Oxidative intramolecular bromo-amination of N-alkenyl sulfonamides via umpolung of alkali metal bromides

Article abstract of DOI:10.1021/jo201113r

The oxidative intramolecular bromo-amination of various N-alkenyl sulfonamides and N-alkenoxyl sulfonamides via umpolung of alkali metal bromides occurred exo-selectively to generate cyclic bromoamides in high yields with good diastereoselectivities. This

Full text of DOI:10.1021/jo201113r

NOTE
pubs.acs.org/joc
Oxidative Intramolecular Bromo-Amination of N-Alkenyl
Sulfonamides via Umpolung of Alkali Metal Bromides
Katsuhiko Moriyama,* Yuta Izumisawa, and Hideo Togo*
Department of Chemistry, Graduate School of Science, Chiba University, Yayoi-cho 1-33, Inage-ku, Chiba 263-8522, Japan
S Supporting Information
b
ABSTRACT: The oxidative intramolecular bromo-amination of various N-alkenyl
sulfonamides and N-alkenoxyl sulfonamides via umpolung of alkali metal bromides
occurred exo-selectively to generate cyclic bromoamides in high yields with good
diastereoselectivities. This method provided the desired products without elaborat-
ing the stoichiometric amount of corresponding organic waste.
ntramolecular halo-amination1 is an important tool for the
synthesis of nitrogen-containing heterocycles, which are useful
Scheme 1. Intramolecular Bromo-Cyclization of Alkenes
I
building blocks of biologically active natural products and
pharmacological products.2 In particular, some bromo com-
pounds have also been noted in the biosynthesis of halogenated
marine natural products3 and medicinal plants.3a,4 As for the
bromo-amination of alkenes by both intermolecular and intra-
molecular reactions with N-protected amines, straightforward
methods using transition metal catalysts and stoichiometric
amounts of brominating reagents have been developed. How-
ever, those methods present a disadvantage in that toxic heavy
metals (Os,5 Mn,6 V,6 Cu,6,7 or Pd7,8) are required. On the other
hand, such organic brominating reagents as N-bromosuccinimide
(NBS),9 1,3-dibromo-5,5-dimethylhydantoin (DBDMH),10 2,4,4,6-
tetrabromocyclohexa-2,5-dienone (TBCO),11 and bromodiethyl-
sulfonium bromopentachloroantimonate (BDSB)12 have been used
as active bromo sources for chemoselective bromo-cyclization reac-
tions. However, they present a particular problem in that the stoi-
chiometric amount of the corresponding organic waste is increased
(Scheme 1, eq 1). To overcome this problem, it is very important to
develop a bromo cyclization using nonorganic bromo reagents
under heavy-metal-free conditions. Therefore, we focused on the
oxidative bromo-cyclization via umpolung of alkali metal bromides,
which can oxidize bromide ion (BrÀ) (inorganic bromide) to activate
bromonium-like species (Br+) using various kinds of oxidants
(Scheme 1, eq 2).13
not suitable to give 2a in moderate yield together with many
byproducts (entry 1). In contrast, the use of NBS gave 2a in 90%
yield (entry 2). When 1a was treated with KBr as the bromo
reagent and m-CPBA or Oxone as the oxidant in CH2Cl2, 2a was
obtained in low yields (entries 3 and 4). Then, solvent effects on
the intramolecular bromo-amination using KBr/Oxone were
investigated (entries 5À7). Whereas the treatment of 1a in
THF and AcOEt gave 2a in 70% and 92% yields, respectively
(entries 5 and 6), the reaction in MeCN gave 2a in >99% yield as
the best result (entry 7). Use of other oxidants, such as m-CPBA,
H2O2, PhI(OAc)2, or t-BuOCl, in this reaction with 1a decreased
the yield of 2a (entries 8À11). Furthermore, use of NaBr instead
of KBr also decreased the yield of 2a (entry 12) and the use of
KBr alone was totally ineffective for the transformation of 1a into
2a (entry 13).
In the past, the exo-selective intramolecular bromo-amination
was developed. However, the reaction required NBS as the
bromo reagent.14 We report here an exo-selective intramolecular
bromo-amination of N-alkenyl sulfonamides and N-alkenoxyl
sulfonamides via umpolung of inorganic bromides.
First, we screened a series of bromo reagents and oxidants for
the intramolecular bromo-amination with 1a (Table 1). The use
of Br2 as bromo reagent for intramolecular bromo-amination was
Received: June 3, 2011
Published: August 08, 2011
r
2011 American Chemical Society
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dx.doi.org/10.1021/jo201113r J. Org. Chem. 2011, 76, 7249–7255
|

The Journal of Organic Chemistry
NOTE
Table 1. Screening of Intramolecular Bromo-amination with
1aa
synthesis of bromo isoxazolidines. We report here the first
synthesis of bromo isoxazolidines via the oxidative intramolecu-
lar bromo-amination of N-alkenoxyl sulfonamide derivatives 3
(Scheme 2). Treatment of 3a (R1 = R2 = R3 = H) with KBr and
Oxone in a 4:1 mixture of MeCN and toluene gave 4a in 93%
yield. The same treatment of 2-aryl substituted N-alkenoxyl
sulfonamides bearing H, MeO, and CF3 at aryl group 3b, 3c,
and 3d (R1 = Ph, 4-MeO-C6H4, and 4-CF3ÀC6H4, R2 = R3 = H)
also provided corresponding products 4b, 4c, and 4d in excellent
yields (90À97%) with moderate diastereoselectivities (dr = 4:1).
Use of disubstituted internal alkene 3e (R1 = 1-naphthyl, R2 =
Me, R3 = H) and terminal alkene 3f (R1 = 4ÀCl-C6H4, R2 = H,
R3 = Me) provided corresponding products 4e and 4f in 91% and
95% yields, respectively. Moreover, treatment of 2-thienyl sub-
stituted N-alkenoxyl sulfonamides 3g (R1 = 2-thienyl, R2 =
R3 = H) and 2-butyl substituted N-alkenoxyl sulfonamides 3h
(R1 = n-butyl, R2 = R3 = H) also gave desired products 4g and 4h
in 82% and 98% yields, respectively.
The proposed reaction mechanism is depicted in Scheme 3.
The key step is the generation of the activated bromonium-like
species (Br+), but not Br2, via oxidative umpolung of KBr with
Oxone in MeCN at room temperature (Table 1, entries 1 vs 7).
We speculate that there are two pathways for the bromo-
amination of N-alkenyl sulfonamides 1 with Br+. First, the
reaction may occur via intermolecular bromination of the olefin
moiety, and then, the bromonium cation intermediate may be
intramolecularly attacked by the sulfonamide to form cyclization
products 2 (path A). Alternatively, sulfonamides may undergo
direct bromination to form N-bromo sulfonamides, followed by
intramolecular bromonium ion transfer to the olefin moiety, and
the cyclization of bromonium cation intermediate proceeds to
afford desired products 2 (path B). Some of the mechanistic
approaches to the intramolecular bromo-amination indicate that
the activated bromonium-like species first brominate the olefin
moiety of the substrates (path A) (see Experimental Section).22
In conclusion, we have developed an oxidative intramolecular
bromo-amination that involves N-alkenyl sulfonamides and
N-alkenoxyl sulfonamides using the umpolung of alkali metal
bromides with Oxone. This reaction provides the desired pro-
ducts without elaborating the stoichiometric amount of the
corresponding organic waste, thus contributing to green sustain-
able chemistry. We expect that activated bromonium-like species
(Br+) would be further applicable to fine organic synthesis, such
as enantioselective reactions or catalyst-mediated reactions.
entry Br
oxidant
solvent time (h) conv. (%) yield of 2a (%)b
1
2
3
4
5
6
7
8
9
Br2
MeCN
MeCN
CH2Cl2
CH2Cl2
THF
1
3
>99
>99
>99
>99
>99
>99
>99
>99
0
57
90
37
19
70
92
>99
32
0
NBS
KBr m-CPBA
KBr Oxone
KBr Oxone
KBr Oxone
KBr Oxone
KBr m-CPBA
KBr H2O2
2
20
8
AcOEt
MeCN
MeCN
MeCN
24
2
2
64
12
24
3
10 KBr PhI(OAc)2 MeCN
>99
>99
>99
0
75
82
60
0
11 KBr t-BuOCl
12 NaBr Oxone
13 KBr
MeCN
MeCN
MeCN
64
a Reaction of 1a (0.25 mmol) was carried out with Br source (1.2 equiv)
and oxidant (1.2 equiv) in solvent (1 mL). b Isolated yield.
Next, we investigated the scope of the intramolecular bromo-
amination of N-alkenyl sulfonamides 1 via the umpolung reac-
tion of KBr under optimized reaction conditions (Table 2). The
reaction of N-alkenyl sulfonamides bearing other sufonyl groups,
such as benzenesulfonyl (1b), 1-naphthalenesulfonyl (1c),
4-fluorobenzenesulfonyl (1d), n-butanesulfonyl (1e), and (1S)-
camphorsulfonyl (1f), also gave the corresponding products in
excellent yields (Table 2, entries 1À5). A variety of substituted
alkenes underwent the intramolecular bromo-amination to give the
intramolecular bromo-amination to give the corresponding amino-
bromides. When N-(2,2-dialkyl substituted) and N-(1,2-dialkyl
substituted) 4-penten-1-yl sulfonamides 1g, 1h, 1i, and 1j were
used, cyclization products 2g, 2h, 2i, and 2j were obtained in >99%,
97%, >99%, and 96% yields, respectively (entries 6À9). N-Alkenyl
sulfonamides with cyclic alkene 1k and internal alkenes (E)-1l and
(Z)-1m were efficiently converted into corresponding products 2k,
2l, and 2m in high yields (89À91%) with good diastereoselectivities
(dr = 77:23 to >99:<1) (entries 10À12). Disubstituted terminal
alkene 1n could be also used and corresponding product 2n with a
quaternary carbon center was obtained in 90% yield (entry 13).
Moreover, the same treatment of the chiral N-alkenyl sulfonamides
(1o and 1p) derived from R-amino acids also provided correspond-
ing products 2o and 2p in excellent yields with moderate diaster-
eoselectivities (>99% and 93% yields, dr = 77:23 and 57:43),
respectively (entries 14 and 15).
The present method for the oxidative intramolecular bromo-
amination of N-alkenyl sulfonamides was applied to the synthesis
of bromo isoxazolidines from N-alkenoxyl sulfonamide deriva-
tives. Isoxazolidines are useful for the synthesis of biologically
active compounds.15 They also serve as precursors to β-amino
alcohols,16 β-amino ketones,17 β-amino acids,18 and 3-isoxazolidines.19
Isoxazolidines have been synthesized via the 1,3-dipolar cycload-
dition reaction of nitrones with alkenes16a,20 and the Pd-cata-
lyzed cyclization of N- or O-homoallyl hydroxylamines.21 To the
best of our knowledge, however, there has been no report of the
’ EXPERIMENTAL SECTION
General Procedure for the Intramolecular Bromo-amina-
tion of N-Alkenyl Sulfonamides with a Metal Bromide/Oxone
System (Table 1, entry 7). To a solution of 1a (59.8 mg, 0.25 mmol)
and Oxone (184.4 mg, 0.30 mmol) in acetonitrile (1 mL) was added KBr
(35.7 mg, 0.30 mmol) under argon atmosphere. The solution was stirred
at room temperature for 3 h. Saturated NaHCO3 aqueous solution
(10 mL) was added to the reaction mixture, and the product was extracted
with AcOEt (15 mL Â 3). The combined extracts were washed by brine
(10 mL) and dried over Na2SO4. The organic phase was concentrated
under reduced pressure and the crude product was purified by silica gel
column chromatography (eluent: hexane/AcOEt = 5/1), to give the
desired product 2a (79.2 mg, >99% yield).
2-(Bromomethyl)-1-tosylpyrrolidine (2a): 1H NMR (400 MHz,
CDCl3) δ 1.51À1.61 (m, 1H), 1.69À1.80 (m, 1H), 1.81À1.89 (m,
1H), 1.90À1.98 (m, 1H), 2.44 (s, 3H), 3.15 (dt, J = 10.1, 7.1 Hz, 1H),
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dx.doi.org/10.1021/jo201113r |J. Org. Chem. 2011, 76, 7249–7255

The Journal of Organic Chemistry
NOTE
Table 2. Exo-selective Intramolecular Bromo-amination of Various N-Alkenylsulfonamidesa
a Reaction of 1 (0.25 mmol) was carried out with KBr (1.2 equiv) and Oxone (1.2 equiv) in MeCN (1 mL). b Isolated yield. c Reaction was carried out in
MeCN (2 mL). d Reaction was carried out under dark conditions. e Reaction was carried out with Oxone (2.0 equiv) in a mixture of MeCN and toluene
(4:1) (1 mL).
3.36 (t, J = 9.7 Hz, 1H), 3.51À3.44 (m, 1H), 3.74À3.79 (m, 1H),
3.80À3.87 (m, 1H), 7.34 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H).
13C NMR (100 MHz, CDCl3) δ 21.5, 23.7, 30.2, 36.0, 49.8, 60.3, 127.5
(2C), 129.8 (2C), 134.0, 143.8. IR (neat) 1338, 1161, 1091, 1034,
986 cmÀ1. MS (ESI) calcd for C12H17BrNO2S [M + H]+ 318.0158,
found 318.0151. Anal. calcd for C12H16BrNO2S: C, 45.29; H, 5.07; N,
4.40%. Found: C, 45.60; H, 5.16; N, 4.27%.
2-(Bromomethyl)-1-(phenylsulfonyl)pyrrolidine (2b):yield 95%, 72.2 mg.
1H NMR (400 MHz, CDCl3) δ 1.51À1.61 (m, 1H), 1.68À1.80 (m, 1H),
1.80À1.90 (m, 1H), 1.91À2.00 (m, 1H), 3.17 (dt, J = 10.1, 7.5 Hz, 1H), 3.37
(t, J = 9.8 Hz, 1H), 3.46À3.53 (m, 1H), 3.78 (dd, J = 10.1, 3.3 Hz, 1H),
3.81À3.89 (m, 1H), 7.56 (t, J = 7.6 Hz, 2H), 7.60À7.66 (m, 1H), 7.86 (d,
J = 7.6 Hz, 1H). 13C NMR (100 MHz, CDCl3) δ 23.7, 30.1, 35.9, 49.7, 60.3,
127.3 (2C), 129.1 (2C), 132.9, 136.7. IR (KBr) 1337, 1199, 1162, 1092,
1030 cmÀ1. MS (ESI) calcd for C11H15BrNO2S [M + H]+ 304.0001, found
304.0005.
7.52À7.64 (m, 2H), 7.64À7.71 (m, 1H), 7.93 (d, J = 8.2 Hz, 1H), 8.09 (d,
J = 8.5 Hz, 1H), 8.25 (d, J = 7.6 Hz, 1H), 8.86 (d, J = 8.7 Hz, 1H). 13C
NMR (100 MHz, CDCl3) δ 24.0, 30.4, 35.6, 49.5, 59.7, 124.2, 125.1,
126.9, 128.2, 128.9, 129.0, 130.0, 133.5, 134.3, 134.6. IR (neat) 1347,
1159, 1133, 1029, 989 cmÀ1. MS (ESI) calcd for C15H17BrNO2S[M +H]+
354.0158, found 354.0152.
2-(Bromomethyl)-1-((4-fluorophenyl)sulfonyl)pyrrolidine (2d): yield
1
93%, 74.9 mg. H NMR (400 MHz, CDCl3) δ 1.52À1.65 (m, 1H),
1.71À1.82 (m, 1H), 1.82À1.93 (m, 1H), 1.93À2.02 (m, 1H), 3.15 (dt, J=
10.1, 7.3 Hz, 1H), 3.37 (t, J = 9.8 Hz, 1H), 3.44À3.52 (m, 1H), 3.76 (dd,
J = 9.8, 3.1 Hz, 1H), 3.79À3.87 (m, 1H), 7.23 (t, J = 8.7 Hz, 2H),
7.84À7.91 (m, 2H). 13C NMR (100 MHz, CDCl3) δ 23.8, 30.2, 35.8,
49.8, 60.4, 116.5 (d, J = 22.0 Hz, 2C) 130.1 (d, J = 8.6 Hz, 2C), 133.2,
165.3(d, J = 256.8Hz). IR (KBr) 1343, 1231, 1169, 1093, 1057 cmÀ1. MS
(ESI) calcd for C11H14BrFNNaO2S [M + Na]+ 343.9727, found
343.9722.
2-(Bromomethyl)-1-(naphthalen-1-ylsulfonyl)pyrrolidine (2c): yield
2-(Bromomethyl)-1-(butylsulfonyl)pyrrolidine (2e): yield >99%, 71.1 mg.
1H NMR (400 MHz, CDCl3) δ0.96(t,J= 7.5 Hz, 3H), 1.47 (sext, J=7.5Hz,
2H), 1.75À2.18 (m, 6H), 2.95À3.02(m, 2H), 3.35À3.48(m, 3H), 3.64(dd,
J = 10.3, 3.2 Hz, 1H), 4.04À4.12 (m, 1H). 13C NMR (100 MHz, CDCl3)
1
96%, 85.0 mg. H NMR (400 MHz, CDCl3) δ 1.63À1.73 (m, 1H),
1.82À1.92 (m, 2H), 1.93À2.04 (m, 1H), 3.36 (t, J = 9.7 Hz, 1H),
3.30À3.43 (m, 2H), 3.68 (dd, J = 10.1, 3.2 Hz, 1H), 4.12À4.20 (m, 1H),
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dx.doi.org/10.1021/jo201113r |J. Org. Chem. 2011, 76, 7249–7255

The Journal of Organic Chemistry
NOTE
Scheme 2. Exo-selective Intramolecular Bromo-amination of
Various N-Alkenoxyl Sulfonamides
Scheme 3. Plausible Reaction Mechanism
25.7, 26.0, 37.4, 37.5, 45.8, 60.0, 61.8, 127.5 (2C), 129.7 (2C), 134.8,
143.7. IR (KBr) 1345, 1157, 1092, 1043, 1024 cmÀ1. MS (ESI) calcd for
C14H21BrNO2S [M + H]+ 346.0471, found 346.0463.
3-(Bromomethyl)-2-tosyl-2-azaspiro[4.5]decane (2h):yield 97%, 93.7 mg.
1H NMR (400 MHz, CDCl3) δ 0.59À0.69 (m, 1H), 0.74À0.84 (m, 1H),
1.05À1.50 (m, 8H), 1.63 (dd, J = 13.3, 8.5 Hz, 1H), 1.95 (dd, J = 13.3, 7.5 Hz,
1H), 2.43 (s, 3H), 3.15 (d, J = 11.0 Hz, 1H), 3.35 (d, J = 11.0 Hz, 1H), 3.50
(dd, J = 9.8, 9.0 Hz, 1H), 3.75À3.84 (m, 1H), 3.94 (dd, J = 9.8, 3.0 Hz, 1H),
7.33 (d, J = 8.6 Hz, 2H), 7.74 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 21.5, 22.7, 23.6, 25.7, 33.9, 36.1, 37.7, 41.4, 44.0, 59.0, 59.2, 127.4
(2C), 129.7 (2C), 134.6, 143.7. IR (KBr) 1350, 1220, 1160, 1090, 1031 cmÀ1
.
MS (ESI) calcd for C17H25BrNO2S [M + H]+ 386.0784, found 386.0776.
Anal. calcd for C17H24BrNO2S: C, 52.85; H, 6.26; N, 3.63%. Found: C, 52.81;
H, 6.27; N, 3.55%.
cis-2-(Bromomethyl)-1-tosyloctahydro-1H-indole (2i, Diastereomer
1
Mixtures): yield >99%, 93.0 mg. Major-diastereomer: H NMR (400
MHz, CDCl3) δ 0.99À1.31 (m, 2H), 1.32À1.48 (m, 2H), 1.48À1.74
(m, 4H), 1.80À2.04 (m, 2H), 2.07À2.18 (m, 1H), 2.44 (s, 3H), 3.41 (t,
J = 9.8 Hz, 1H), 3.62À3.71 (m, 1H), 3.71À3.78 (m, 1H), 4.00 (dd, J =
9.8, 3.6 Hz, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz, 2H). 13C
NMR (100 MHz, CDCl3) δ 20.1, 21.6, 24.3, 25.7, 31.1, 34.1, 36.2, 37.8,
60.7, 61.4, 127.4 (2C), 129.8 (2C), 134.7, 143.6. Minor-diastereomer:
1H NMR (400 MHz, CDCl3) δ 0.85À0.99 (m, 1H), 0.99À1.31 (m,
2H), 1.32À1.48 (m, 2H), 1.48À1.74 (m, 4H), 1.80À2.04 (m, 2H), 2.43
(s, 3H), 3.28 (t, J = 10.8 Hz, 1H), 3.82À3.89 (m, 1H), 3.92À4.02 (m,
2H), 7.30(d, J= 8.2 Hz, 2H), 7.74 (d, J=8.2Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 20.0, 21.5, 23.5, 25.6, 27.9, 31.6, 34.5, 35.5, 59.0, 61.6, 127.3
(2C), 129.6 (2C), 138.4, 143.2. IR (KBr) 1345, 1162, 1096, 1032,
1004 cmÀ1. MS (ESI) calcd for C16H23BrNO2S [M + H]+ 372.0627,
found 372.0624.
a Reaction of 3 (0.25 mmol) was carried out with KBr (1.2 equiv) and
Oxone (1.2 equiv) in MeCN (1 mL). The relative configuration of 4 was
determined by NOE experiments. b Isolated yield. c Reaction was carried
out under dark conditions. d Starting materials with a 2:1 mixture of E/Z
isomers were used. e Reaction was carried out in a mixture of MeCN and
toluene (1:1) (1 mL).
δ 13.6, 21.7, 24.6, 25.2, 30.4, 36.2, 49.4, 50.2, 59.7. IR (KBr) 1334, 1142, 1067,
1035, 989 cmÀ1. MS (ESI) calcd for C9H18BrNNaO2S [M + Na]+ 306.0134,
found 306.0133.
trans-2-(Bromomethyl)-1-tosyloctahydro-1H-indole (2j, Diastereo-
mer Mixtures): yield 96%, 89.4 mg. Major-diastereomer: 1H NMR (400
MHz, CDCl3) δ 0.98À1.48 (m, 6H), 1.55À1.73 (m, 1H), 1.73À1.88
(m, 2H), 2.25À2.34 (m, 2H), 2.43 (s, 3H), 2.90 (dt, J = 10.8, 3.2 Hz,
1H), 3.60 (dd, J = 9.8, 8.2 Hz, 1H), 3.88 (dd, J = 9.8, 3.2 Hz, 1H), 4.27
(dq, J = 8.2, 3.2 Hz, 1H), 7.29 (d, J = 8.2 Hz, 2H), 7.74 (d, J = 8.2 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ 21.5, 25.0 (2C), 29.3, 29.6, 36.4,
38.4, 45.3, 60.2, 66.3, 127.0 (2C), 129.6 (2C), 139.6, 143.0. Minor-
2-(Bromomethyl)-1-((1S)-10-Camphorsulfonyl)pyrrolidine (2f, Dia-
stereomer Mixtures): yield 98%, 92.7 mg. Major-diastereomer: 1H NMR
(400 MHz, CDCl3) δ 0.90 (s, 3H), 1.14 (s, 3H), 1.39À1.48 (m, 1H),
1.62À1.71 (m, 1H), 1.88À2.22 (m, 7H), 2.34À2.45 (m, 1H), 2.47À2.58
(m, 1H), 2.88 (d, J = 14.9 Hz, 1H), 3.33À3.43 (m, 2H), 3.43À3.54 (m,
2H), 3.67 (dd, J = 10.3, 3.3 Hz, 1H), 4.02À4.11 (m, 1H). 13C NMR (100
MHz, CDCl3) δ 19.8, 20.0, 24.3, 25.2, 26.9, 30.4, 36.1, 42.6, 42.8, 45.8,
47.9, 49.4, 58.3, 60.1, 215.5. Minor-diastereomer: 1H NMR (400 MHz,
CDCl3) δ 0.90 (s, 3H), 1.15 (s, 3H), 1.39À1.48 (m, 1H), 1.62À1.71 (m,
1H), 1.88À2.22 (m, 7H), 2.34À2.45 (m, 1H), 2.47À2.58 (m, 1H), 2.84
(d, J = 14.6 Hz, 1H), 3.33À3.43 (m, 2H), 3.43À3.54 (m, 2H), 3.70 (dd,
J = 10.1, 3.2 Hz, 1H), 3.99À4.08 (m, 1H). 13C NMR (100 MHz, CDCl3)
δ 19.8, 20.0, 24.2, 25.1, 26.9, 30.5, 35.9, 42.6, 42.8, 45.1, 47.9, 49.6, 58.2,
60.1, 215.3. IR (KBr) 1745, 1341, 1200, 1146, 1037 cmÀ1. MS (ESI) calcd
for C15H24BrNNaO3S [M + Na]+ 400.0552, found 400.0550.
1
diastereomer: H NMR (400 MHz, CDCl3) δ 0.98À1.48 (m, 6H),
1.55À1.88 (m, 3H), 1.99 (dd, J = 12.6, 5.5 Hz, 1H), 2.25À2.34 (m, 1H),
2.46 (s, 3H), 2.46À2.52 (m,1H), 3.29 (dd, J = 11.4, 10.6 Hz, 1H),
3.76À3.84 (m, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.70 (d, J = 8.1 Hz, 2H).
13C NMR (100 MHz, CDCl3) δ 21.6, 24.5, 25.2, 29.4, 32.4, 33.1, 35.8,
42.7, 61.3, 67.3, 127.8 (2C), 129.7 (2C), 133.0, 143.8. IR (KBr) 1333,
1148, 1118, 1088, 1035 cmÀ1. MS (ESI) calcd for C16H23BrNNaO2S
[M + Na]+ 394.0447, found 394.0443.
2-(Bromomethyl)-4,4-dimethyl-1-tosylpyrrolidine (2g): yield >99%,
86.5 mg. 1H NMR (400 MHz, CDCl3) δ 0.53 (s, 3H), 1.05 (s, 3H), 1.70
(dd, J = 13.0, 8.5 Hz, 1H), 1.88 (dd, J = 13.0, 7.6 Hz, 1H), 2.44 (s, 3H),
3.14 (d, J = 10.8 Hz, 1H), 3.19 (d, J = 10.8 Hz, 1H), 3.52 (t, J = 9.6 Hz,
1H), 3.82À3.91 (m, 1H), 3.94 (dd, J = 9.6, 3.0 Hz, 1H), 7.33 (d, J = 7.8
Hz, 2H), 7.74 (d, J = 7.8 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.5,
cis-6-Bromo-1-tosyloctahydrocyclopenta[b]pyrrole (2k): yield 91%,
78.3 mg. 1H NMR (400 MHz, CDCl3) δ 1.45À1.54 (m, 2H), 1.67À1.76
(m, 1H), 2.00À2.07 (m, 1H), 2.13À2.28 (m, 2H), 2.45 (s, 3H),
2.74À2.82 (m, 1H), 3.01 (td, J = 10.1, 7.3 Hz, 1H), 3.45 (td, J = 10.1, 6.1
Hz, 1H), 3.89 (d, J= 7.6 Hz, 1H), 4.77 (d, J= 3.9 Hz, 1H), 7.35 (d, J=8.5Hz,
7252
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NOTE
2H), 7.73 (d, J = 8.5 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.6, 29.8,
30.7, 33.9, 41.9, 50.0, 57.6, 73.3, 127.9 (2C), 129.8 (2C), 132.8, 143.9. IR
(KBr) 1345, 1157, 1094, 1026 cmÀ1. MS (ESI) calcd for C14H18BrNNaO2S
[M + Na]+ 366.0134, found 366.0126. Anal. calcd for C14H18BrNO2S: C,
48.84; H, 5.27; N, 4.07%. Found: C, 48.96; H, 5.20; N, 4.02%.
syn-2-(1-Bromomethyl)-1-tosylpyrrolidine (2l): yield 89%, 73.9 mg.
1H NMR (400 MHz, CDCl3) δ 1.40 (dt, J = 12.1, 7.6 Hz, 1H), 1.68 (d,
J = 7.1 Hz, 1H), 1.68À1.80 (m, 1H), 1.82À1.92 (m, 1H), 1.95À2.03 (m,
1H), 2.43 (s, 3H), 3.34 (dd, J = 7.6, 5.9 Hz, 2H), 3.69 (dt, J = 8.2, 4.7 Hz,
1H), 4.61 (dq, J = 7.1, 4.7 Hz, 1H), 7.32 (d, J = 8.2 Hz, 2H), 7.73 (d, J =
8.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.5, 23.1, 24.5, 27.9, 49.4,
55.1, 65.0, 127.5 (2C), 129.7 (2C), 135.1, 143.6. IR (KBr) 1343, 1156,
1092, 1044, 996 cmÀ1. MS (ESI) calcd for C13H19BrNO2S [M + H]+
332.0314, found 332.0314.
anti-2-(1-Bromomethyl)-1-tosylpyrrolidine (2m): yield 90%, 74.8
mg. 1H NMR (400 MHz, CDCl3) δ 1.37À1.49 (m, 1H), 1.66 (d, J =
7.1 Hz, 3H), 1.71À1.83 (m, 2H), 1.95À2.05 (m, 1H), 2.45 (s, 3H), 3.26
(dt, J = 10.7, 7.1 Hz, 1H), 3.47 (dt, J = 10.7, 6.2 Hz, 1H), 3.93 (dt, J = 8.0,
4.1 Hz, 1H), 4.68 (dq, J = 7.1, 4.1 Hz, 1H), 7.34 (d, J = 8.1 Hz, 2H), 7.73
(d, J = 8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 18.6, 21.5, 24.5,
27.0, 50.8, 51.0, 64.1, 127.6 (2C), 129.8 (2C), 133.6, 143.8. IR (KBr)
1341, 1160, 1087, 1004, 978 cmÀ1. MS (ESI) calcd for C13H19BrNO2S
[M + H]+ 332.0314, found 332.0307.
3-(Bromomethyl)-2-tosylisoxazolidine (4a): yield 93%, 74.7 mg. 1H
NMR (400 MHz, CDCl3) δ 2.17À2.30 (m, 1H), 2.46 (s, 3H),
2.43À2.53 (m, 1H), 3.35 (t, J = 9.7 Hz, 1H), 3.66 (dd, J = 10.2, 4.9
Hz, 1H), 3.94À4.06 (m, 2H), 4.44À4.53 (m, 1H), 7.36 (d, J = 8.0 Hz,
2H), 7.86 (d, J = 8.0 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.7,
34.2, 34.3, 59.9, 70.2, 129.2 (2C), 129.8 (2C), 132.5, 145.3. IR (KBr)
1349, 1308, 1169, 1088, 1011 cmÀ1. MS (ESI) calcd for C11H15BrNO3S
[M + H]+ 319.9951, found 319.9944. Anal. calcd for C11H14BrNO3S: C,
41.26; H, 4.41; N, 4.37%. Found: C, 41.57; H, 4.22; N, 4.29%.
3-(Bromomethyl)-5-phenyl-2-tosylisoxazolidine (4b, Diastereomer
Mixtures): yield 97%, 96.1 mg. Data are for the major diastereomer: 1H
NMR (400 MHz, CDCl3) δ 2.25 (ddd, J = 12.6, 10.8, 7.8 Hz, 1H), 2.45
(s, 3H), 2.90 (ddd, J = 12.6, 7.8, 6.0 Hz, 1H), 3.51 (t, J = 10.1 Hz, 1H),
3.79 (dd, J = 10.1, 4.8 Hz, 1H), 4.58À4.68 (m, 1H), 5.14 (dd, J = 10.8,
6.0 Hz, 1H), 7.23À7.39 (m, 7H), 7.89 (d, J = 8.4 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ 21.7, 34.8, 42.5, 60.9, 83.7, 126.9 (2C), 128.7
(2C), 129.0, 129.3 (2C), 129.8 (2C), 132.5, 135.9, 145.4. IR (KBr) 1358,
1172, 1087, 1027, 1006 cmÀ1. MS (ESI) calcd for C17H18BrNNaO3S
[M + Na]+ 418.0083, found 418.0071. Anal. calcd for C17H18BrNO3S:
C, 51.52; H, 4.58; N, 3.53%. Found: C, 51.66; H, 4.54; N, 3.36%.
3-(Bromomethyl)-5-(4-methoxyphenyl)-2-tosylisoxazolidine (4c,
Diastereomer Mixtures): yield 90%, 95.9 mg. Data are for the major
1
diastereomer: H NMR (400 MHz, CDCl3) δ 2.24 (ddd, J = 12.8,
2-(Bromomethyl)-2-methyl-1-tosylpyrrolidine (2n): yield 90%, 74.8 mg.
1H NMR (400 MHz, CDCl3) δ 1.57 (s, 3H), 1.67À1.92 (m, 3H),
2.25À2.33 (m, 1H), 2.42 (s, 3H), 3.31À3.39 (m, 1H), 3.39À3.46 (m,
1H), 3.76 (d, J = 10.3 Hz, 1H), 3.86 (d, J = 10.3 Hz, 1H), 7.29 (d, J = 8.3 Hz,
2H), 7.76 (d, J = 8.3 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.5, 22.5,
24.0, 39.3, 41.0, 49.8, 67.3, 127.3 (2C), 129.5 (2C), 137.8, 143.1. IR (KBr)
1338, 1155, 1120, 1064, 1005 cmÀ1. MS (ESI) calcd for C13H19BrNO2S
[M + H]+ 332.0314, found 332.0309.
10.8, 8.0 Hz, 1H), 2.45 (s, 3H), 2.84 (ddd, J = 12.8, 7.8, 5.5 Hz, 1H),
3.52 (t, J = 10.4 Hz, 1H), 3.78 (s, 3H), 3.79 (dd, J = 10.4, 4.6 Hz, 1H),
4.57À4.68 (m, 1H), 5.06 (dd, J = 10.8, 5.5 Hz, 1H), 6.86 (d, J = 8.8 Hz,
2H), 7.22 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.88 (d, J =
8.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.7, 34.9, 42.2, 55.3,
61.0, 83.5, 114.0 (2C), 127.4, 128.5 (2C), 129.3 (2C), 129.8 (2C),
132.5, 145.3, 160.2. IR (KBr) 1517, 1356, 1254, 1166, 1030 cmÀ1. MS
(ESI) calcd for C18H21BrNO4S [M + H]+ 426.0369, found 426.0356.
3-(Bromomethyl)-2-tosyl-5-(4-(trifluoromethyl)phenyl)isoxazolidine
(4d, Diastereomer Mixtures): yield 91%, 105.6 mg. Data are for the major
diastereomer: 1H NMR (400 MHz, CDCl3) δ 2.22 (ddd, J = 12.8, 10.2,
8.9 Hz, 1H), 2.46 (s, 3H), 2.97 (ddd, J = 12.8, 8.0, 6.1 Hz, 1H), 3.49 (dd,
J = 10.2, 8.9 Hz, 1H), 3.76 (dd, J = 10.2, 4.6 Hz, 1H), 4.64À4.74 (m, 1H),
5.28 (dd, J = 10.5, 6.1 Hz, 1H), 7.37 (d, J = 8.2Hz, 2H), 7.42 (d, J = 8.2 Hz,
2H), 7.60 (d, J = 8.2 Hz, 2H), 7.88 (d, J = 8.2 Hz, 2H). 13C NMR (100
MHz, CDCl3) δ 21.7, 34.7, 42.7, 60.7, 82.7, 125.6 (d, J = 3.8 Hz, 2C),
127.0 (2C), 127.3, 129.3 (2C), 129.7 (d, J = 15.3 Hz), 129.9 (2C), 132.3,
140.3, 145.6. IR (KBr) 1363, 1332, 1168, 1124, 1036 cmÀ1. MS (ESI)
calcd for C18H18BrF3NO3S [M + H]+ 464.0137, found 464.0127.
3-(1-Bromoethyl)-5-(naphthalen-1-yl)-2-tosylisoxazolidine (4e, Dia-
stereomer Mixtures): yield 91%, 104.73 mg. Major-diastereomer: 1H
NMR (400 MHz, CDCl3) δ 0.66 (d, J = 7.3 Hz, 3H), 2.44 (s, 3H),
3.16À3.26 (m, 1H), 3.49 (dd, J= 11.4, 10.1Hz, 1H), 3.96(dd, J =10.1, 4.5
Hz, 1H), 4.52À4.60 (m, 1H), 5.53 (d, J = 4.5 Hz, 1H), 7.36 (d, J = 8.3 Hz,
2H), 7.40À7.53 (m, 4H), 7.56 (d, J = 7.3 Hz, 1H), 7.80 (d, J = 8.2 Hz,
1H), 7.87 (d, J = 8.4 Hz, 1H), 7.91 (d, J = 8.3 Hz, 2H). 13C NMR
(100 MHz, CDCl3) δ 8.2, 21.7, 29.8, 41.8, 65.5, 82.0, 121.9, 123.8, 125.1,
125.7, 126.3, 128.4, 129.0, 129.6 (3C), 129.8, 129.9 (2C), 131.3, 133.3,
145.5. Minor-diastereomer: 1H NMR (400 MHz, CDCl3) δ 1.23 (d, J =
6.6 Hz, 3H), 2.43 (s, 3H), 2.88À2.99 (m, 1H), 3.73- 3.88 (m, 2H), 4.32
(dt, J = 7.5, 4.1 Hz, 1H), 5.57 (d, J = 10.3 Hz, 1H), 7.33 (d, J = 8.0 Hz, 2H),
7.42À7.58 (m, 3H), 7.85 (t, J = 7.6 Hz, 2H), 7.93 (d, J = 8.4 Hz, 2H), 8.03
(d, J = 8.5 Hz, 1H), 8.11 (d, J = 8.5 Hz, 1H). 13C NMR (100 MHz,
CDCl3) δ 15.0, 21.7, 34.5, 48.1, 66.1, 85.9, 123.3, 125.1, 125.2, 125.9,
126.5, 128.8, 129.2 (2C), 129.8 (3C), 129.9, 131.9, 132.9, 133.8, 145.2. IR
(KBr) 1362, 1334, 1168, 1091, 1038 cmÀ1. MS (ESI) calcd for C22H23-
BrNO3S [M + H]+ 460.0577, found 460.0563.
(5S)-2-(Bromomethyl)-5-methyl-1-tosylpyrrolidine (2o, Diastereo-
1
mer Mixtures): yield >99%, 83.0 mg. Major-diastereomer: H NMR
(400 MHz, CDCl3) δ 1.14 (d, J = 6.4 Hz, 3H), 1.50À1.57 (m, 2H),
2.07À2.12 (m, 2H), 2.43 (s, 3H), 3.23 (t, J = 10.1 Hz, 1H), 3.90 (dd, J =
9.8, 3.3 Hz, 1H), 4.02À4.16 (m, 2H), 7.30 (d, J = 8.1 Hz, 2H), 7.75 (d,
J = 8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 20.5, 21.6, 27.8, 30.9,
34.6, 57.4, 60.6, 127.1 (2C), 129.7 (2C), 138.9, 143.3. Minor-diaster-
1
eomer: H NMR (400 MHz, CDCl3) δ 1.35 (d, J = 6.4 Hz, 3H),
1.58À1.74 (m, 2H), 2.02À2.20 (m, 2H), 2.44 (s, 3H), 3.33 (t, J = 10.8
Hz, 1H), 3.71 (q, J = 6.4 Hz, 1H), 3.80 (dd, J = 9.6, 3.2 Hz, 1H),
3.79À3.87 (m, 1H), 7.33 (d, J = 8.2 Hz, 2H), 7.73 (d, J = 8.2 Hz, 2H).
13C NMR (100 MHz, CDCl3) δ 21.6, 23.2, 28.9, 31.8, 36.4, 58.3, 62.1,
127.6 (2C), 129.9 (2C), 134.4, 143.8. IR (neat) 1340, 1157, 1095,
1040 cmÀ1. MS (ESI) calcd for C13H18BrNNaO2S [M + Na]+
354.0134, found 354.0125.
(5R)-2-(Bromomethyl)-5-isopropyl-1-tosylpyrrolidine (2p, Dia-
1
stereomer Mixtures): yield 93%, 83.8 mg. Major-diastereomer: H
NMR (400 MHz, CDCl3) δ 0.40 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 6.9
Hz, 3H), 1.23À1.34 (m, 1H), 1.60À1.72 (m, 1H), 1.72À1.85 (m,
1H), 1.85À2.00 (m, 1H), 2.00À2.10 (m, 1H), 2.42 (s, 3H), 3.28 (t,
J = 10.0 Hz, 1H), 3.85À3.89 (m, 1H), 4.03 (dd, J = 9.7, 2.2 Hz, 1H),
4.15À4.21 (m, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.73 (d, J = 8.1 Hz, 2H).
13C NMR (100 MHz, CDCl3) δ 15.2, 19.8, 21.5, 22.9, 29.3, 31.2,
34.6, 61.9, 65.7, 126.8 (2C), 129.5 (2C), 138.9, 143.1. Minor-
1
diastereomer: H NMR (400 MHz, CDCl3) δ 0.91 (d, J = 7.0 Hz,
3H), 0.99 (d, J = 7.0 Hz, 3H), 1.60À1.72 (m, 1H), 1.72À1.85 (m,
1H), 1.85À2.00 (m, 1H), 2.00À2.10 (m, 1H), 2.30À2.41 (m, 1H),
2.44 (s, 3H), 3.25 (t, J = 11.2 Hz, 1H), 3.41À3.47 (m, 1H),
3.76À3.84 (m, 2H), 7.34 (d, J = 8.1 Hz, 2H), 7.72 (d, J = 8.1 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ 17.4, 20.0, 21.5, 25.2, 28.9,
29.3, 35.9, 62.0, 68.1, 127.6 (2C), 129.8 (2C), 134.3, 143.7. IR
(KBr) 1330, 1214, 1154, 1096, 989 cmÀ1. MS (ESI) calcd for
C15H23BrNO2S [M + H]+ 360.0627, found 360.0620.
3-(Bromomethyl)-5-(4-chlorophenyl)-3-methyl-2-tosylisoxazolidine (4f,
Diastereomer Mixtures): yield 95%, 105.6 mg. Data are for the major
diastereomer: 1H NMR (400 MHz, CDCl3) δ 1.99 (s, 3H), 2.43 (s, 3H),
2.63 (dq, J= 12.8, 7.3 Hz, 2H), 3.61 (d, J= 10.5 Hz, 1H), 3.74 (d, J= 10.5 Hz,
7253
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The Journal of Organic Chemistry
NOTE
1H), 5.55 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 8.6 Hz, 2H), 7.26À7.34 (m,
4H), 7.85 (d, J = 8.6 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.7,
21.9, 41.4, 48.8, 70.8, 81.7, 128.0 (2C), 128.8 (4C), 129.5 (2C), 134.5,
135.1, 135.5, 144.8. IR (neat) 1494, 1333, 1161, 1092 cmÀ1. MS (ESI)
calcd for C18H20BrClNO3S [M + H]+ 444.0030, found 444.0018.
3-(Bromomethyl)-5-(thiophen-2-yl)-2-tosylisoxazolidine (4g, Dia-
stereomer Mixtures): yield 82%, 82.5 mg. Data are for the major
(s, 3H), 2.99 (t, J = 7.3 Hz, 2H), 4.96À5.08 (m, 2H), 5.80 (ddt, J = 17.2,
10.4, 6.6 Hz, 1H), 7.32 (d, J = 8.1 Hz, 2H), 7.66 (d, J = 8.1 Hz, 2H). 13
C
NMR (100 MHz, CDCl3) δ 21.5, 26.8, 30.6, 34.7, 49.6, 115.3, 127.4
(2C), 129.6 (2C), 134.4, 137.5, 143.2. IR (neat) 1460, 1341, 1160,
1091 cmÀ1. MS (ESI) calcd for C13H20NO2S [M + H]+ 254.1209, found
254.1201.
1
diastereomer: H NMR (400 MHz, CDCl3) δ 2.36 (ddd, J = 12.8,
’ ASSOCIATED CONTENT
9.8, 7.1 Hz, 1H), 2.45 (s, 3H), 2.97 (ddd, J = 12.8, 7.8, 6.3 Hz, 1H), 3.51
(t, J = 10.1 Hz, 1H), 3.77 (dd, J = 10.1, 4.9 Hz, 1H), 4.64À4.74 (m, 1H),
5.50 (dd, J = 9.8, 6.3 Hz, 1H), 6.97 (dd, J = 5.0, 3.6 Hz, 1H), 7.04À7.08
(m, 1H), 7.32 (dd, J = 5.0, 1.1 Hz, 1H), 7.36 (d, J = 8.1 Hz, 2H), 7.89 (d,
J = 8.1 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 21.7, 34.5, 42.4, 60.9,
79.4, 126.8, 126.9, 127.5, 129.3 (2C), 129.8 (2C), 132.4, 138.3, 145.4. IR
(KBr) 1354, 1326, 1169, 1092, 1032 cmÀ1. MS (ESI) calcd for C15H17-
BrNO3S2 [M + H]+ 401.9828, found 401.9817.
1
Supporting Information. H and 13C NMR spectra of
S
b
products in the intramolecular bromo-amination and in a me-
chanical study for intramolecular bromo-amination. Thismaterial
is available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
3-(Bromomethyl)-5-butyl-2-tosylisoxazolidine (4h, Diastereo-
mer Mixtures): yield 98%, 92.2 mg. Data are for the major diastereomer:
1H NMR (400 MHz, CDCl3) δ 0.87 (t, J = 7.0 Hz, 3H), 1.16À1.37 (m,
4H), 1.41À1.69 (m, 2H), 1.79 (ddd, J = 12.5, 10.2, 7.8 Hz, 1H), 2.46 (s,
3H), 2.59 (ddd, J = 12.5, 7.8, 5.5 Hz, 1H), 3.38 (t, J = 9.7 Hz, 1H), 3.71
(dd, J = 10.2, 4.6 Hz, 1H), 3.98À4.07 (m, 1H), 4.37À4.48 (m, 1H), 7.36
(d, J = 8.5 Hz, 2H), 7.85 (d, J = 8.5 Hz, 2H). 13C NMR (100 MHz,
CDCl3) δ 13.8, 21.7, 22.4, 28.1, 32.2, 34.9, 40.4, 60.7, 82.4, 129.2 (2C),
Corresponding Authors
*Email: moriyama@faculty.chiba-u.jp; togo@faculty.chiba-u.jp.
’ ACKNOWLEDGMENT
Financial support in the form of a Grant-in-Aid for Scientific
Research (No. 20550033) from the Ministry of Education, Culture,
Sports, Science and Technology, Japan, the Iodine Research Project
in Chiba University, and the Eisai Award in Synthetic Organic
Chemistry, Japan (K.M.) is gratefully acknowledged.
129.8 (2C), 132.5, 145.2. IR (neat) 1454, 1360, 1167, 1091, 1017 cmÀ1
.
MS (ESI) calcd for C15H23BrNO3S [M + H]+ 376.0577, found 376.0565.
Mechanical Study for Oxidative Intramolecular Bromo-ami-
nation of N-Alkenyl Sulfonamides via Umpolung of Alkali
Metal Bromides (Scheme 3).22 N-Bromination of N-pentyl-tosyla-
mide (5) via Oxidative Umpolung of KBr (eq 1): To a solution of 5(60.3mg,
0.25 mmol) and Oxone (184.4 mg, 0.30 mmol) in acetonitrile (1 mL) was
added KBr (35.7 mg, 0.30 mmol) under argon atmosphere. The solution was
stirred at room temperature for 15 h. Saturated NaHCO3 aqueous solution
(10 mL) was poured into the reaction mixture, and the product was extracted
with AcOEt (15 mL Â 3). The combined extracts were washed by brine
(10 mL) and dried over Na2SO4. The organic phase was concentrated under
reduced pressure, and the residue was the pure desired product 6 (70.7 mg,
88% yield) without further purification.
’ REFERENCES
(1) For recent contributions to intramolecular halo-amination, see
the following selected samples: (a) Jones, A. D.; Knight, D. W.; Hibbs,
D. E. J. Chem. Soc., Perkin Trans. 1 2001, 1182–1203. (b) Mccormick,
J. L.; Osterman, R.; Chan, T.-M.; Das, P. R.; Pramanik, B. N.; Ganguly,
A. K.; Girijavallabhan, V. M.; McPhail, A. T.; Saksena, A. K. Tetrahedron
Lett. 2003, 44, 7997–8000. (c) Minakata, S.; Morino, Y.; Oderaotoshi,
Y.; Komatsu, M. Org. Lett. 2006, 8, 3335–3337. (d) Marcotullio, M. C.;
Campagna, V.; Sternativo, S.; Costantino, F.; Curini, M. Synthesis
2006, 2760–2766. (e) Michael, F. E.; Sibbald, P. A.; Cochran, B. M.
Org. Lett. 2008, 10, 793–796. (f) Davies, S. G.; Nicholson, R.; Price,
P. D.; Roberts, P. M.; Russell, A. J.; Savory, E. D.; Smith, A. D.; Thomson,
J. E. Tetrahedron: Asymmetry 2009, 20, 758–772. (g) Majumdar, K. C.;
Ray, K.; Ponra, S. Tetrahedron Lett. 2010, 51, 5437–5439.
(2) For a review, see: O’Hagan, D. Nat. Prod. Rep. 2000, 17, 435–446.
(3) (a) Gribble, G. W. Chemosphere 2003, 52, 289–297. (b) Butler, A.;
Carter-Franklin, J. N. Nat. Prod. Rep. 2004, 21, 180–188. (c) Neumann,
C. S.; Fujimori, D. G.; Walsh, C. T. Chem. Biol. 2008, 15, 99–109.
(4) Runguphan, W.; Qu, X.; O’Connor, S. E. Nature 2010, 468,
461–464.
N-Pentyl-tosylamide (5): 1H NMR (400 MHz, CDCl3) δ 0.83 (t, J =
6.9 Hz, 3H), 1.18À1.28 (m, 4H), 1.41À1.49 (m, 2H), 2.43 (s, 3H), 2.91
(q, J = 6.9 Hz, 2H), 4.71 (brd, J = 5.0 Hz, 1H), 7.31 (d, J = 8.2 Hz, 2H),
7.76 (d, J = 8.2 Hz, 2H). 13C NMR (100 MHz, CDCl3) δ 13.8, 21.5,
22.1, 28.6, 29.1, 43.1, 127.0 (2C), 129.6 (2C), 136.9, 143.3. IR (neat)
3281, 1425, 1325, 1160, 1094 cmÀ1. MS (ESI) calcd for C12H20NO2S
[M + H]+ 242.1209, found 242.1201.
1
N-Bromo-N-pentyl-tosylamide (6): H NMR (400 MHz, CDCl3)
δ 0.90 (t, J = 7.1 Hz, 3H), 1.28À1.37 (m, 4H), 1.58À1.68 (m, 2H), 2.47
(s, 3H), 3.14 (t, J = 7.1 Hz, 2H), 7.38 (d, J = 8.2 Hz, 2H), 7.83 (d, J = 8.2 Hz,
2H). 13C NMR (100 MHz, CDCl3) δ 13.9, 21.7, 22.1, 27.8, 28.0, 57.8, 129.4
(2C), 129.5 (2C), 130.6, 144.9. IR (neat) 1441, 1354, 1166, 1089 cmÀ1. MS
(ESI) calcd for C12H19BrNO2S [M + H]+ 320.0314, found 320.0304.
General Procedure for the Competitive Bromination of N-Sulfona-
mides (eq 2): To a solution of 5 (60.3 mg, 0.25 mmol), 7 (63.3 mg,
0.25 mmol) and Oxone (184.4 mg, 0.30 mmol) in acetonitrile (1 mL)
was added KBr (35.7 mg, 0.30 mmol) under argon atmosphere. The
solution was stirred at room temperature for 15 h. Saturated NaHCO3
aqueous solution (10 mL) was poured into the reaction mixture, and the
product was extracted with AcOEt (15 mL Â 3). The combined extracts
were washed by brine (10 mL) and dried over Na2SO4. The organic
phase was concentrated under reduced pressure, and the residue was a
mixture of products 5 (48.5 mg, 80% yield), 7 (1.4 mg, 2% yield), and
unknown products, yield (%) of which was estimated by 1H NMR analysis.
(5) Qi, X.; Lee, S.-H.; Kwon, J. Y.; Kim, Y.; Kim, S.-H.; Lee, Y.-S.;
Yoon, J. J. Org. Chem. 2003, 68, 9140–9143.
(6) Thakur, V. V.; Talluri, S. K.; Sudalai, A. Org. Lett. 2003, 5,
861–864.
(7) (a) Manzoni, M. R.; Zabawa, T. P.; Kasi, D.; Chemler, S. R.
Organometallics 2004, 23, 5618–5621. (b) Jiang, F.; Wu, Z.; Zhang, W.
Tetrahedron 2011, 67, 1501–1505.
(8) (a) Jonasson, C.; Karstens, W. F. J.; Hiemstra, H.; B€ackvall, J.-E.
Tetrahedron Lett. 2000, 41, 1619–1622. (b) Jonasson, C.; Horvꢀath, A.;
B€ackvall, J.-E. J. Am. Chem. Soc. 2000, 122, 9600–9609.
(9) (a) Sakakura, A.; Ukai, K.; Ishihara, K. Nature2007, 445, 900–903.
(b) Tanuwidjaja, J.; Ng, S.-S.; Jamison, T. F. J. Am. Chem. Soc. 2009,
131, 12084–12085. (c) Zhou, L.; Tan, C. K.; Yeung, Y.-Y. J. Am. Chem. Soc.
2010, 132, 10245–10247. (d) Zhou, L.; Tan, C. K.; Jiang, X.; Chen, F.;
Yeung, Y.-Y. J. Am. Chem. Soc. 2010, 132, 15474–15476.
(10) Murai, K.; Matsushita, T.; Nakamura, A.; Fukushima, S.; Shimura,
M.; Fujioka, H. Angew. Chem., Int. Ed. 2010, 49, 9174–9177.
(11) Tanaka, A.; Oritani, T. Biosci. Biotech. Biochem. 1995, 59, 516–517.
1
N-Methyl-N-(4-penten-1-yl)-tosylamide (7). H NMR (400 MHz,
CDCl3) δ 1.58À1.68 (m, 2H), 2.06À2.14 (m, 2H), 2.43 (s, 3H), 2.71
7254
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The Journal of Organic Chemistry
NOTE
(12) Snyder, S. A.; Treitler, D. S. Angew. Chem., Int. Ed. 2009, 48,
7899–7903.
(13) For reviews, see: (a) Eissen, M.; Lenoir, D. Chem.—Eur. J. 2008,
14, 9830–9841. (b) Podgorsek, A.; Zupan, M.; Iskra, J. Angew. Chem., Int.
Ed. 2009, 48, 8424–8450.
(14) (a) Tamaru, Y.; Kawamura, S.; Tanaka, K.; Yoshida, Z. Tetrahedron
Lett. 1984,25,1063–1066. (b) Tamaru, Y.; Kawamura, S.; Bando, T.; Tanaka,
K.; Hojo, M.; Yoshida, Z. J. Org. Chem. 1988, 53, 5491–5501. (c) Breternitz,
H.-J.; Schaumann, E. J. Chem. Soc., Perkin Trans. 1 1999, 1927–1931.
(d) Fujioka, H.; Murai, K.; Ohba, Y.; Hirose, H.; Kita, Y. Chem. Commun.
2006, 832–834.
(15) (a) Kumar, K. R. R.; Mallesha, H.; Basappa; Rangappa, K. S.
Eur. J. Med. Chem. 2003, 38, 613–619. (b) Minter, A. R.; Brennan, B. B.;
Mapp, A. K. J. Am. Chem. Soc. 2004, 126, 10504–10505. (c) Ishiyama,
H.; Tsuda, M.; Endo, T.; Kobayashi, J. Molecules 2005, 10, 312–316.
(d) Pouilhꢁes, A.; Amado, A. F.; Vidal, A.; Langlois, Y.; Kouklovsky, C.
Org. Biomol. Chem. 2008, 6, 1502–1510.
(16) (a) Frederickson, M. Tetrahedron 1997, 53, 403–425. (b) Cicchi,
S.; Goti, A.; Brandi, A.; Guarna, A.; Sarlo, F. D. Tetrahedron Lett. 1990,
31, 3351–3354.
(17) Murahashi, S.; Kodera, Y.; Hosomi, T. Tetrahedron Lett. 1988,
29, 5949–5952.
(18) Hanselmann, R.; Zhou, J.; Ma, P.; Confalone, P. N. J. Org. Chem.
2003, 68, 8739–8741.
(19) Piperno, A.; Chiacchio, U.; Iannazzo, D.; Giofrꢁe, S. V.; Romeo,
G.; Romeo, R. J. Org. Chem. 2007, 72, 3958–3960.
(20) For reviews, see: (a) Gothelf, K. V.; Jørgensen, K. A. Chem. Rev.
1998, 98, 863–910. (b) Gothelf, K. V.; Jørgensen, K. A. Chem. Commun.
2000, 1449–1458.
(21) For recent contributions to the Pd-catalyzed cyclization, see the
following selected samples: (a) Peng, J.; Jiang, D.; Lin, W.; Chen, Y. Org.
Biomol. Chem. 2007, 5, 1391–1396. (b) Peng, J.; Lin, W.; Yuan, S.;
Chen, Y. J. Org. Chem. 2007, 72, 3145–3148. (c) Hay, M. B.; Wolfe, J. P.
Angew. Chem., Int. Ed. 2007, 46, 6492–6494. (d) Jiang, D.; Peng, J.;
Chen, Y. Tetrahedron 2008, 64, 1641–1647. (e) Lemen, G. S.; Giampietro,
N. C.; Hay, M. B.; Wolfe, J. P. J. Org. Chem. 2009, 74, 2533–2540.
(22) To explain the reaction mechanism for oxidative intramolecular
bromo-amination of N-alkenyl sulfonamides via umpolung of alkali metal
bromides with Oxone, we investigated the competitive bromination of
sulfonamides. First, the treatment of N-pentyl-tosylamide (5) with KBr
and Oxone gave N-bromo-N-pentyl-tosylamide (6) in 88% yield (eq 1).
When a mixture of 5 and N-methyl-N-(4-penten-1-yl)-tosylamide
(7) were treated with KBr and Oxone in MeCN, 7 was predominantly
converted into some of unknown products (20% consumption of 5 and
98% consumption of 7) (eq 2). Moreover, the brominative conversion of
7 with 6 was much less effective than the reaction in eq 2 with KBr and
Oxone (27% consumption of 7) (eq 2 vs eq 3). These results indicate
indirectly that the oxidative bromination preferentially occurs in the olefin
moiety not in the sulfonamide nitrogen of substrate.
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