Radical addition of alkyl halides to 2-methylene-1,3-dithiane monoxide as a ketene equivalent

Article abstract of DOI:10.1246/cl.2009.248

Radical addition reaction of alkyl halides with ketene dithioacetal monoxide in the presence of tributyltin hydride and a catalytic amount of 2,2'-azobis(isobutyronitrile) (AIBN) proceeds smoothly to provide the corresponding adducts in moderate to high y

Full text of DOI:10.1246/cl.2009.248

248
Chemistry Letters Vol.38, No.3 (2009)
Radical Addition of Alkyl Halides to 2-Methylene-1,3-dithiane Monoxide
as a Ketene Equivalent
Suguru Yoshida, Hideki Yorimitsu,ꢀ and Koichiro Oshimaꢀ
Department of Material Chemistry, Graduate School of Engineering, Kyoto University,
Kyoto-daigaku Katsura, Nishikyo-ku, Kyoto 615-8510
(Received December 22, 2008; CL-081198; E-mail: yori@orgrxn.mbox.media.kyoto-u.ac.jp,
oshima@orgrxn.mbox.media.kyoto-u.ac.jp)
Bu3SnH (2 equiv)a
AIBN (0.1 equiv)
Radical addition reaction of alkyl halides with ketene di-
thioacetal monoxide in the presence of tributyltin hydride and
a catalytic amount of 2,20-azobis(isobutyronitrile) (AIBN) pro-
ceeds smoothly to provide the corresponding adducts in moder-
ate to high yields.
S
S
+
Br
5a
(3 equiv)
S
S
benzene
reflux, 2 h
1a–c
3
O
O
S
S
SMe
Ketene is one of the most important building blocks for syn-
thesis of carbonyl compounds.1,2 However, few radical reactions
using ketene have been reported,3 because of the difficulty to
control the regiochemistry in the addition of radicals to ketene4
(eq 1). Radical addition to ketene equivalents, instead of ketene
itself, has also been limited,5 although the reaction provides us
with an alternative route to various carbonyl compounds via rad-
ical pathways. Therefore, development of new methods for the
radical addition reaction to a novel ketene equivalent as a radical
acceptor would provide a powerful synthetic tool.
S
S
SMe
1a
1b
0%
1c
43%
84%
(70%)b
aSlow addition over 1 h.
b5a (1.0 equiv), 1a (1.2 equiv), AIBN (0.2 equiv),
Ph3SnH (2.0 equiv, slow addition over 1 h), benzene, reflux, 2 h.
Scheme 2.
separated by silica-gel column purification without contamina-
tion by tin residues due to the high polarity of 3a.
O
R
O
O
R
R
+
+
+
ð1Þ
C
O
R
The use of triphenyltin hydride instead of tributyltin hydride
could decrease the amount of alkyl halide. Thus, the reaction of
tert-butyl bromide (5a) (1.0 equiv) with ketene dithioacetal
monoxide 1a (1.2 equiv) in the presence of triphenyltin hydride
(2.0 equiv) and AIBN (0.2 equiv) gave the corresponding adduct
3a in 70% yield.9
Then, we examined the scope of alkyl halides (Table 1). In
the case of tertiary alkyl bromides (Entries 1–4), desired prod-
ucts were obtained in high yields. The phenylsulfanyl group was
tolerated under the reaction conditions (Entry 4). Secondary and
primary alkyl halides also underwent the radical reaction
smoothly with 1a (Entries 5–7). Secondary alkyl iodides 5e
and 5f were converted to the corresponding adducts in good
yields in the reactions with 1a, although the products were
mixtures of two diastereomers. Primary alkyl iodide 5g reacted
with 1a to provide 3g in moderate yield.
We next examined the utility of the products (Scheme 3).
The dithioacetal monoxide moiety could be removed smoothly
without using toxic mercury reagents. Treatment of sulfoxide
3b with a catalytic amount of sulfuric acid in hot toluene afford-
ed aldehyde 6 in almost quantitative yield. In addition, sulfoxide
3b could be reduced easily into 1,3-dithiane.10 Treatment of sulf-
oxide 3b with trifluoroacetic anhydride and sodium iodide gave
1,3-dithiane 7 in high yield.
Recently, we have been pursuing the synthetic utility of
ketene dithioacetal monoxides as ketene equivalents.6 Ketene
dithioacetal monoxides should be good candidates for a radical
acceptor because radical intermediate 2, generated by the addi-
tion of alkyl radical to ketene dithioacetal monoxide 1, would
be well-stabilized by both sulfanyl and sulfinyl groups due to
captodative effect7 (Scheme 1). The stability of intermediate 2
could prevent undesired side reactions such as polymerization.
Here, we report radical addition of alkyl halides to ketene
dithioacetal monoxide 1 as a ketene equivalent.
Tributyltin hydride (2.0 equiv) was added to a mixture of
tert-butyl bromide (5a) (3.0 equiv) and a ketene dithioacetal de-
rivative 1a, 1b, or 1c (1.0 equiv) over 1 h in the presence of 0.1
equiv of 2,20-azobis(isobutyronitrile) (AIBN) as a radical initia-
tor in boiling benzene (Scheme 2).8 Among three ketene dithio-
acetal derivatives, 2-methylene-1,3-dithiane 1-oxide (1a) was
found to be the best radical acceptor. The reaction of 5a with
1a afforded 3a in 84% yield. To our surprise, the reaction with
acyclic reagent 1b failed to afford the corresponding adduct,
instead yielding a complex mixture. Treatment of 5a with 2-
methylene-1,3-dithiane (1c) provided the desired product 3c in
only 43% yield. It is worth noting that sulfoxide 3a could be
In order to develop the further utility of the radical addition
products of ketene dithioacetal monoxide, tertiary alkyl bromide
8 bearing an amide moiety11 was subjected to the reaction with
1a (Scheme 4). The reaction proceeded efficiently to give de-
sired adduct 9 in high yield. Then, the product 9 was treated with
hydrochloric acid followed by an addition of benzoyl chloride to
O
O
O
Sn−H
− Sn
SR
SR
O
SR
SR
SR
SR
+
R
R
R
R
H
H
1
2
3
4
Scheme 1.
Copyright Ó 2009 The Chemical Society of Japan

Chemistry Letters Vol.38, No.3 (2009)
249
Table 1. Reactions of alkyl halides with sulfoxide 1a in the
presence of tributyltin hydride and a catalytic amount of AIBN
provide dihydropyrrole 10 bearing a quaternary carbon atom in
good yield. This result shows that the radical addition reaction
would be useful for the synthesis of heterocycles bearing such
a quaternary carbon moiety.
In conclusion, we have developed radical addition of alkyl
halides to 2-methylene-1,3-dithiane 1-oxide as a ketene equiva-
lent in the presence of tributyltin hydride and a catalytic amount
of AIBN. The reaction afforded alkanal equivalents protected as
dithioacetal monoxide, which can be removed easily with sulfu-
ric acid. The products could be subjected to a variety of organic
transformations.
Bu3SnH (2 equiv)
O
O
AIBN (0.1 equiv)
S
S
RX
+
R
S
1a
5
benzene
reflux, 2 h
S
3
(3 equiv)
5
3
Entry
1
RX
Yield/%a
84
5a
3a
Br
This work was supported by Grants-in-Aid for Scientific
Research, COE Research, and Global COE Research from JSPS.
S.Y. acknowledges JSPS for financial support.
2
3
4
5
5b
5c
5d
5e
3b
3c
3d
3e
84
n-C8H17
Br
91
(d.r. = 17:1)
67
Br
References and Notes
1
2
For recent review, see: T. T. Tidwell, Eur. J. Org. Chem. 2006, 563.
Selected examples: a) H. Staudinger, Justus Liebigs Ann. Chem.
1907, 356, 51. b) H. Wynberg, E. G. J. Staring, J. Am. Chem. Soc.
1982, 104, 166. c) H. Wynberg, E. G. J. Staring, J. Org. Chem.
1985, 50, 1977. d) T. Machiguchi, J. Okamoto, J. Takachi, T.
Hasegawa, S. Yamabe, T. Minato, J. Am. Chem. Soc. 2003, 125,
14446.
PhS
Br
5
75b
(d.r. = 8:1)
I
80b
(d.r. = 6:1)
6
7
5f
3f
3
W. Huang, H. Henry-Riyad, T. T. Tidwell, J. Am. Chem. Soc. 1999,
121, 3939.
I
58b
(d.r. = 3:1)
4
5
K. Sung, T. T. Tidwell, J. Org. Chem. 1998, 63, 9690.
K. Ogura, N. Sumitani, A. Kayano, H. Iguchi, M. Fujita, Chem. Lett.
1992, 1487.
n-C6H13
I
5g
3g
aIsolated yields. AIBN (0.2 equiv).
b
6
a) S. Yoshida, H. Yorimitsu, K. Oshima, J. Organomet. Chem. 2007,
692, 3110. b) S. Yoshida, H. Yorimitsu, K. Oshima, Synlett 2007,
1622. c) S. Yoshida, H. Yorimitsu, K. Oshima, Org. Lett. 2007, 9,
5573. d) S. Yoshida, H. Yorimitsu, K. Oshima, Chem. Lett. 2008,
37, 786. e) S. Yoshida, H. Yorimitsu, K. Oshima, Heterocycles
2008, 76, 679.
O
cat. H2SO4
toluene
reflux, 2 h
n-C8H17
H
6
O
S
99%
7
8
H. G. Viehe, Z. Janousek, R. Merenyi, Acc. Chem. Res. 1985, 18,
148.
n-C8H17
S
S
Experimental procedure: A benzene (1.0 mL) solution of 2-methyl-
ene-1,3-dithiane 1-oxide (1a, 49.4 mg, 0.33 mmol), 2-bromo-2-
methylpropane (0.11 mL, 0.99 mmol), and 2,20-azobis(isobutyroni-
trile) (5.0 mg, 0.030 mmol) was placed in a flask under an atmo-
sphere of argon. Then, a benzene (1.0 mL) solution of tributyltin hy-
dride (0.18 mL, 0.66 mmol) was added over 1 h with a syringe pump
at reflux. After the addition was completed, the mixture was stirred
for an additional 1 h at the same temperature. The reaction mixture
was poured into saturated aqueous NaHCO3 (5 mL) and extracted
with EtOAc (3 ꢁ 10 mL). The combined organic layer was dried
over anhydrous Na2SO4 and concentrated in vacuo. Purification
by chromatography on silica gel (hexane/AcOEt = 1/2) provided
2-(2,2-dimethylpropyl)-1,3-dithiane 1-oxide (3a, 58.0 mg, 84%).
Smooth hydrogen abstraction from triphenyltin hydride would in-
crease the efficiency of the reaction, because of the weaker Sn–H
bond of triphenyltin hydride. See: C. Chatgilialoglu, M. Newcomb,
Adv. Organomet. Chem. 1999, 44, 67.
3b
n-C8H17
S
(CF3CO)2O
NaI
acetone
0 °C to 25 °C
1 h
7
92%
Scheme 3.
NHBoc
1. aq. HCl
CH3CN
25 °C, 24 h
O
Ph
Bu3SnH
cat. AIBN
NHBoc
S
Et
Et
Br
8
N
+
Et
Et
benzene
reflux, 2 h
S
O
2. PhCOCl
25 °C, 12 h
Et
O
9
S
Et
9
10
62%
S
90 %
1a
Boc = tert-Butoxycarbonyl
10 M. deGreef, S. Z. Zard, Tetrahedron 2004, 60, 7781.
11 A. Sliwinska, A. Zwierzak, Tetrahedron 2003, 59, 5927.
Scheme 4.
Published on the web (Advance View) February 7, 2009; doi:10.1246/cl.2009.248