Radical chain reactions using THP as a solvent

Article abstract of DOI:10.1016/j.tetlet.2007.11.039

THP (tetrahydropyran) has been found to show an excellent stability towards autooxidation, compared with THF. Tributyltin hydride mediated radical cyclization, when conducted in THF as a solvent, suffers from competition of hydrogen abstraction from the solvent, whereas the use of THP resulted in the course to negligible degree. Tributyltin hydride, TTMSS, and hexanethiol mediated radical reactions were carried out successfully using THP as a solvent.

Full text of DOI:10.1016/j.tetlet.2007.11.039

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Tetrahedron Letters 49 (2008) 367–370
Radical chain reactions using THP as a solvent
Hiroshi Yasuda,a,* Yoshitaka Uenoyama,b Osamu Nobuta,b
Shoji Kobayashib and Ilhyong Ryub,*
aCorporate R&D Center, Showa Denko K.K., 5-1, Ogimachi, Kawasaki-Ku, Kawasaki, Kanagawa 210-0867, Japan
bDepartment of Chemistry, Graduate School of Science, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan
Received 6 October 2007; revised 3 November 2007; accepted 6 November 2007
Available online 3 December 2007
Abstract—THP (tetrahydropyran) has been found to show an excellent stability towards autooxidation, compared with THF.
Tributyltin hydride mediated radical cyclization, when conducted in THF as a solvent, suffers from competition of hydrogen
abstraction from the solvent, whereas the use of THP resulted in the course to negligible degree. Tributyltin hydride, TTMSS,
and hexanethiol mediated radical reactions were carried out successfully using THP as a solvent.
Ó 2007 Elsevier Ltd. All rights reserved.
Tin, silicon, thiyl radicals are frequently utilized in radi-
cal chain reactions.1 Generally, benzene is preferred as
a solvent in terms of its strong C–H bond, however, it
is sometimes experienced that the key radical species
react with benzene to form undesirable aromatic
byproducts. Some other drawbacks of benzene include
its toxicity and the narrow temperatures inherent to
relatively high freezing point of 5.5 °C also limit the
use of benzene, and in this context, toluene is often used
as a substitute of benzene. If the substrate exposed to
radical reaction conditions has low solubility to
benzene, polar solvents have to be chosen. THF (tetra-
hydrofuran) which can dissolve a wide range of organic
molecules is sometimes used in radical reactions;
however, rather weak C–H bond adjacent to oxygen is
always risk-exposing for valuable substrates. In this
Letter, we report that THP (tetrahydropyran), whose
boiling point is 88 °C, can be used for radical chain reac-
tions, such as tributyltin hydride mediated reduction
and cyclization, TTMSS (tris(trimethylsilyl)silane) and
thiol mediated hydrosilylation and hydothiolation of
alkenes and alkynes.2
ease. As shown in Figure 1, THP showed very strong
reluctance towards autooxidation even for 30 days expo-
sure to air, whereas 500 ppm of the peroxide was formed
for the case of THF. The quality of THP can last 60
days when 250 ppm of BHT (dibutylhydroxytoluene)
was added as an anti-oxidant.
Having affirmative data on the stability to autooxida-
tion with THP in hand, we then tested THP for radical
reduction and cyclization of organic halides using
tributyltin hydride and AIBN. Reduction of organic
bromides 1a, 1b, and 1c was successfully carried out
(Scheme 1). For example, a solution of 3b-bromo-5-
cholestene (1b, 1 mmol), AIBN (0.1 mmol), and Bu3SnH
(1.5 mmol) in tetrahydropyran (5 mL) was stirred for
2 h at reflux.3 The reaction mixture was treated with
At the outset, we checked the formation of peroxide by
autooxidation of THF and THP to compare the relative
Keywords: Radical reaction; THP; Tin radical; Silicon radical; Thiyl
radical.
*
Corresponding authors. Tel./fax: +81 72 254 9695; e-mail: ryu@
c.s.osakafu-u.ac.jp
Figure 1. Stability of THF and THP towards autooxidation.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.039

368
H. Yasuda et al. / Tetrahedron Letters 49 (2008) 367–370
Table 1. Tin-mediated radical reaction of 1d in THP and other
AIBN, Bu3SnH
RBr
RH
solvents
THP
reflux, 1.5-2 h
1
2
Bu3SnH
+
Br
Br
1.2 equiv
0.05 M
1d
2a
82%
+
+
1a
2d"
2d'
2d
H
2b
2c
82%(85%)a
67%
Entry
Solvent
Initiator
Conditions
Product ratioa
H
H
1
2
3
4
5
6
THF
C6H6
Toluene
THP
C6H6
THP
AIBN
AIBN
AIBN
AIBN
66 °C, 2 h
80 °C, 2 h
80 °C, 2 h
80 °C, 2 h
15 °C, 4.5 h
15 °C, 4 h
79
91
89
86
93
88
4
5
5
4
3
3
17
4
6
10
4
9
Br
Br
1b
H
H
H
b
BEt3
BEt3
BzO
b
1c
a Estimated by GC. Yields are 70–95%.
b Hexane solution was used.
aRecycled THP was used.
Scheme 1. Radical reduction of 1a–c in THP.
Table 2. Radical addition reaction of TTMSSa and n-HexSHb in THP
Entry
1
Substrate
Product
Yieldc (%)
85
(TMS)3Si
1a
2e
2f
(TMS)3Si
2
3
86
76
CN
1f
CN
(TMS)3Si
(TMS)3Si
1g
2g
O
O
4
5
85 (E/Z = 10/90)
OMe
OMe
1h
2h
Si(TMS)3
O
40 (cis/trans = 23/77)
45
O
O
2i
1i
Si(TMS)2
2i0
OH
6
81
OH
n-C6H13
S
S
1j
2j
7
8
66 (E/Z = 50/50)
64 (E/Z = 52/48)
n-C6H13
1k
1l
2k
2l
OH
n-C6H13
S
S
OH
CO2Et
CO2Et
EtO2C
EtO2C
n-C6H13
9
67 (49/51)
1m
2m
n-C6H13
S
S
10
11
1g
1i
2n
2o
72 (E/Z = 92/8)
n-C6H13
78 (65/35)
O
a Conditions: substrate (1 mmol), (TMS)3SiH (1.1–1.2 mmol), V-65 (2,20-azobis(2,4-dimethyl valeronitrile)) (20 mol %), THP (2 mL), 70 °C, 4 h.
b Conditions: substrate (1 mmol), n-HexSH (1.2–1.5 equiv), THP (2 or 10 mL (entries 7, 10, and 11)), AIBN (2,20-azobis(isobutyronitrile))
(20 mol %), 80 °C, 2–3 h.
c Isolated yield after silica gel chromatography.

H. Yasuda et al. / Tetrahedron Letters 49 (2008) 367–370
369
saturated KF solution. The resulting suspension involv-
ing Bu3SnF was filtered and the filtrate was separated
and dried over anhydrous MgSO4. Purification by flash
column chromatography (silica gel, hexane) gave 5-
cholestene (2b) (82%). Similarly, reduction of 17a-bromo-
estradiol 3-benzoate (1c) gave 17-hydro-estradiol 3-ben-
zoate (2c) in 67% yield after chromatographic purifica-
tion. It should be stated that, unlike water-miscible
THF, THP made two layers when mixed with water,
which facilitated the biphasic aqueous/organic workup
procedure in the above case. If required, the recovery
of THP is inherently easy to carry out unlike the case
of water soluble ether solvents.4,5
radical addition of TTMSS and hexanethiol to alkenes
and alkynes can be successfully carried out using THP
as the solvent. Thus, for these reactions, THP serves
as a good substitute for toxic benzene, less polar tolu-
ene, and air-unstable, water-miscible THF for these
types of radical reactions.
Acknowledgments
We thank MEXT and JSPS for financial support of this
work. We also thank Ayaka Hibi for experimental help.
References and notes
Then, we checked the cyclization of 2-(4-butenyl)phenyl
radical using tributyltin hydride and AIBN with differ-
ent solvents (Table 1).6 Under the employed conditions
the radical cyclization courses leading to 2d and 2d0 are
principal, whereas the direct hydrogen abstraction path
by aryl radicals from tributyltin hydride and solvent
leading to 2d00 competes to some extent. In the case of
THF, the 83/17 ratio of cyclization/uncyclization was
observed (entry 1), whereas the ratios 90/10, 94/6, and
96/4 were observed for THP, toluene, and benzene,
respectively (entries 2–4). These results suggest that the
direct hydrogen abstraction path of aryl radicals from
solvent competes most seriously with THF, whereas
such a path is rather modest for THP and toluene, com-
pared with THF.7,8
1. Radical in Organic Synthesis; Renaud, P., Sibi, M. P.,
Eds.; Wiley-VCH: Weinheim, Germany, 2001; Vols. 1 and
2.
2. For the use of THP in SmI2 reaction, see: Kagan, H. B.
Tetrahedron 2003, 59, 10351.
3. A solution of 3b-bromo-5-cholestene (1b, 444 mg,
0.99 mmol), AIBN (16.2 mg, 0.099 mmol) and Bu3SnH
(393 lL, 1.5 mmol) in tetrahydropyran (5 mL) was
refluxed for 2 h. The reaction mixture was cooled to room
temperature, quenched with saturated KF solution (2 mL)
and stirred for 24 h at room temperature. The resulting
suspension was filtered through a pad of Celite, washed
with THP, and the ethereal layer of the filtrate was
separated. Drying with anhydrous MgSO4, concentration
and purification by flash column chromatography (silica
gel, hexane) gave 5-cholestene (2b, 302 mg, 0.82 mmol,
28
82%). ½aꢀD ꢁ51.7 (c 1.28, CHCl3); 1H NMR (400 MHz,
We then turned our attention to TTMSS (tris(trimethyl-
silyl)silane) mediated hydrosilylation of alkenes and
alkynes9 using THP as a solvent (Table 2). All worked
well and gave the corresponding hydrosilylated products
in good to high yields. Silylation-radical-cyclization
sequence of bisallyl ether 1i was also successful, which
gave a mixture of 2i and 2i0 (entry 5). We also confirmed
that radical addition reactions of hexanethiol to alkenes
and alkynes worked well using THP as a solvent (entries
6–11).
CDCl3) d 0.68 (s, 3H), 0.86 (d, 3H, J = 2.0 Hz), 0.87 (d,
3 H, J = 1.6 Hz), 0.92 (d, 3H, J = 6.8 Hz), 0.92–1.62 (m,
23H), 1.00 (s, 3H), 1.69–1.76 (m, 1H), 1.78–1.87 (m, 2H),
1.91–2.03 (m, 3H), 2.18–2.29 (m, 1H), 5.27 (br dt, 1H,
J = 5.2, 1.6 Hz); 13C NMR (100 MHz, CDCl3) d 12.0,
18.9, 19.6, 20.9, 22.7, 23.0, 24.0, 24.4, 28.17, 28.23, 28.4,
31.99, 32.04, 33.1, 36.0, 36.4, 37.7, 39.7, 40.0, 42.5, 50.7,
56.3, 57.0, 119.1, 143.9; FT-IR (film) m 3033, 2932, 2866,
1671, 1465, 1445, 1376, 1334, 1254, 1168, 1145, 1049,
1026 cmꢁ1; MS (EI, 70 eV) m/z (%): 370 (M+, 100), 355
(91), 301 (29), 275 (36), 257 (46), 215 (74), 161 (37), 147
(43), 145 (45), 135 (37), 109 (53); HRMS (EI, 70 eV) calcd
for C27H46 (M+) 370.3600, found 370.3573.
Finally, we carried out tributyltin hydride mediated
radical carbonylation10 to give acrylic amide. As shown
in Scheme 2, the desired amide was obtained in compa-
rable yield with the case when we used benzene for the
same reaction.11 Thus, a series of chain propagation
steps: tin radical addition to carbon–carbon triple bond,
carbonyaltion of the resulting vinyl radical, ionic trap-
ping of the ketenyl radicals, hydrogen-migration,
b-fission to leave tin radical out, were consistent with
the use of THP.
4. For measured mutual solubility: THP to water: 8.57 wt%;
water to THP 2.5 wt%.
5. One referee suggested the use of dioxane and DME as a
substitute for THF. However, dioxane is highly toxic and
prone to cause peroxide formation by air. Since these ether
solvents are miscible with water, the recovery/reuse is not
easy to carry out, when aqueous workup is employed as in
the case of tin hydride/RX reactions.
6. (a) Beckwith, A. L. J.; Gara, W. B. J. Chem. Soc., Perkin
Trans. 2 1975, 795; (b) Shankaran, K.; Sloan, C. P.;
Snieckus, V. Tetrahedron Lett. 1985, 26, 6001; (c) Bow-
man, W. R.; Krintel, S. L.; Schilling, M. B. Org. Biomol.
Chem. 2004, 2, 585.
In summary, we have demonstrated that the tributyltin
hydride mediated radical reduction, cyclization, and
7. Yamamoto, Y.; Maekawa, M.; Akindele, T.; Yamada, K.;
Tomioka, K. Tetrahedron 2005, 61, 379.
+
+
CO
HNEt2
1k
0.04 M
50 equiv
8. We also tested THP as a solvent for allyltributyltin
mediated radical reactions of iodooctane, however, the
slow SH20 addition reaction to give 1-dodecene allowed for
the competition of the direct abstraction of a-hydrogen
from THP to give octane. For rate constants of primary
alkyl radical addition to allyltin, see: (a) Curran, D. P.;
van Elburg, E. J.; Giese, B.; Gilges, S. Tetrahedron Lett.
AIBN, Bu3SnH (30 mol%)
O
THP
NEt2
78 atm, 90 C, 4 h
2p
75%
Scheme 2. Radical aminocarbonylation of 1k to 2p in THP.

370
H. Yasuda et al. / Tetrahedron Letters 49 (2008) 367–370
1990, 31, 2861; For rate constants of H-abstraction of
10. For reviews on radical carbonylations, see: (a) Ryu, I.;
Sonoda, N. Angew. Chem., Int. Ed. 1996, 35, 1050; (b)
Ryu, I.; Sonoda, N.; Curran, D. P. Chem. Rev. 1996, 96,
177; (c) Ryu, I. C. Chem. Soc. Rev. 2001, 30, 16. Also see a
review on acyl radicals: (d) Chatgilialoglu, C.; Crich, D.;
Komatsu, M.; Ryu, I. Chem. Rev. 1999, 99, 1991.
alkyl radicals from tributyltin hydride, see: (b) Chatgili-
aloglu, C.; Ingold, K. U.; Scaiano, J. C. J. Am. Chem. Soc.
1981, 103, 7739.
9. (a) Kulicke, K. J.; Chatgilialoglu, C.; Kopping, B.; Giese,
B. Helv. Chim. Acta 1992, 75, 935; (b) Koping, B.;
Chatgilialoglu, C.; Zehnder, M.; Giese, B. J. Org. Chem.
1992, 57, 3994; (c) Miura, K.; Oshima, K.; Utimoto, K.
Chem. Lett. 1992, 2477.
11. Uenoyama, Y.; Fukuyama, T.; Nobuta, O.; Matsubara,
H.; Ryu, I. Angew. Chem., Int. Ed. 2005, 44, 1075.