Radical alkylations of alkyl halides and unactivated C-H bonds using vinyl triflates

Article abstract of DOI:10.1055/s-0029-1219960

Radical alkylations of activated alkyl iodides and bromides were achieved using vinyl triflates in the presence of hexadimethyltin, whereas those of unactivated C-H bonds using vinyl triflates proceeded cleanly under tin-free conditions. Georg Thieme Verl

Full text of DOI:10.1055/s-0029-1219960

LETTER
1647
Radical Alkylations of Alkyl Halides and Unactivated C–H Bonds Using Vinyl
Triflates
Radical
A
i
lkylatio
n
ns using Vinyl Tri
Y
f
lates oung Lee,a Kyoung-Chan Lim,a Xiangjian Meng,b Sunggak Kim*a,b
a
Department of Chemistry, Korea Advanced Institute of Science & Technology, Daejeon 305-701, Korea
Division of Chemistry and Biological Chemistry, School of Physical and Mathematical Sciences, Nanyang Technological University,
21 Nanyang Link, Singapore 637371
b
Fax +65(6791)1961; E-mail: sgkim@ntu.edu.sg
Received 5 April 2010
are accessible by two methods involving: the sulfonyla-
tion of enolates with sulfonic anhydrides,9 and gold-cata-
lyzed addition of sulfonic acids to alkynes.10 In the radical
reaction of vinyl sulfonates, we have been interested in the
feasibility of b-cleavage of the oxygen–sulfonyl (O–
SO2R2) bond (Scheme 2, equation 1), even though a sim-
Abstract: Radical alkylations of activated alkyl iodides and bro-
mides were achieved using vinyl triflates in the presence of hexa-
dimethyltin, whereas those of unactivated C–H bonds using vinyl
triflates proceeded cleanly under tin-free conditions.
Key words: alkylation, radical reaction, ketone, vinyl triflate
–
ilar b-cleavage of the O–SO3 bond was reported in anion-
ic transannular, self-terminating radical cyclizations
(Scheme 2, equation 2).11 The success of the present ap-
proach depends very much on the efficiency of the addi-
tion of an alkyl radical to the vinyl sulfonates and on the
b-cleavage of the O–SO2R bond.
Alkylation is one of the most important and fundamental
organic reactions for the formation of carbon–carbon
bonds and is routinely performed with metal enolates and
alkylating agents.1 Despite extensive studies of radical re-
actions during last three decades, radical-mediated alkyla-
tions of carbonyl compounds have not been well studied,
mainly due to inefficiency of intermolecular radical reac-
tions. To solve this problem, one of the most attractive ap-
proaches is to develop highly efficient radical acceptors.2
The radical acceptors should possess both an activating
group and an eliminating group to generate a carbonyl
group, and such compounds include: stannyl enolates,3 O-
benzyl enols,4 and O-tert-alkyl enols.5 In this regard, we
reported two approaches to achieve radical alkylations of
carbonyl compounds using ketene N,O-acetals
(Scheme 1, equation 1)6 and tert-butyl ketene enol ethers
as acceptors (Scheme 1, equation 2).7
SO2R2
O
O
R1
R2SO2
(1)
+
R1
Ph
Ph
1
–
SO3
O
O
(2)
SO3
+
R
H
R
2
O
OSO2Et
Ph
R
Ph
4
3
EtSO2
R
OTBS
N
O
OTBS
N
OTBDPS
R
Cbz
R
(1)
(2)
R
N
H
EtI
Cbz
Et
SO2
Cbz
RI
OTBS
O
OTBS
R2
R1
R2
Scheme 2 Alkylation of RI with vinyl sulfonate 3
O
Scheme 1
The key feature in our initial approach is the b-elimination
of intermediate 1 to yield a carbonyl compound, along
with liberation of an ethanesulfonyl radical (equation 1
and Scheme 2).12 Second, thermal decomposition of the
ethanesulfonyl radical followed by iodine atom transfer
from an alkyl iodide to an ethyl radical would generate the
alkyl radical for the chain-propagation reaction. Another
important issue is the addition of the ethanesulfonyl radi-
cal to vinyl sulfonate 3, which should be slower than ther-
mal conversion of the ethanesulfonyl radical into the ethyl
radical. Finally, it is noteworthy that the present approach
can be performed under tin-free conditions.
As part of our continued interest in radical alkylations, we
have studied the feasibility of using vinyl sulfonates as
radical acceptors. Although vinyl sulfonates are very use-
ful functional groups for the formation of carbon–carbon
bonds via cross-coupling reactions,8 their synthetic use-
fulness has not been well studied, probably due to the dif-
ficulties involved in their preparation. Vinyl sulfonates
SYNLETT 2010, No. 11, pp 1647–1650
Advanced online publication: 04.06.2010
x
x
.x
x
.2
0
1
0
DOI: 10.1055/s-0029-1219960; Art ID: U02610ST
© Georg Thieme Verlag Stuttgart · New York

1648
J. Y. Lee et al.
LETTER
We began our studies with vinyl sulfonate 3. When 3 was sulfonyl radical undergoes decomposition spontaneously
treated with ethyl iodoacetate and AIBN in toluene for at room temperature to generate a trifluoromethyl radical
two hours, a-ethanesulfonyl ketone 5 was isolated in 78% along with liberation of sulfur dioxide.13 Fuchs reported
yield, which indicates two important results (Scheme 3). the radical-mediated alkynylations, alkenylations, and al-
First, b-elimination of O–SO2Et occurred smoothly. Sec- lylations of unactivated C–H bonds using the correspond-
ond, the addition of the ethanesulfonyl radical to vinyl sul- ing trifluoromethyl sulfone (triflone; Scheme 4).13
fonate 3 is much faster than thermal decomposition of the
ethanesulfonyl radical. To achieve radical alkylation of
vinyl sulfonates, the reaction was performed in the pres-
ence of hexamethylditin (1.2 equiv) under thermal and
Radical-mediated alkylations of alkyl iodides and bro-
mides were carried out using two vinyl triflates, 7 and 9.
The reaction of benzyl iodoacetate with vinyl triflate 7
and hexamethylditin (0.5 equiv) in benzene under irradia-
photochemically initiated conditions. Treatment of 3 with
tion at 300 nm for five hours afforded a-alkylated product
ethyl iodoacetate and AIBN in toluene at 80 °C for two
8 in 75% yield (Scheme 5, equation 1). When the reaction
was repeated with vinyl triflate 9 under similar conditions,
hours generated a mixture of the addition product 5 and
the desired product 6 that was isolated in a ratio of 4:3.
the desired a-keto ester 10 was isolated in 66% yield
When the reaction was repeated under photochemically
along with recovery of the starting material (27%;
initiated conditions (300 nm), a similar result was ob-
Scheme 5, equation 2). Additional experimental results
are summarized in Table 1. Using vinyl triflate 7, a-iodo
esters and ketones worked well, yielding the correspond-
tained. Apparently, the addition of the ethanesulfonyl rad-
ical to the vinyl sulfonate competed with quenching of the
ethanesulfonyl radical with hexamethylditin.
ing 1,4-dicarbonyl compounds (entries 2–4). Iodomethyl-
phenylsulfone and diethyl bromomalonate both smoothly
underwent alkylations in good yields (entries 1 and 5). In
OSO2Et
toluene
+
I
CO2Et
the case of vinyl triflate 9, the reaction did not go to com-
pletion after five hours, and gave lower yields in most cas-
es. Apparently, 9 is a more electron-deficient radical
acceptor than 7, so the rate of addition of an electrophilic
alkyl radical to 9 is reduced. Furthermore, the present
method reaches a limit with nucleophilic radicals. For in-
stance, when 4-phenoxybutyl iodide was treated with 9
and hexamethylditin under irradiation at 300 nm for five
hours, the reaction did not proceed well, yielding the de-
sired product (19%) and the reduction product (42%)
along with recovered starting material (27%; Scheme 6).
The low efficiency of the nucleophilic alkyl radical reac-
tion was not expected and the reason is not clear at
present.
Ph
3
O
O
OEt
SO2Et
+
Ph
Ph
5
O
6
5
6
AIBN, 80 °C, 2 h
0%
78%
48%
50%
(Me3Sn)2, AIBN, 80 °C, 2 h
(Me3Sn)2, 300 nm, 12 h
Scheme 3
36%
24%
We next studied the feasibility of radical alkylations of
unactivated C–H bonds using vinyl triflates 7 and 9. Rad-
ical-mediated chlorocarbonylation14 and acylation of un-
activated C–H bonds,15 along with Fuchs approach,13
R
X
X
+
R
SO2CF3
X = O or CH2
Scheme 4
O
9, (Me3Sn)2
benzene
300 nm
PhO(CH2)4
I
R
H
+
R
CO2Et
(19%)
To obviate the problems involved in the direct addition
process, we searched for possible ways to induce facile
decomposition of alkylsulfonyl radicals to alkyl radicals.
It is well known that the highly reactive trifluoromethane-
(42%)
R = PhO(CH2)4
Scheme 6
O
O
OSO2CF3
(Me3Sn)2 (0.5 equiv)
+
I
Ph
hν, C6H6, 5 h
BnO
BnO
Ph
(1)
(2)
O
7
8: 75%
O
O
OSO2CF3
I
O
(Me3Sn)2 (0.5 equiv)
CO2Et
+
BnO
BnO
I
+
hν, C6H6, 5 h
CO2Et
BnO
O
9
10: 66%
27%
Scheme 5
Synlett 2010, No. 11, 1647–1650 © Thieme Stuttgart · New York

LETTER
Radical Alkylations using Vinyl Triflates
1649
were reported previously. Furthermore, dimethylzinc-
mediated radical reactions involving C–H bond cleavage
have been recently investigated by Tomioka.16 Our inves-
tigations were based on Fuchs approach (Scheme 7),13
and required that the reaction proceeds via hydrogen atom
abstraction from C–H bonds by the highly electrophilic
trifluoromethyl radical to generate 13. Addition of radical
13 to vinyl triflate 11 followed by elimination of the ad-
duct radical 14, would provide carbonyl compound 15
along with liberation of a trifluoromethanesulfonyl radi-
cal. Fragmentation of the trifluoromethanesulfonyl radi-
cal to the trifluoromethyl radical and sulfur dioxide
propagates the chain. This approach is attractive because
it not only avoids the use of highly toxic organotin com-
pounds, but also introduces a b-carbonyl group to the un-
activated C–H bonds in a single step. Reaction of 9 in
refluxing tetrahydrofuran in the presence of AIBN initia-
tor for nine hours gave the desired a-keto ester in 65%
yield (Scheme 8). Table 2 summarizes some experimental
results using vinyl triflates 7 and 9 and illustrates the effi-
ciency and scope of the present method. The method was
quite general and worked well with cyclic and acyclic
ethers (entries 1 and 2), cyclic and acyclic alkanes (entries
3–5), and tetrahydrothiophene (entry 6). The yields
ranged from 54 to 78%. Similar results were also obtained
with vinyl triflate 7 (entries 7–9).17,18
Table 1 Radical Alkylation of Carbonyl Compounds using Vinyl
Triflates 7and 9a
Entry Substrate
Products
Yield (%)b
O
O
1
69
PhO2S
I
PhO2S
Ph
61 (19)
72
PhO2S
O
CO2Et
Ph
O
2
I
EtO
EtO
O
O
O
O
O
70
CO2Et
EtO
O
O
3
68
Ph
I
EtO
EtO
O
64 (31)
71
CO2Et
EtO
O
O
4
Ph
I
Ph
Ph
O
OSO2CF3
O
R
X
X
R
H
54 (29)
CO2Et
11
Ph
AIBN or hν
O
O
12
15
E
O
O
E
X = CH2, O, S
CF3
5c
67
E
E
Ph
E
Br
SO2CF3
58 (23)
HCF3
SO2
CO2Et
E
X
X
R
a Reagents and conditions: (Me3Sn)2 (0.5 equiv), benzene, 300 nm,
11
OSO2CF3
5 h.
14
b Yield of isolated product. The numbers in the parenthesis indicate
the yield of recovered starting material.
c E = CO2Et
13
Scheme 7 Radical alkylation of unactivated C–H bonds
O
CO2Et
Table 2 Radical Alkylation of Carbonyl Compounds Using Vinyl
Triflates 7 and 9a
OSO2CF3
O
AIBN
+
reflux
9 h
O
CO2Et
Entry Substrate
Product
Yield (%)b
9
16 (65%)
O
O
CO2Et
Scheme 8
1
63
O
O
O
In conclusion, we have observed the b-cleavage of oxy-
gen–sulfonyl bonds together with the formation of the car-
bonyl group. The reaction was applied to achieve the
radical alkylation of alkyl iodides and bromides bearing
a-electron-withdrawing groups and, using vinyl triflate
acceptors, to unactivated C–H bonds.
MeO
O
2
73
OMe
MeO
MeO
CO2Et
CO2Et
3
4
76
78
O
CO2Et
O
Synlett 2010, No. 11, 1647–1650 © Thieme Stuttgart · New York

1650
J. Y. Lee et al.
LETTER
Table 2 Radical Alkylation of Carbonyl Compounds Using Vinyl
Triflates 7 and 9a (continued)
(8) (a) Ritter, K. Synthesis 1993, 735. (b) Roth, G. P.; Fuller, C.
E. J. Org. Chem. 1989, 54, 4899. (c) Pridgen, L. N.; Huang,
G. K. Tetrahedron Lett. 1998, 39, 8421. (d) Limmert, M.
E.; Roy, A. H.; Hartwig, J. F. J. Org. Chem. 2005, 70, 9364.
(9) (a) Huffman, M. A.; Yasuda, N. Synlett 1999, 471.
(b) Baxter, J. M.; Steinhubel, D.; Palucki, M.; Davies, I. W.
Org. Lett. 2005, 7, 215.
Entry Substrate
Product
Yield (%)b
CO2Et
O
5
67c
(10) Cui, D.-M.; Meng, Q.; Zheng, J.-Z.; Zhang, C. Chem.
Commun. 2009, 1577.
4
CO2Et
(11) (a) Wille, U. J. Am. Chem. Soc. 2002, 124, 14. (b) Wille, U.
Org. Lett. 2000, 2, 3485.
O
(12) (a) Kim, S.; Kim, S. Bull. Chem. Soc. Jpn. 2007, 80, 809.
(b) Kim, S.; Kim, S.; Otsuka, N.; Ryu, I. Angew. Chem. Int.
Ed. 2005, 44, 6183. (c) Kim, S.; Lim, C. J. Angew. Chem.
Int. Ed. 2002, 41, 3265.
(13) For alkynylations, see: (a) Gong, J.; Fuchs, P. L. J. Am.
Chem. Soc. 1996, 118, 4486. (b) Gong, J.; Fuchs, P. L.
Tetrahedron Lett. 1997, 38, 787. For alkenylations, see:
(c) Xiang, J.; Fuchs, P. L. J. Am. Chem. Soc. 1996, 118,
11986. (d) Xiang, J.; Jiang, W.; Gong, J.; Fuchs, P. L. J. Am.
Chem. Soc. 1997, 119, 4123. (e) For allylation, see: Xiang,
J.; Evarts, J.; Rivkin, A.; Curran, D. P.; Fuchs, P. L.
Tetrahedron Lett. 1998, 39, 4163.
(14) (a) Kharasch, M. S.; Brown, H. C. J. Am. Chem. Soc. 1942,
64, 329. (b) Tabushi, I.; Hamuro, J.; Oda, R. J. Org. Chem.
1968, 33, 2108.
(15) (a) Bentrude, W. G.; Darnall, K. R. J. Am. Chem. Soc. 1968,
90, 3588. (b) Citterio, A.; Filippini, L. Synthesis 1986, 473.
(c) Kim, S.; Kim, N.; Chung, W.-j.; Cho, C. H. Synlett 2001,
937.
S
S
CO2Et
6
72
54
O
O
O
O
Ph
7
O
O
Ph
Ph
8
66
73
O
O
9
a The reaction was carried out using AIBN as initiator at reflux for 9 h.
b Yield of isolated product.
c A 3:2 mixture of the two compounds was obtained.
Acknowledgment
(16) Akindele, T.; Yamada, K.-I.; Tomioka, K. Acc. Chem. Res.
2009, 42, 345; and references cited therein.
We thank the Center for Molecular Design and Synthesis at KAIST
and Nanyang Technological University for financial support.
(17) Typical procedure for radical alkylation of a carbonyl
compound: A solution of iodomethyl phenylsulfone (56 mg,
0.2 mmol), vinyl triflate 7 (76 mg, 0.3 mmol), and
hexamethylditin (33 mg, 0.1 mmol) in benzene (1 mL; 0.2 M
in iodide) was degassed with nitrogen for 10 min, and the
solution was then irradiated in a photochemical reactor (300
nm) for 5 h. The solvent was evaporated under reduced
pressure and the residue was purified by silica gel column
chromatography (EtOAc–hexane, 1:10) to give 1-phenyl-3-
(phenylsulfonyl)propan-1-one (38 mg, 69%) as a colorless
oil. 1H NMR (CDCl3, 400 MHz): d = 3.45–3.49 (m, 2 H),
3.52–3.56 (m, 2 H), 7.42–7.46 (m, 2 H), 7.55–7.57 (m, 3 H),
7.63–7.64 (m, 1 H), 7.88–7.94 (m, 4 H); 13C NMR (CDCl3,
100 MHz): d = 31.3, 51.0, 127.9 (C2), 128.0 (C2), 128.7
(C2), 129.4 (C2), 133.7, 133.9, 135.8, 139.0, 195.3
(18) Typical procedure for radical alkylation of an unactivated
C–H bond: A solution of vinyl triflate 9 (76 mg, 0.3 mmol)
and AIBN (5 mg, 0.03 mmol) in THF (1 mL) was degassed
with nitrogen for 10 min, and the solution was heated at
reflux (80 °C) for 9 h under nitrogen. The solvent was
evaporated under reduced pressure and the residue was
purified by silica gel column chromatography (EtOAc–
hexane, 1:50) to give 16 (41 mg, 65%) as a colorless oil. 1H
NMR (CDCl3, 400 MHz): d = 1.33 (t, J = 7.2 Hz, 3 H), 1.48–
1.55 (m, 1 H), 1.84–1.92 (m, 2 H), 2.06–2.14 (m, 1 H), 2.94
(dd, J = 16.5, 5.7 Hz, 1 H), 3.10 (dd, J = 16.5, 7.1 Hz, 1 H),
3.67–3.73 (m, 1 H), 3.80–3.85 (m, 1 H), 4.29 (q, J = 7.2 Hz,
2 H), 4.26–4.32 (m, 1 H); 13C NMR (CDCl3, 100 MHz): d =
13.9, 25.4, 31.4, 45.1, 62.4, 67.9, 74.3, 160.8, 192.6
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Synlett 2010, No. 11, 1647–1650 © Thieme Stuttgart · New York