p-MeOC6H4N2+ BF4-/TiCl3: a novel initiator for halogen atom-transfer radical reactions in aqueous media

Article abstract of DOI:10.1016/j.tetlet.2008.10.070

With the combination of p-methoxybenzene-diazonium tetrafluoroborate with TiCl₃ as the initiator, a wide range of halogen atom-transfer radical addition or cyclization reactions could be efficiently implemented in aqueous solution at room tempe

Full text of DOI:10.1016/j.tetlet.2008.10.070

Tetrahedron Letters 49 (2008) 7380–7382
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þ
ꢀ
p-MeOC6H4N2 BF4 /TiCl3: a novel initiator for halogen
atom-transfer radical reactions in aqueous media
*
Lidong Cao, Chaozhong Li
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, Shanghai 200032, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
With the combination of p-methoxybenzene-diazonium tetrafluoroborate with TiCl3 as the initiator, a
wide range of halogen atom-transfer radical addition or cyclization reactions could be efficiently imple-
mented in aqueous solution at room temperature.
Received 9 September 2008
Revised 8 October 2008
Accepted 10 October 2008
Available online 21 October 2008
Ó 2008 Elsevier Ltd. All rights reserved.
In the past three decades, we have witnessed significant pro-
gress in radical reactions toward organic synthesis.1 Among vari-
ous types of radical processes, halogen atom-transfer radical
addition (ATRA) reactions, pioneered by Kharasch,2 further devel-
oped by Curran and others,3 have received considerable attention
because of their atom-economic nature and high efficiency.4 The
choice of initiators is crucial to the successful implementation of
ATRA transformations. Bis(tributyltin) has been widely used as
the initiator for ATRA.3 However, the high toxicity and difficult sep-
aration of the tin-containing residue limit its value in industrial
application. Triethylborane, developed by Oshima and co-workers,
is the other frequently used initiator, allowing the ATRA to be car-
ried out under very mild conditions in various solvents including
water.5 However, it is highly air sensitive while the initiation re-
quires oxygen whose amount is difficult to control. Other tin-free
initiators, including peroxides such as dilauroyl peroxides,6
a few cases, when stoichiometric amounts of diazonium ions were
used, the reactions produced primarily the iodine ATRA products
between olefins and alkyl iodides.13c We were intrigued by this
side reaction owing to our interest in ATRA reactions.14 We won-
dered (1) if this diazonium salt–reductant combination could be
developed into a catalytic system to initiate ATRA reactions and
(2) if the initiator could have a wide generality for ATRA. Thus,
ꢀ
we first chose o-MeOC6H4N2þBF4 (I-1) as the aryl radical precur-
sor, and TiCl3 as the reductant to explore this possibility. Ethyl
iodoacetate (1) and 1-octene (2a) were used as the model sub-
strates. The results are summarized in Table 1.
Our initial trial on the addition of 1 to 2a in CH2Cl2 or CH3CN in
the presence of 20 mol % of I-1 and of 20 mol % of TiCl3 was disap-
pointing (Table 1, entries 1 and 2). However, when the solvent was
switched to ethanol, we were delighted to find that the expected
product 3a was observed in 36% yield (Table 1, entry 3). The reac-
tion also proceeded in water, albeit in a lower yield (Table 1, entry
4). These different solvent effects should be attributed to their dif-
ferent abilities to solvate both the organic and inorganic (TiCl3) re-
agents. With this idea in mind, we tried the mixture of ethanol and
water in different ratios. We were pleased to find that, with EtOH/
H2O (4:1, v:v) as the solvent, the yield of 3a was increased to 76%
(Table 1, entry 7). Lowering the amounts of I-1 and TiCl3 to
10 mol % resulted in only a slight decrease of the product yield (Ta-
ble 1, entry 9).
water-soluble azo compounds,7 copper,8 chromium(II) acetate,9
11
bimetallic Rh–Ru complexes,10 and Mn2(CO)10
,
are less com-
monly adopted due to either the harsh conditions required or the
lack of generality. It is therefore highly desirable to develop novel
tin-free initiators that are safe and widely applicable. We report
here that p-MeOC6H4N2þBF4ꢀ/TiCl3 serves as a powerful initiator,
allowing a wide range of ATRA reactions to be performed in aque-
ous media under mild conditions.
Arenediazonium ions have long been used as the sources for
aryl radicals.12 Upon treatment with a reductant, arenediazonium
salts undergo N2 elimination to give the corresponding aryl radi-
cals, which are able to participate in a number of further transfor-
mations, such as H-abstraction or addition to C@C bonds.13 For
example, Heinrich and co-workers nicely introduced the carbo-
diazenylation of olefins by the three-component condensation of
arenediazonium salts, olefins, and alkyl iodides.13c–f However, in
We next screened the diazonium salts. Among the four diazo-
ꢀ
nium salts tested (I-1–I-4), p-MeOC6H4N2þBF4 (I-2) gave the best
result. The ATRA proceeded smoothly at room temperature, and
the substrate 1 was all consumed within 2 h. The reaction was
clean, and the product 3a was achieved in 90% isolated yield (Table
1, entry 10). Note that only a trace amount of 3a could be detected
without the presence of the diazonium salts (Table 1, entry 13).
With regard to the reductant, TiCl3 was proven to be much superior
over other reductants (Table 1, entries 14–17).
With the optimized conditions in hand (Table 1, entry 10), we
then examined the generality of this initiation system. As shown
* Corresponding author. Tel.: +86 21 5492 5160; fax: +86 21 5492 5099.
E-mail address: clig@mail.sioc.ac.cn (C. Li).
0040-4039/$ - see front matter Ó 2008 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2008.10.070

L. Cao, C. Li / Tetrahedron Letters 49 (2008) 7380–7382
7381
Table 1
able for the addition reactions of sulfone 5e and perfluoroalkyl io-
dide 5g.15 The ATRA to alkynes could also be nicely initiated, as
evidenced by the reaction of 5b with phenylacetylene.14f Moreover,
bromine ATRA of active bromides, such as 5g and 5h, was also suc-
cessful under the optimized conditions. In all the tested cases, the
desired products were achieved in high to excellent yields, illus-
trating the wide scope of application of I-2/TiCl3.
Optimization of reaction conditions
I
+
I
CO2Et
C6H13
2a
EtO2C
C6H13
1
3a
-
ArN2+BF4 :
Ar = o-MeO-C6H4 (I-1), p-MeO-C6H4 (I-2), p-COMe-C6H4 (I-3), Ph (I-4)
The above investigation dealt with intermolecular ATRA. As an
extension, iodine atom-transfer radical cyclization (ATRC) reac-
tions, which provide a synthetically useful entry to heterocycles
such as lactones and lactams, could also be conducted with the
initiation of I-2/TiCl3. As shown in Table 4, a number of substituted
N-allyliodoacetamides 8 underwent efficient ATRC to give the
5-exo-cyclization products 9a–f. The amount of the initiator could
be reduced to 5 mol %, when the substrates were more prone to
cyclization (Table 4, entries 1 and 5). The 8-endo-cyclization reac-
tions14a of esters 10 also proceeded under the optimized conditions
without any difficulty.
Initiatora (mol %)
Solvent
Time (h)
Yieldb (%)
y
Entr
1
2
3
4
5
6
7
8
9
I- 1 (20) +T iCl3 (20)
I- 1 (20) +T iCl3 (20)
I- 1 (20) +T iCl3 (20)
I- 1 (20) +T iCl3 (20)
I- 1 (20) +T iCl3 (20)
I- 1 (20) +T iCl3 (20)
I- 1 (20) +T iCl3 (20)
I- 1 (20) +T iCl3 (20)
I- 1 (10) +T iCl3 (10)
CH2Cl2
CH3CN
EtOH
H2O
EtOH/H2O(2:3)
EtOH/H2O(3:2)
EtOH/H2O(4:1)
EtOH/H2O(9:1)
EtOH/H2O(4:1)
4
4
4
4
4
4
2
3
3
Trace
Trace
36
10
14
46
76
59
64
10
I- 2 (10) +T iCl3 (10)
EtOH/H2O(4:1)
2
97(90)
The above results clearly demonstrate the efficiency of I-2/TiCl3
in initiating the ATRA and ATRC reactions. With the initiation of I-
2/TiCl3, the reactions can be performed in the dark under nitrogen
atmosphere, while sunlamp irradiation is required for bis(tributyl-
tin) and oxygen is required for triethylborane. Both I-2 and TiCl3
are readily available and are fairly stable. The speed of initiation
can be easily adjusted by the appropriate addition of TiCl3. In addi-
tion, aqueous ethanol is used as the solvent, making the I-2/TiCl3
protocol of more practical value.
The active species in the I-2/TiCl3-chain process are the aryl
radicals. Initiation relies on the fact that the aryl radical is gener-
ated selectively, and it abstracts an iodine atom from the substrate
rather than adding to the C@C bond. This is because the rate
constant for the iodine atom abstraction of a phenyl radical
from an alkyl iodide is close to the diffusion-controlled limit
11
12
13
14
15
16
17
I- 3 (10) +T iCl3 (10)
I- 4 (10) +T iCl3 (10)
TiCl3 (10)
I- 2 (10) +SnCl2 (10)
I- 2 (10) +CuCl (10)
I- 2 (10) +H Qc (10)
I- 2 (10) +FeCl2 (10)
EtOH/H2O(4:1)
EtOH/H2O(4:1)
EtOH/H2O(4:1)
EtOH/H2O(4:1)
EtOH/H2O(4:1)
EtOH/H2O(4:1)
EtOH/H2O(4:1)
3
4
2
4
3
3
4
69(60)
74(67)
Trace
32
6
29
7
a
Conditions: 1 (0.5 mmol), 2a (1.5 mmol), solvent (5 mL), I/TiCl3, rt, N2.
b
1H NMR yield with 4-nitroacetophenone as the internal standard and the iso-
lated yield in parentheses.
c
HQ: hydroquinone.
in Table 2, the reactions of 1 with various mono-substituted al-
kenes afforded the expected products in satisfactory yields. A num-
ber of functional groups were well tolerated. The reaction of 1 with
1,6-diene 4 via tandem radical processes was also nicely accom-
plished to give the cyclized product 3j in 90% isolated yield. These
results have clearly demonstrated that I-2/TiCl3 is equal to
(Bu3Sn)2 or Et3B in initiating the above-mentioned ATRA reactions.
Next, we performed the reactions of various alkyl halides 5 with
1-octene (Table 3). Under the initiation of I-2/TiCl3 indicated
above, substituted iodoesters 5a and 5b smoothly underwent ATRA
to 1-octene. Iodoacetonitrile 5c and even iodoacetic acid 5d could
also be used as the reactants. The initiation system was again suit-
Table 3
I-2/TiCl3-initiated ATRA to 1-octene and phenylacetylene
I-2 (10 mol%)
TiCl3 (10 mol%)
C6H13
R
+
X
R
C6H13
2a
X
EtOH/H2O (4:1)
rt, 3 h
5
6
C6H13
I
C6H13
F
F
ICF2SO2Ph 5e
I(CF2)5CF3 5f
BrCCl3 5g
I
I
CO2Et
5a
PhO2S
EtO2C
I
6e (86%)
6a (88%, 55/45)
Table 2
I-2/TiCl3-initiated ATRA reactions of 1
O
O
O
C6H13
I
C6H13
I-2 (10 mol%)
TiCl3 (10 mol%)
CF3(CF2)5
O
I
I
+
I
CO2Et
R
6f (90%)
EtO2C
R
6b (86%, 55/45)
5b
EtOH/H2O (4:1)
rt, 3 h
1
2
3
C6H13
Br
C6H13
R =
(CH2)2COCH3 (3g, 77%)
(CH2)2CO2Et (3h, 77%)
I
I
CN
5c
Cl3C
n-C4H9 (3b, 88%)
NC
I
6c (86%)
6g (91%)
O
n-C10H21 (3c, 74%)
(CH2)4OH (3d, 80%)
(CH2)3Br (3e, 88%)
CH2OAc (3f, 76%)
(3i, 75%)
(CH2)3
N
C6H13
I
C6H13
CO2H
5d
O
Br3C
CBr4 5h
HO2C
Br
6d (67%)
6h (80%)
EtO2C CO2Et
EtO2C CO2Et
see above
O
+
CO2Et
I
O
O
I
EtO2C
see above
1
I
O
+
Ph
I
4
Ph
= 55/45)
3j (90%)
trans
/
cis = 10:1
5b
7a (81%,
E/
Z

7382
L. Cao, C. Li / Tetrahedron Letters 49 (2008) 7380–7382
Table 4
was washed with brine, and dried over anhydrous MgSO4. After re-
I-2/TiCl3-initiated iodine atom-transfer radical cyclization
moval of the solvent under reduced pressure, the crude product
was purified by column chromatography on silica gel using hex-
ane/ethyl acetate (50:1, v/v) as the eluent to give the product 3a
as a colorless oil (146 mg, 90%).6
I
R1
O
R1
I-2 / TiCl3
N
I
R2
EtOH/H2O (4:1), rt, 3 h
N
R2
O
Acknowledgments
9
8
Entry
R1
R2
I-2/TiCl3 (mol %)
Product (yield)a
This project was supported by the National NSF of China (Grant
Nos. 20672136, 20772142 and 20832006) and by the Shanghai
Municipal Committee of Science and Technology (Grant No.
07XD14038).
1
2
3
4
5
6
H
H
H
H
Me
Me
Allyl
Ts
Ms
Me
Allyl
Ts
5
9a (99%)
9b (96%)
9c (86%)
9d (40%)
9e (96%)b
9f (91%)c
10
10
20
5
10
References and notes
I
1. For reviews see: (a) Giese, B. Radicals in Organic Synthesis: Formation of Carbon–
Carbon Bonds; Pergamon: Oxford, UK, 1986; (b) Curran, D. P. Synthesis 1988,
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Rev. 2003, 103, 3263.
I-2 (10 mol%)
TiCl3 (10mol%)
I
R
R
O
O
EtOH/H2O (4:1), rt, 3 h
O
O
10
R = H
Me
11a (88%)a
11b (90%)a, d
a
Isolated yield based on 8 or 10.
trans/cis = 78:22.
b
c
trans/cis = 84:16.
trans/cis = 17:83.
2. (a) Kharasch, M. S.; Skell, P. S.; Fisher, P. J. Am. Chem. Soc. 1948, 70, 1055; (b)
Kharasch, M. S.; Jensen, E. V.; Urry, W. H. Science 1945, 102, 128.
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d
(>109 Mꢀ1 sꢀ1),16 which is about 100 times faster than the rate of
phenyl radical addition to
a
monosubstituted alkene
(ꢁ3 ꢂ 107 Mꢀ1 sꢀ1).17 More importantly, the rate constant for the
iodine atom-transfer from the substrate 1a to the adduct radical
4. Byers, J. In Radicals in Organic Synthesis; Renaud, P., Sibi, M. B., Eds.; Wiley-VCH:
Weinheim, Germany, 2001; Vol. 1, p 72.
is around 2.7 ꢂ 107 Mꢀ1 sꢀ1 3a,18
,
at least one order of magnitude
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higher than that for the trapping of the adduct radical by the dia-
zonium ion I-2 (estimated to be ꢁ1 ꢂ 106 Mꢀ1 sꢀ1).19 This allows
the iodine atom-transfer chain process to proceed smoothly with-
out the intervention of a termination event. On the other hand, the
bromine ATRA of bromoacetates to alkenes is unlikely to happen
because bromine atom-transfer to the adduct radical is much slo-
wer.3a,18 This sets one limitation for the application of I-2/TiCl3.
In summary, we have demonstrated that p-methoxyben-
zenediazonium tetrafluoroborate in combination with TiCl3 suc-
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under mild conditions, making it a useful complement to the exist-
ing initiation systems.
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Typical procedure for the halogen atom-transfer radical
reactions
To the solution of ethyl iodoacetate (1, 107 mg, 0.5 mmol) and
1-octene (2a, 168 mg, 1.5 mmol) in EtOH (4 mL) and H2O (1 mL)
was added p-methoxybenzenediazonium tetrafluoroborate (I-2,
7.5 mg, 0.034 mmol) at room temperature under nitrogen atmo-
sphere. Aqueous titanium(III) chloride (30% wt % solution in 2 N
hydrochloric acid, 13
vigorous stirring. After 1 h, additional portions of I-2 (3.5 mg,
0.016 mmol) and aqueous titanium(III) chloride (7 L, 0.016 mmol)
lL, 0.034 mmol) was added dropwise under
l
were added successively. The reaction was monitored by TLC. After
the iodoacetate 1 disappeared (1 h), the resulting mixture was ex-
tracted with ethyl ether (3 ꢂ 20 mL). The combined organic layer
19. Citterio, A.; Minisci, F. J. Org. Chem. 1982, 47, 1759.