffering from
giving a complex mixture (for the reaction with 2e) or no conver-
sion (for the reactions with 2f or 2g).
The reaction would proceed in a manner similar to standard
atom-transfer radical reactions (Scheme 1).5 Undecyl radical,
Table 1. Atom-transfer radical addition of ethyl iodoacetate 2a
to 1-alkynyl sulfides 1
R1 C C SR2 1
R1
SR2
I
+
20 mol% DLP
O
O
benzene, reflux, 4 h
DLP = (n-C11H23CO2)2
I
EtO
3
EtO
2a (1.5 equiv)
Table 2. Atom-transfer radical addition of ꢀ-iodo esters and
nitrile 2b–2d to butyl 1-octynyl sulfide (1a)
Yield/%a
[E/Z or Z/E]
nC6H13 C C SnBu 1a
nC6H13 SnBu
R3
Entry
1
R1
R2
3
20 mol% DLP
+
benzene, reflux, 4 h
R3
I
I
3
1
2
3
4
5
6
1a n-C6H13
1b t-BuMe2SiO(CH2)3
1c
1d
1e
1f
n-Bu
n-Bu
n-Bu
Me
3aa 71 [56/44]
3ba 60b [54/46]
3ca 55b [56/44]
3da 82 [57/43]
3ea 72 [52/48]
2 (1.5 equiv)
Entry
2
R3
3
Yield/%a [E/Z or Z/E]
THPO(CH2)3
n-C10H21
n-C6H13
i-Pr
1
2
3
2b
2c
2d
CO2Bn
CO2t-Bu
CN
3ab
3ac
3ad
84 [55/45]
74 [55/45]
74 [54/46]
Ph
n-C12H25 3fa 53b [54/46]
b
aIsolated yields. Compounds 1 (30–40%) were recovered.
aIsolated yields.
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.5 (2009)
463
5637. c) G. Hilt, S. Luers, K. Harms, J. Org. Chem. 2004,
¨
nHex
O
SnBu
69, 624. d) N. Riddell, W. Tam, J. Org. Chem. 2006, 71,
1934. e) S. Aoyagi, K. Sugimura, N. Kanno, D. Watanabe,
K. Shimada, Y. Takikawa, Chem. Lett. 2006, 35, 992.
D. Melandri, P. C. Montevecchi, M. L. Navacchia, Tetrahe-
dron 1999, 55, 12227.
Pd(OAc)2 (5 mol%)
PPh3 (20 mol%)
K2CO3 (3 equiv)
nHex
O
SnBu
Ar
I
3aa [56/44]
+
EtO
2
3
THF, reflux, 9 h
EtO
4
ArB(OH)2
(2 equiv)
Typical experimental procedure: Under argon, a mixture of
butyl 1-octynyl sulfide (1a, 0.099 g, 0.50 mmol) and benzyl
iodoacetate (2b, 0.21 g, 0.75 mmol) was heated in boiling ben-
zene (1 mL) in the presence of DLP (0.040 g, 0.10 mmol) for
4 h. After the reaction mixture was cooled to ambient temper-
ature, the solvent was removed in vacuo. Purification by silica
gel column chromatography (hexane/ethyl acetate = 40/1)
afforded 3ab in 84% yield (0.20 g, 0.42 mmol, stereoisomeric
ratio = 55/45). Benzyl 3-[(butylsulfanyl)iodomethylidene]-
nonanoate (3ab): IR (neat): 2927, 2856, 1738, 1456, 1150,
Ar =
Ph (4a) 88% [58/42]
p-Me–C6H4 (4b) 98% [58/42]
p-F–C6H4 (4c) 93% [60/40]
Scheme 2.
nHex
O
SnBu
Ar
nHex
O
O
conc. H2SO4 (1 equiv)
EtOH, reflux, 35 h
Ar
EtO
4a–4c
EtO
5
696 cmꢁ1 1H NMR (CDCl3): ꢃ 0.86–0.95 (m, 6H), 1.22–
;
Ar =
Ph (5a) 86%
1.35 (m, 6H), 1.35–1.45 (m, 4H), 1.45–1.57 (m, 2H), 2.37 (t,
J ¼ 8:0 Hz, 0:55 ꢂ 2H), 2.56 (t, J ¼ 8:0 Hz, 0:45 ꢂ 2H),
2.69 (t, J ¼ 7:5 Hz, 0:55 ꢂ 2H), 2.72 (t, J ¼ 7:5 Hz, 0:45 ꢂ
2H), 3.46 (s, 0:45 ꢂ 2H), 3.63 (s, 0:55 ꢂ 2H), 5.14 (s,
0:55 ꢂ 2H), 5.16 (s, 0:45 ꢂ 2H), 7.31–7.41 (m, 5H); 13C NMR
(CDCl3): ꢃ 13.88 (two signals overlapped), 14.27 (two signals
overlapped), 21.97, 22.00, 22.75, 22.76, 27.19, 28.27, 29.24,
29.26, 31.06, 31.13, 31.74, 31.76, 35.81, 37.67, 38.12, 39.27,
43.56, 48.41, 66.82, 66.88, 95.31, 96.35, 128.32 (two signals
overlapped), 128.38, 128.42, 128.70, 128.72, 135.88, 135.93,
147.78, 148.62, 169.64, 169.82; Found: C, 53.42; H, 6.70%.
Calcd for C21H31IO2S: C, 53.16; H, 6.59%.
The use of AIBN [2,20-azobis(isobutyronitrile)] instead of DLP
decreased the yield of 3aa drastically because the initiation
step, iodine-abstraction from 2a by 1-cyano-1-methylethyl
radical, did not work efficiently.
a) J. Byers, in Radicals in Organic Synthesis, ed. by P. Renaud,
M. P. Sibi, Wiley-VCH, Weinhelm, 2001, Vol. 1, Chap. 1.5,
pp. 72–89. b) D. P. Curran, Synthesis 1988, 489. c) H.
Yorimitsu, H. Shinokubo, K. Oshima, Synlett 2002, 674.
None of the undecylated alkenyl sulfides were observed.
N. Miyaura, A. Suzuki, Chem. Rev. 1995, 95, 2457.
p-Me–C6H4 (5b) 87%
p-F–C6H4 (5c) 88%*
* Conc. H2SO4 (4 equiv) was used.
Scheme 3.
We then attempted transformation of 1-iodo-1-alkenyl sul-
fides 3 to exploit the utility of 3 in organic synthesis. The
Suzuki–Miyaura cross-coupling reaction7 of 3aa with phenyl-,
p-methylphenyl-, or p-fluorophenylboronic acid in the presence
of a palladium catalyst afforded the corresponding arylated prod-
uct, 1-aryl-1-alkenyl sulfide 4 in excellent yield (Scheme 2).
Finally, we investigated hydrolysis of the resulting 1-aryl-1-
alkenyl sulfides 4 under acidic conditions. Several conventional
conditions8 failed to hydrolyze 4. Instead, treatment of 4 with
concentrated sulfuric acid in boiling ethanol provided the corre-
sponding ꢁ-keto esters 5a–5c in high yields (Scheme 3).
In conclusion, we have achieved atom-transfer radical addi-
tion of ꢀ-iodo esters to 1-alkynyl sulfides. The products could
be converted into ꢁ-keto esters easily.9
4
5
6
7
8
This work was supported by Grants-in-Aid for Scientific
Research and GCOE Research from the Ministry of Education,
Culture, Sports, Science and Technology, Japan. A.S. acknowl-
edges JSPS for financial support.
For general hydrolysis of 1-alkenyl sulfides to ketones with
TiCl4, see: T. Mukaiyama, K. Kamio, S. Kobayashi, H. Takei,
Bull. Chem. Soc. Jpn. 1972, 45, 3723.
9
Recent examples for the synthesis of ꢁ-keto esters: a) S. Xue,
Y.-K. Liu, L.-Z. Li, Q.-X. Guo, J. Org. Chem. 2005, 70, 8245.
b) W. Lin, R. J. McGinness, E. C. Wilson, C. K. Zercher,
Synthesis 2007, 2404. c) M. P. DeMartino, K. Chen, P. S.
Baran, J. Am. Chem. Soc. 2008, 130, 11546. d) W. Wang, B.
Xu, G. B. Hammond, J. Org. Chem. 2009, 74, 1640.
References and Notes
´
a) J. Barluenga, G. P. Romanelli, L. J. Alvarez-Garcıa, I.
1
´
´
´
´
Llorente, J. M. Gonzalez, E. Garcıa-Rodrıguez, S. Garcıa-
Granda, Angew. Chem., Int. Ed. 1998, 37, 3136. b) L. K.
McConachie, A. L. Schwan, Tetrahedron Lett. 2000, 41,
Published on the web (Advance View) April 11, 2009; doi:10.1246/cl.2009.462