Base-promoted selective β-fragmentation of homoallylamines

Article abstract of DOI:10.1016/j.tetlet.2010.06.031

A selective β-fragmentation of homoallylamines with the combination of iodobenzene diacetate, iodine, and sodium acetate is reported. The desired carbon-carbon bond cleavage proceeded via a radical β-scission pathway under mild conditions with good functional group tolerance.

Full text of DOI:10.1016/j.tetlet.2010.06.031

Tetrahedron Letters 51 (2010) 4275–4277
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Base-promoted selective b-fragmentation of homoallylamines
Weixun Li a, Jianhong Gan b, Renhua Fan a,
*
a Department of Chemistry, Fudan University, 220 Handan Road, Shanghai 200433, China
b College of Food Science, Shanghai Fisheries University, 334 Jungong Road, Shanghai 200090, China
a r t i c l e i n f o
a b s t r a c t
Article history:
A selective b-fragmentation of homoallylamines with the combination of iodobenzene diacetate, iodine,
and sodium acetate is reported. The desired carbon–carbon bond cleavage proceeded via a radical b-scis-
sion pathway under mild conditions with good functional group tolerance.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 23 March 2010
Revised 3 June 2010
Accepted 8 June 2010
Available online 11 June 2010
The selective cleavage of saturated carbon–carbon bonds is a to-
pic of interest in organic synthesis.1,2 b-Scission of alcohols under
radical conditions has been thoroughly investigated and widely
used to provide a simple and classic way to a wide range of com-
pounds.3,4 b-Scission of cycloalkyloxyl radicals with small ring size
leads to the ring opening to yield medium- and large-sized carbon-
and hetero-cycles.5 For the alkoxyl radicals with an adjacent func-
tionality, the b-scission gives rise to stable carbon radicals, which
are ready to be oxidized and trapped by nucleophiles.6 However,
to the best of our knowledge, compared to the extensive studies
on the alkoxyl radical fragmentation (ARF), carbon–carbon b-scis-
sion of amines has been a particularly elusive reaction and received
much less scrutiny.
In our previous papers, we have reported the intra- and inter-
molecular amination of sp3 C–H bonds with sulfonamides with
the combination of PhI(OAc)2 and I2 under the transition-metal-
free conditions.7 Sulfonamidyl radicals,8 which are generated from
the reactions of sulfonamides with acetyl hypoiodite,9 are pro-
posed as the reactive intermediates. With the aim of extending this
approach, we investigated the b-scission of sulfonamidyl radicals
(Scheme 1).
Preliminary survey was carried out under the Suárez cleavage
conditions (2 equiv of PhI(OAc)2 and 1 equiv of I2 in Cl(CH2)2Cl at
room temperature) and various N-Ts amines were examined
(Scheme 2).10 The formation of sulfonimine 11a was only observed
in the reaction of N-Ts homoallylamine 10a, albeit in a low yield
(6% yield, determined by the 1H NMR spectroscopy of the unpurified
reaction mixture). Additionally, the reaction afforded an unexpected
cyclization product 12, which was assigned as 3-iodo-5-phenyl-1-
tosylpyrrolidin-2-yl acetate, in 31% yield. Its structure and relative
stereochemistry were unambiguously establishedby its single-crys-
tal diffraction analysis (Fig. 1).
The preliminary results indicated that the b-scission of homoal-
lylamine is particularly favorable due to the generation of a stable
allylic radical (Scheme 3). However, the allyl group is also reactive
to acetyl hypoiodite to give rise to an iodoacetoxylation product II.
In the presence of another molecular acetyl hypoiodite, intermedi-
ate II is further converted into the corresponding sulfonamidyl rad-
ical III, which is ready to undergo the subsequent 1,5-H migration,
oxidation, and cyclization to afford 3-iodo-5-phenyl-1-tosylpyrr-
olidin-2-yl acetate 12.
Based on the analysis of reaction pathway, we supposed that
acids (HOAc and HI), which were generated in the reaction, might
protonate the amine group of substrate to inhibit the formation of
sulfonamidyl radical I. To verify our hypothesis, a set of experi-
ments were carried out. When 1 equiv of AcOH was added, no sul-
fonimine was detected (Table 1, entry 1). On the contrary, the
presence of an inorganic base promoted the formation of sulfonim-
ine (Table 1, entries 2–4). With the addition of 2 equiv of NaOAc,
the yield of 11a increased to 28%. Due to their sensitivity to the oxi-
dative conditions, organic bases were not good to the reaction (Ta-
ble 1, entries 5 and 6). Although lower temperatures slowed down
the reaction (5 min at 25 °C, 30 min at 0 °C, 75 min at À10 °C), the
yield of 11a was dramatically improved to 65% when the reaction
was carried out at 0 °C (Table 1, entry 7). A longer reaction time re-
sulted in the decomposition of sulfonimine (Table 1, entry 9). The
R1
H
NHSO2R2
NHSO2R2
R1
Ar
R2SO2NH2
R1
R1
SO2R2
PhI(OAc)2, I2
N
Ar
H
N
R3
R2
R1
R3
R1
R3
R1
I
NR3
β-scission
- R2
N
N
R1
- I
R2
R2
* Corresponding author. Tel.: +86 21 6564 3462; fax: +86 21 6510 2412.
E-mail address: rhfan@fudan.edu.cn (R. Fan).
Scheme 1.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.06.031

4276
W. Li et al. / Tetrahedron Letters 51 (2010) 4275–4277
Table 1
H
Ts
R2
Ts
N
Evaluation of reaction conditionsa
(2 equiv) PhI(OAc)2, (1 equiv) I2
Cl(CH2)2Cl, 25 ºC
N
Ph
1-10
Ph
NTs
NHTs
PhI(OAc)2, I2, additive
conditions
11a
Ph
11a
Ph
H
Ts
H
Ts
H
Ts
H
Ts
H
Ts
N
N
N
N
N
Cl
OAc
Ph
COOMe
Ph
CH3
Ts
Ph
Ph
Ph
Entry DIB (equiv) I2 (equiv) Additive (equiv) Conditions
11ab (%)
2
1
3
4
5
1
2
2
2
2
2
2
2
2
2
2
2
2
2
3
1
0.5
1
1
1
1
1
1
1
1
1
HOAc (1)
Cl(CH2)2Cl, 25 °C
Cl(CH2)2Cl, 25 °C
Cl(CH2)2Cl, 25 °C
Cl(CH2)2Cl, 25 °C
Cl(CH2)2Cl, 25 °C
Cl(CH2)2Cl, 25 °C
Cl(CH2)2Cl, 0 °C
0
28
21
23
0
Ts
NaOAc (2)
K2CO3 (2)
t-BuOK (2)
DBU (2)
HN
H
Ts
H
Ts
H
H
Ts
3
1
N
N
N
N
COOEt
4
1
Ph
COOMe
Ph
Ph
Ph
Ph
Ph
5
1
COOEt
6
1
Et3N (2)
0
65
6
7
10a
8
9
7
8
9
1
1
1
1
1
1
1
1
NaOAc (2)
NaOAc (2)
NaOAc (2)
NaOAc (3)
NaOAc (1)
NaOAc (0.5)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
NaOAc (1)
Cl(CH2)2Cl, À10 °C 41
Scheme 2. b-Scission of N-Ts amines.
Cl(CH2)2Cl, 0 °C
Cl(CH2)2Cl, 0 °C
Cl(CH2)2Cl, 0 °C
Cl(CH2)2Cl, 0 °C
Cl(CH2)2Cl, 0 °C
Cl(CH2)2Cl, 0 °C
Cl(CH2)2Cl, 0 °C
Cl(CH2)2Cl, 0 °C
Cl(CH2)2Cl, 0 °C
CH2Cl2, 0 °C
12c
55
73
48
46
73
43
25
81
56
18
41
0
10
11
12
13
14
15
16
17
18
19
20
21
22
1
2
0.5
0.5
0.5
0.5
0.5
0.5
Toluene, 0 °C
CH3CN, 0 °C
MeOH, 0 °C
DMF, 0 °C
0
a
The reactions were performed with 10a (0.2 mmol), PhI(OAc)2, I2, and additive
(as noted) in solvent (1 mL).
b
Yields were determined by the 1H NMR spectroscopy of the unpurified reaction
mixture with Br(CH2)2Br as the standard.
c
The reaction was stirred at 0 °C for 2 h.
Table 2
b-Scission of homoallylaminesa
Figure 1. X-ray diffraction structure of 12.
R1
R1
(1 equiv) PhI(OAc)2
(0.5 equiv) I2, (1 equiv) NaOAc
H
N
N
R2
R2
Cl(CH2)2Cl, 0 ºC
PhI(OAc)2 + I2
11
10
-PhI
Ts
I
Ts
R2
R1
11
Yieldb (%)
NHTs
Entry
NTs
N
N
AcOI
β-scission
- HOAc
Ph
Ph
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
C6H5
p-CH3O–C6H4
o,m-Di-CH3O–C6H3
p-CH3–C6H4
p-F–C6H4
p-Br–C6H4
p-Cl–C6H4
o-Cl–C6H4
1-Naphthyl
2-Furan
Ts
11a
11b
11c
11d
11e
11f
11g
11h
11i
75
71
—
—
—
- I
Ph
Ph
Ph
10a
PhSO2
CH3SO2
CF3SO2
tert-BuSO2
PhCO
CF3CO
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
Ts
I
11a
AcOI
Ts
N
Ts
Ph
I
NHTs I
I
N
I
—
—
AcOI
OAc
OAc
OAc
OAc
OAc
Ph
- HOAc
- I
60
50
61
58
63
66
30
71
50
83
—
III
II
1, 5-H migration
11j
11k
11i
OAc
Ts
Ts
Ph
Ts
N
NH
I
NH
I
I
11m
11n
11o
11p
11q
11r
11s
11t
- H+
- e
Ph
Ph
12
V
IV
2-Thiophen
2-Pyridin
i-Bu
Scheme 3. A plausible reaction pathway.
—
—
t-Bu
amounts of reagents were optimized (Table 1, entries 10–17). The
best ratio of substrate, AcONa, PhI(OAc)2, and I2 was 1:1:1:0.5, with
which the yield of 1 increased to 81%. Sulfonimine also was formed
in CH2Cl2, toluene, and CH3CN, but not in MeOH and DMF (Table 1,
entries 18–22).
a
The reactions were performed with substrate 10 (2 mmol), PhI(OAc)2 (2 mmol),
I2 (1 mmol), and NaOAc (2 mmol) in anhydrous Cl(CH2)2Cl (10 mL).
b
Isolated yields.
While homoallylic benzenesulfonamides were effective sub-
strates for the b-scission, the reactions of some other sulfonyla-
mides and amides did not afford any sulfonimines (Table 2,
entries 1–7).11 The reaction was found to tolerate a range of differ-
ent substituents with different electronic demands on the aromatic
rings involving electron withdrawing and electron donating (Table
2, entries 8–15). The position of the substituent had an influence

W. Li et al. / Tetrahedron Letters 51 (2010) 4275–4277
4277
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(2 equiv) CH2(COOEt)2
(0.5 equiv) t-BuOK
t-BuOH, 0-25 ºC
NHTs
COOEt
(1 equiv) PhI(OAc)2
(1 equiv) NaOAc
(0.5 equiv) I2
Ph
COOEt
NHTs
13
Cl(CH2)2Cl, 0 ºC
64%
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(3 equiv) MeO2CC CCO2Me
0.2 equiv Ph3P
Ph
MeO2C
OMe
O
10a
Benzene, reflux
Ph
N
Ts
14
56%
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Scheme 4.
on the yields of sulfonimines. For example, reaction of p-chloro
substituted substrate gave rise to sulfonimine 11m in 66% yield,
while reaction of o-chloro-substituted substrate afforded the cor-
responding product 11n in 30% yield. With respect to the hetaryl
substrates (Table 2, entries 16–18), 1-furan-2-yl and 1-thiophen-
2-yl homoallylamines are suitable substrates in this process and
the desired products were isolated in moderate to good yields,
while no sulfonimine was obtained for the reaction of 1-pyridin-
2-yl homoallylamine. When enolizable or nonenolizable aliphatic
derivatives were employed under the conditions, no sulfonimines
were detected (Table 2, entries 19 and 20). However, the analysis
of the unpurified reaction mixtures by 1H NMR spectroscopy indi-
cated the generation of TsNH2 and the corresponding aldehydes.
The aryl N-sulfonylimines formed in the b-scission reactions
were ready to undergo subsequent reactions with diethyl malonate
and dimethyl acetylenedicarboxylate without further purification
(Scheme 4).
´
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In conclusion, we have described a selective base-promoted
b-fragmentation of homoallylamines with the combination of
iodobenzene diacetate with iodine. The desired carbon–carbon
bond cleavage proceeded via a radical b-scission pathway under
mild conditions with good functional group tolerance. Further
studies on the application of this system are ongoing and will be
reported in due course.
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Acknowledgments
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11. General experimental procedure and spectroscopic data: A Schlenk tube with stir
bar was charged with homoallylic benzenesulfonamide (2 mmol), PhI(OAc)2
(644 mg, 2 mmol), and NaOAc (164 mg, 2 mmol). The tube was evacuated and
back-filled with argon, and then Cl(CH2)2Cl (10 mL) and I2 (254 mg, 1 mmol)
were added. The reaction mixture was allowed to stir at 0 °C until substrate
disappeared monitored by TLC. The reaction was quenched with saturated
Na2S2O3, and the reaction mixture was extracted by ethyl acetate (50 mL Â 3).
The organic layer was dried over Na2SO4, concentrated, and purified by
recrystallization (hexane/ethyl acetate) to provide the desired product. N-
Benzylidene-4-methylbenzenesulfonamide 11a 1H NMR (400 MHz, CDCl3) d
9.04 (s, 1H), 7.88–7.94 (m, 4H), 7.62 (t, J = 7.5 Hz, 1H), 7.49 (t, J = 7.6 Hz, 2H),
7.35 (d, J = 8.2 Hz, 2H), 2.44 (s, 3H).
Financial support from National Natural Science Foundation of
China
(20702006) and Fudan University
is gratefully
acknowledged.
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