Approach to the synthesis of indoline derivatives from diaryliodonium salts

Article abstract of DOI:10.1021/jo300874m

An effective method of constructing the indoline moiety via intramolecular nucleophilic ring closure of a diaryliodonium salt is described. Diacetoxyiodoarene compounds (1a-1e) were converted into intermediate Koser's reagent and coupled with arylstannanes (7-10) to form diaryliodonium salts (11a-14e). Indoline compounds with different N-protecting groups, 15, 16, 17, and 18, were synthesized in higher yields by treating salts (11a-14e) with Cs₂CO₃ and TEMPO. Regardless of the electronic environment of five para-substituted iodoarenes and the natures of four N-protected arylstannane groups, the conversion proceeded well to afford corresponding indolines in yields of 72-84 and 70-84%, respectively.

Full text of DOI:10.1021/jo300874m

Article
pubs.acs.org/joc
Approach to the Synthesis of Indoline Derivatives from
Diaryliodonium Salts
Kamalkishor P. Landge, Keun Sam Jang, Sang Yeul Lee, and Dae Yoon Chi*
Department of Chemistry, Sogang University, 35 Baekbeomro Mapogu, Seoul 121-742, Republic of Korea
S
* Supporting Information
ABSTRACT: An effective method of constructing the
indoline moiety via intramolecular nucleophilic ring closure
of a diaryliodonium salt is described. Diacetoxyiodoarene
compounds (1a−1e) were converted into intermediate Koser’s
reagent and coupled with arylstannanes (7−10) to form
diaryliodonium salts (11a−14e). Indoline compounds with
different N-protecting groups, 15, 16, 17, and 18, were
synthesized in higher yields by treating salts (11a−14e) with Cs2CO3 and TEMPO. Regardless of the electronic environment of
five para-substituted iodoarenes and the natures of four N-protected arylstannane groups, the conversion proceeded well to
afford corresponding indolines in yields of 72−84 and 70−84%, respectively.
The chiral indolines (S)-indoline-2-carboxylic acid or ester12
INTRODUCTION
■
are important chiral auxiliaries, chiral catalysts, and heterocyclic
alkaloid natural products,13 especially when added to the
pharmacophore of a natural product. Kuwano and Kashiwabara
synthesized (S)-indoline-2-carboxylic acid via the cyclization of
2-substituted or N-substituted anilines using metal-catalyzed,
radical, and/or asymmetric processes.14 Furthermore, the
ruthenium-catalyzed asymmetric enantioselective hydrogenation
of N-protected indoles was found to proceed to chiral indolines
with high enantiomeric excesses. Recently, N-acyl indoline was
prepared via unique one-pot cyclization of 2-aminophenethyl
alcohol with carboxylic acids in the presence of PPh3, CCl4, and
NEt3 without metal.15 A metal-free approach to the synthesis of
indoline was also employed by Correa et al. in 2006.16 In
addition, the Cu-catalyzed C−N bond formation of diary-
liodonium salts17 and the hypervalent iodine reagent18 by
nucleophilic amination have been explored.
Indoline frameworks are an important part in numerous
biologically active natural and non-natural products1 and as
organic dyes for dye-sensitized solar cells.2 N-Protected indolines
have been synthesized using different strategies (Figure 1), such
Herein, we describe a novel method of constructing the
indoline core by metal-free intramolecular nucleophilic ring
closing of diaryliodonium salts. Although aryliodonium salts
exhibit a strong withdrawing effect at the C−I+ bond,19 metal-
free nucleophilic indoline synthesis from a diaryliodonium salt
has not been reported previously. Accordingly, we systematically
explored the feasibility of this intramolecular coupling reaction
and sought to determine its scope and limitations. Initially, we
envisaged that an indoline moiety could be constructed by an
intramolecular nucleophilic ring closure from the corresponding
diaryliodonium salt without a metal catalyst (Figure 2).
Figure 1. Strategies used to synthesize indolines.
as via the Pd- or Cu-catalyzed cyclization of amine, amide, or
carbamate,3 the radical cyclization of O-bromophenethylamine4
(type A), Pd-catalyzed intermolecular 1,2-carboamination from
N-aryl ureas and 1,3-dienes (type B),5 Pd-catalyzed domino
amidation from O-triflyloxy phenethyl carbonates using amide
(type C),6 Pd-catalyzed C−C/C−N coupling of bromoalkyl-
amines (type D),7 intramolecular Diels−Alder reaction of
2-aminofurans (type E),8 and the Pd-catalyzed C−H activation
of arylethylamines (type F).9 A more versatile route for the
synthesis of indoline was reported via aryne annulation10 and via
solid-phase organic synthesis (SPOS) using selenenyl bromide
resin.11
Intramolecular aromatic nucleophilic substitution could
proceed via two routes (a or b). The reaction through route a
provides the desired indoline product via a 5-membered
transition state, whereas route b would result in the acyclic
Received: May 1, 2012
Published: June 6, 2012
© 2012 American Chemical Society
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a
Scheme 2. Synthesis of Organostannane Intermediates
Figure 2. The envisioned synthetic route.
compound via a 7-membered transition state. However, because
the 5-membered transition state is preferred, indoline products
are expected to be formed exclusively.20
RESULTS AND DISCUSSION
■
Heterodiaryliodonium salts can be prepared in different ways.
We chose to adopt a method based on coupling between
arylstannanes and (diacetoxy)iodoarenes. To optimize this
coupling reaction, diacetoxyiodoarenes with different para-
substituents, 1a, 1b, 1c, 1d, and 1e, were chosen. These were
prepared by the oxidative acetoxylation of iodoarenes using
sodium periodate in the presence of sodium acetate and acetic
anhydride in acetic acid at 120 °C for 2 h (Scheme 1).21
a
(a) PBr3, THF, 0 °C, 30 min, 98%; (b) NaCN, EtOH, reflux, 4 h,
88%; (c) BH3−THF, THF, reflux, 1 h, 65%; (d) for 6a, (Boc)2O,
Et3N, MeOH/THF (1:1), 80 °C, 1 h; for 6b, Cbz-Cl, Et3N, MeOH/
THF (1:1), rt, 1 h; for 6c, AcCl, Et3N, MeOH/THF (1:1), rt, 1 h; for
6d, diethylcarbamoyl chloride, Et3N, DMF, rt, 8 h; (e) Pd(PPh3)4,
Sn2Me6, toluene, N2, 120 °C, 1 h.
a
Scheme 1. Synthesis of Diacetoxyiodoarene Compounds
a
Table 1. Synthesis of Diaryliodonium Salts (11−14)
a
(a) NaIO4, NaOAc, glacial AcOH, Ac2O, 120 °C, 2 h.
The synthesis of the arylstannane intermediates began with the
bromination of commercially available 2-iodobenzyl alcohol (2)
with PBr3 at 0 °C in THF to afford 2-iodobenzyl bromide (3) at a
yield of 98% (Scheme 2). Compound 3 was treated with NaCN
and heated to reflux for 4 h in ethanol to provide 2-iodobenzyl
acetonitrile (4) at a yield of 88%. The reduction of compound 4
with BH3−THF complex followed by acidification with hydro-
gen chloride afforded 2-iodobenzyl amine hydrochloride (5).
The amino functionality of 5 was protected with Boc, Cbz, Ac,
and CONEt2 to provide 2-iodobenzyl amines 6a, 6b, 6c, and 6d
at yield of 99, 96, 89, and 92%, respectively. Treating compounds
6a, 6b, 6c, and 6d with Sn2Me6 and heating at 120 °C for 1 h in
the presence of Pd(PPh3)4 afforded the desired arylstannanes 7,
8, 9, and 10 at yields of 84, 86, 76, and 78%, respectively.
The formation of diaryliodonium salts (11−14) from various
organostannanes and diacetoxyiodoarenes were compared using
the same reaction condition (Table 1).22 First, diacetoxyiodoarene
compounds were then converted to intermediate Koser’s reagent
derivatives with p-TsOH·H2O, which were coupled with
arylstannanes, to afford corresponding diaryliodonium salts
(11a−14e). In short, all conversions proceeded efficiently to
provide desired products in reasonable yields (65−75%)
regardless of the electronic environments of the para-
substituents on the diacetoxyiodoarenes and the nature of the
arylstannane N-protecting group.
b
entry
SM
R1
Boc
R2
product
yield (%)
1
7
7
F
11a
11b
11c
11d
11e
12a
12b
12c
12d
12e
13a
13b
13c
13d
13e
14a
14b
14c
14d
14e
70
72
65
75
67
70
75
72
67
70
70
73
68
72
65
73
69
72
68
74
2
Boc
Cl
3
7
Boc
Br
4
7
Boc
OCH3
CH3
F
5
7
Boc
6
8
Cbz
7
8
Cbz
Cl
8
8
Cbz
Br
9
8
Cbz
OCH3
CH3
F
10
11
12
13
14
15
16
17
18
19
20
8
Cbz
9
Ac
9
Ac
Cl
9
Ac
Br
9
Ac
OCH3
CH3
F
9
Ac
10
10
10
10
10
CONEt2
CONEt2
CONEt2
CONEt2
CONEt2
Cl
Br
OCH3
CH3
a
(a) (i) 1a−e, p-TsOH·H2O, CH3CN/CH2Cl2, rt, N2, 1 h; (ii) 7−10,
CH2Cl2, rt, 24 h All reactions were carried out on a 0.5 mmol scale of
precursor.
b
To find the optimal nucleophilic ring closing conditions, we
chose a series of diaryliodonium salts that consisted of one fixed
aryl group (2-(2-N-Boc-aminoethyl)phenyl) and one variable
counterpart (various para-substituted phenyl, 11a−11e) as
model precursors for the N-Boc-indoline 15 (Table 2). First,
compound 11a was subjected to various reaction conditions to
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The optimal conditions used to form 15 from 11a were
extended to diaryliodonium salts with different N-protecting
groups, such as 12a, 13a, and 14a, and afforded the
corresponding N-protected indoline 16, 17, and 18 in yields of
roughly 70% (Table 3). Diaryliodonium salts with a carbamate
Table 2. Optimization of Reaction Conditions for the
Synthesis of Indoline from Diaryliodonium Salts
a
Table 3. Synthesis of Indoline from Diaryliodonium Salts with
Different N-Protecting Groups
b
entry
SM
conditions
time (h) temp (°C) yield (%)
1
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11a
11b
11c
11d
11e
Cs2CO3, DMF
Cs2CO3, DMF
Cs2CO3, DMF
Cs2CO3, DMF
Cs2CO3, DMF
Cs2CO3, DMF
Cs2CO3, DMF
Cs2CO3, DMF/H2O
Cs2CO3, TFE
Cs2CO3, CH3CN
K2CO3, DMF
Na2CO3, DMF
DBU, DMF
0.5
0.5
3
rt
80
rt
56
73
62
84
30
65
84
25
23
73
62
67
42
80
76
72
74
2
3
4
1
80
80
rt
c
5
1
entry
R3
Boc
SM
product
yield (%)
6
24
1
2
3
4
11a
12a
13a
14a
15
16
17
18
84
80
72
70
7
24
24
24
24
3
80
rt
Cbz
d
d
8
Ac
9
80
80
80
80
80
80
80
80
80
CONEt2
10
11
12
13
14
15
16
17
3
3
protecting group (Table 3, entries 1 and 2) afforded yields similar
to 11a, but salts with acetyl or urea protecting group provided
lower yields (Table 3, entries 3 and 4).
Cs2CO3, DMF
Cs2CO3, DMF
Cs2CO3, DMF
Cs2CO3, DMF
1
1
1
1
CONCLUSION
a
■
Reactions were carried out using 0.5 mmol scale of precursor with
3.0 equiv of base in 1.0 mL of solvent in the presence of 0.1 equiv of
We described a simple and effective means of synthesizing the
indoline moiety from diaryliodonium salts. In particular, N-Boc-
indoline (15) was obtained in 84% yield from (2-N-Boc-
aminoethylphenyl)(4-fluorophenyl)iodonium p-toluenesulfo-
nate (11a) in the presence of 0.1 equiv of TEMPO and
3.0 equiv of Cs2CO3 at 80 °C in DMF for 1 h. Other N-protected
indolines 16, 17, and 18 were synthesized under optimized
conditions at yields of 80, 72 and 70%, respectively.
b
c
TEMPO. Isolated yields. Reaction carried out without TEMPO.
d
Determined by NMR yield.
produce 15 (Table 2, entries 1−13). Since the free radical
decomposition of iodonium salts is known to inhibit the reaction,
TEMPO was added as a radical scavenger.23 Initially, compound
11a was treated with 3.0 equiv of Cs2CO3 and 0.1 equiv of
TEMPO in DMF at rt and stirred for 30 min to afford 15 in a
yield of 56% (Table 2, entry 1). When the reaction time was
extended to 3 h, the yield was increased to 62% (Table 2,
entry 3), but prolonged reaction did not have much beneficial
effect (24 h, 65%; Table 2, entry 6). When the reaction was
performed at a higher temperature (80 °C for 30 min), 15 was
obtained at a yield of 73% (Table 2, entry 2), and when the
reaction time was extended to 1 h, the yield increased (84%;
Table 2, entry 4). However, longer reaction times did not
improve yields (24 h, 84%; Table 2, entry 7). To enhance the
solubilities of diaryliodonium salts, water was added as a
cosolvent, but running the reaction in a 50% aqueous DMF
system resulted in a poor yield (25%; Table 2, entry 8) and the
presence of unreacted 11a. Other solvents, that is, 2,2,2-
trifluoroethanol and CH3CN (Table 2, entries 9 and 10), and
other bases, K2CO3, Na2CO3, and DBU, were also examined
(Table 2, entries 11−13), but yields were not improved.
Other diaryliodonium salts, 11b, 11c, 11d, and 11e, were
also reacted under the optimal conditions (80 °C, 1 h) to
produce 15 in yields of 80, 76, 72, and 74%, respectively
(Table 2, entries 14−16). When the reaction was run
without TEMPO, desired product 15 was formed much less
(30%), and some unreacted starting material 11a remained
(Table 2, entry 5).
EXPERIMENTAL SECTION
■
General Procedure for Preparing Diacetoxyiodoarenes from
Iodoarene.21 A stirred suspension of NaIO4 (2.20 g, 10.3 mmol)
and AcONa (1.80 g, 22.0 mmol) in glacial AcOH (15 mL) and
Ac2O (1.5 mL) at rt was treated with the appropriate iodoarene
(10.0 mmol). The reaction mixture was refluxed for the designated
period. The reaction mixture was then poured into water (50 mL).
The resulting mixture was filtered, and the residue was washed
with 10% aq AcOH (2 × 10 mL) and dried under a stream of air.
The remaining product was extracted from the filtrate with DCM
and concentrated on rotary evaporator. Hexane was added to the
obtained residue to collect the solid product. The product was
filtered and washed with excess of hexane to provide correspond-
ing iodoarene.
1-Diacetoxyiodo-4-fluorobenzene (1a).
1
White solid (2.38 g, 70%): mp 179−181 °C; H NMR (400 MHz,
CDCl3) δ 1.99 (s, 6 H), 7.14−7.25 (m, 2 H), 8.05−8.08 (m, 2 H); 13
C
NMR (100 MHz, CDCl3) δ 20.3, 115.5, 118.5 (d, J = 22.7 Hz), 137.5 (d,
J = 9.1 Hz), 164.3 (d, J = 252.4 Hz), 176.4. CAS registry number:
16308−15−9.
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1-Diacetoxyiodo-4-chlorobenzene (1b).
Article
1
(4.00 g, 88%) as a colorless oil: H NMR (400 MHz, CDCl3) δ 3.81
(s, 2H), 7.01−7.06 (m, 1H), 7.37−7.41 (m, 1H), 7.51−7.54 (m, 1H),
7.85 (d, J = 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 29.9, 99.0,
117.1, 128.99, 129.04, 129.8, 133.2, 139.8; MS ESI(GC) m/z 243 (M+,
100). Anal. Calcd. For C8H6IN: C, 39.53; H, 2.49; N, 5.76. Found: C,
39.58; H, 2.48; N, 5.88.
White solid (2.31 g, 65%): mp 112−115 °C (lit.24 109.8−113.2 °C); 1H
NMR (400 MHz, CDCl3) δ 1.99 (s, 6 H), 7.44 (d, J = 8.4 Hz, 2 H), 8.00
(d, J = 8.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 20.3, 118.8, 131.2,
136.3, 138.4, 176.4. CAS registry number: 6973−73−5.
2-(2-Iodophenyl)ethylamine Hydrochloride (5).
1-Diacetoxyiodo-4-bromobenzene (1c).
A stirred solution of 4 (3.04 g, 12.5 mmol) in anhydrous THF (12 mL)
under Ar was treated with a solution of BH3 in THF (1.0 M, 30 mL).
The reaction mixture was refluxed for 1 h and then concentrated under
reduced pressure. The residue was treated with ice-cold solution of HCl
in CH3OH (1.0 N, 20 mL), allowed to stand at 0 °C for 2 h, and filtered.
The residue was washed with MeOH and dried under reduced pressure
to afford the HCl salt 5 (2.30 g, 65%) as a white solid: mp 262−264 °C;
1H NMR (400 MHz, DMSO-d6) δ 2.98−3.38 (m, 4H), 6.99−7.40 (m,
1H), 7.34−7.38 (m, 2H), 7.85 (d, J = 7.6 Hz, 1H), 8.35 (br s, 3H); 13C
NMR (100 MHz, DMSO-d6) δ 38.1, 39.0, 101.2, 129.3, 129.5, 130.4, 139.8,
140.5; MS ESI m/z 284 (M+), 231 (100). Anal. Calcd. For C8H11ClIN: C,
33.89; H, 3.91; N, 4.94. Found: C, 33.83; H, 3.92; N, 4.99.
1
White solid (2.00 g, 50%): mp 120−122 °C; H NMR (400 MHz,
CDCl3) δ 1.99 (s, 6 H), 7.59 (d, J = 8.4 Hz, 2 H), 7.92 (d, J = 8.4 Hz,
2 H); 13C NMR (100 MHz, CDCl3) δ 20.2 119.6, 126.7, 134.1, 136.4,
176.4. CAS registry number: 41018−52−4.
4-Diacetoxyiodoanisole (1d).25
t-Butyl 2-Iodophenethylcarbamate (6a).
A stirred solution of 5 (1.00 g, 3.5 mmol) in 1:1 MeOH−THF (10 mL)
was treated with Boc2O (0.8 mL, 3.9 mmol) and Et3N (0.7 mL,
5.3 mmol). The reaction mixture was refluxed for 1 h and then
concentrated under reduced pressure. The residue was dissolved in
EtOAc (100 mL), washed with water and saturated aq NaCl, dried over
Na2SO4, and concentrated under reduced pressure. Flash column
chromatography (SiO2, 30% EtOAc/hexanes) provided 6a (1.3 g, 99%)
White solid (2.56 g, 73%): mp 93−96 °C (lit.24 92.4−96.0 °C; lit.°C); 1H
NMR (200 MHz, CDCl3) δ 1.98 (s, 6H), 3.84 (s, 3H), 6.95 (d, J =
9.2 Hz, 2H), 8.00 (d, J = 9.2 Hz, 2H); 13C NMR (50 MHz, CDCl3) δ 20.6,
29.5, 104.2, 127.9, 137.3, 141.7, 175.9. CAS registry number: 16308−14−8.
1-Diacetoxyiodo-4-methylbenzene (1e).
1
as a white solid: mp 73−76 °C; H NMR (400 MHz, CDCl3) δ 1.44
(s, 9H), 2.91 (t, J = 7.2 Hz, 2H), 3.34−3.36 (m, 2H), 4.59 (s, 1H), 6.87−
6.92 (m, 1H), 7.18−7.28 (m, 2H), 7.79 (d, J = 8.0 Hz, 1H); 13C NMR
(50 MHz, CDCl3) δ 28.4, 40.4, 40.8, 79.2, 100.6, 128.2, 128.4, 130.1, 139.5,
141.6, 155.8; MS ESI m/z 370 ([M + Na]+, 100). Anal. Calcd. For
C13H18INO2: C, 44.97; H, 5.23; N, 4.03. Found: C, 44.96; H, 5.14; N, 4.15.
White solid (2.65 g, 79%): mp 108−110 °C (lit.24 106−110 °C); 1H NMR
(400 MHz, CDCl3) δ 1.99 (s, 6 H), 2.43 (s, 3H), 7.28 (d, J = 8.4 Hz, 2 H),
7.96 (d, J = 8.4 Hz, 2 H); 13C NMR (125 MHz, CDCl3) δ 20.5, 21.7, 118.5,
131.9, 135.1, 142.8, 176.5. CAS registry number: 16308−16−0.
Benzyl 2-(2-Iodophenyl)ethylcarbamate (6b).
2-Iodobenzyl Bromide (3).
A stirred solution of 5 (1.00 g, 3.5 mmol) in 1:1 MeOH−THF (10 mL)
was treated with Cbz−Cl (0.6 mL, 3.8 mmol) and Et3N (0.7 mL,
5.3 mmol). The reaction mixture was stirred at rt for 1 h and then
concentrated under reduced pressure. The residue was dissolved in
EtOAc (100 mL), washed with water and saturated aq NaCl, dried
(Na2SO4), and concentrated under reduced pressure. Flash column
chromatography (SiO2, 30% EtOAc/hexanes) provided 6b (1.28 g,
96%) as a white solid: mp 75−77 °C; 1H NMR (400 MHz, CDCl3) δ
2.86 (t, J = 6.9 Hz, 2H), 3.33−3.39 (m, 2H), 4.74 (s, 1H), 5.01 (s, 2H),
6.81 (t, J = 7.4 Hz, 1H), 7.08−7.26 (m, 7H), 7.72 (d, J = 7.6 Hz, 1H); 13C
NMR (125 MHz, CDCl3) δ 40.8, 41.1, 66.8, 100.7, 128.23, 128.24,
128.51, 128.59, 128.62, 130.2, 136.7, 139.8, 141.5, 156.4; MS ESI m/z
404 ([M + Na]+, 100). Anal. Calcd. For C16H16INO2: C, 50.41; H, 4.23;
N, 3.67. Found: C, 50.48; H, 4.18; N, 3.79.
A stirred sample of commercially available 2-iodobenzyl alcohol 2
(5.00 g, 21.4 mmol) in THF (25 mL) at 0 °C under Ar was treated with
PBr3 (1.2 mL, 12.8 mmol). The reaction mixture was stirred at 0 °C for
30 min and concentrated under reduced pressure to provide the crude
product. Flash column chromatography (SiO2, 30% EtOAc/hexanes)
1
afforded 3 (6.50 g, 98%) as a yellow solid: mp 56−60 °C; H NMR
(200 MHz, CDCl3) δ 4.60 (s, 2H), 6.93−7.02 (m, 1H), 7.26−7.37
(m, 1H), 7.47 (dd, J = 7.8, 1.8 Hz, 1H), 7.85 (d, J = 8.0 Hz, 1H); 13C
NMR (50 MHz, CDCl3) δ 38.7, 100.0, 128.8, 130.0, 130.4, 140.0, 140.2;
MS ESI(GC) m/z 298 (M+), 296 (M+), 217 (100). Anal. Calcd for
C7H6BrI: C, 28.31; H, 2.04. Found: C, 28.35; H, 1.84.
2-Iodobenzyl Cyanide (4).
N-[2-(2-Iodophenyl)]ethylacetamide (6c).
A sample of 3 (4.35 g, 14.7 mmol) in EtOH (40 mL) was treated with
NaCN (2.16 g, 44.0 mmol) and refluxed for 4 h. After removal of organic
solvent under reduced pressure, water (40 mL) was added to the
residue. The resulting mixture was extracted with EtOAc (40 mL × 3),
and the combined organic extracts were washed with saturated aq NaCl,
dried (Na2SO4), and concentrated under reduced pressure. Flash
column chromatography (SiO2, 20% EtOAc/hexanes) provided 4
A stirred solution of 5 (1.00 g, 3.5 mmol) in THF (10 mL) was treated
with acetyl chloride (0.3 mL, 3.8 mmol) and Et3N (0.7 mL, 5.3 mmol).
The reaction mixture was stirred at rt for 1 h and concentrated under
reduced pressure. The residue was dissolved in EtOAc (100 mL),
washed with water and saturated aqueous NaCl, dried (Na2SO4), and
concentrated under reduced pressure. Flash column chromatography
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(SiO2, 30% EtOAc/hexanes) provided 6c (0.9 g, 89%) as a white solid:
mp 71−74 °C; 1H NMR (400 MHz, CDCl3) δ 1.91 (s, 3H), 2.92 (t, J =
6.8 Hz, 2H), 3.44−3.50 (m, 2H), 5.56 (s, 1H), 6.87−6.91 (m, 1H),
7.12−7.28 (m, 2H), 7.78−7.81 (m, 1H); 13C NMR (125 MHz, CDCl3)
δ 23.5, 39.7, 40.3, 100.8, 128.5, 128.6, 130.1 139.7, 141.7, 170.3; MS ESI
m/z 312 ([M + Na]+, 100). Anal. Calcd. For C10H12INO: C, 41.54; H,
4.18; N, 4.84. Found: C, 41.54; H, 4.17; N, 4.88.
1,1-Diethyl-3-[2-(2-trimethylstannylphenyl)]ethylurea (10).
White solid, 664 mg, 78%: mp 81−84 °C; 1H NMR (400 MHz, CDCl3)
δ 0.31 (s, 9H), 1.08 (t, J = 2.8 Hz, 6H), 2.86 (t, J = 2.8 Hz, 2H), 3.21 (q,
J = 2.8 Hz, 4H), 3.46−3.51 (m, 2H), 4.23 (s, 1H), 7.19−7.30 (br m, 3H),
7.45 (d, J = 3.0 Hz, 1H); 13C NMR (125 MHz, CDCl3) δ −8.0, 13.9,
39.2, 41.3, 42.3, 126.0, 128.7, 128.8, 136.7, 142.6, 146.1, 157.2; MS ESI
m/z 407 [M + Na]+, 369 (100). Anal. Calcd. For C16H28N2OSn: C,
50.16; H, 7.37; N, 7.31. Found: C, 50.10; H, 7.45; N, 7.47.
1,1-Diethyl-3-[2-(2-iodophenyl)]ethylurea (6d).
A stirred solution of 5 (1.00 g, 3.5 mmol) in DMF (10 mL) was treated
with diethylcarbamoyl chloride (0.5 mL, 3.9 mmol) and Et3N (0.7 mL,
5.3 mmol). The reaction mixture was stirred at rt for 8 h and diluted with
EtOAc (100 mL). Resulting mixture was washed with water (20 mL × 3)
and saturated aq NaCl, dried (Na2SO4), and concentrated under
reduced pressure. Flash column chromatography (SiO2, 50% EtOAc/
General Procedure for the Synthesis of Diaryl Iodonium Salts
(11−14). A sample of diacetoxyiodoarene (0.5 mmol) in CH2Cl2
(1.0 mL) at rt under N2 was treated with a solution of p-TsOH·H2O
(0.5 mmol) in CH3CN (1.0 mL). The reaction mixture was stirred for
1 h and then treated with a solution of aryl stannane (7, 8, 9, or 10)
(0.5 mmol) in CH2Cl2 (1.0 mL). The reaction mixture was stirred for
24 h and concentrated under reduced pressure. The residue was purified
by flash column chromatography (SiO2, 10% MeOH/CH2Cl2) to
provide corresponding salt that contained trace amount of tin impurity.
To remove inorganic impurities, the salt was treated with Et2O (20 mL),
sonicated for 10 min, and filtered through a paper filter. The residue was
dried under reduced pressure to afford pure salt as a white solid.
(2-(2-(t-Butoxycarbonylamino)ethyl)phenyl)(4-fluorophenyl)-
iodonium p-Toluenesulfonate (11a).
1
hexanes) provided 6d (1.11 g, 92%) as a colorless oil: H NMR (400
MHz, CDCl3) δ 1.11 (t, J = 1.6 Hz, 6H), 2.90−3.03 (m, 2H), 3.17−
3.27 (m, 4H), 3.48−3.54 (m, 2H), 4.37 (s, 1H), 6.91−6.95 (m, 1H),
7.24−7.30 (m, 2H), 7.84 (d, J = 3.6 Hz, 1H); 13C NMR (125 MHz,
CDCl3) δ 14.0, 40.90, 40.92, 41.3, 100.8, 128.3, 128.5, 130.4, 139.6,
142.4, 157.3; MS ESI m/z 369 ([M + Na]+, 100). Anal. Calcd.
For C13H19IN2O: C, 45.10; H, 5.53; N, 8.09. Found: C, 45.12; H,
5.54; N, 8.04.
Typical Procedure for the Preparation of Aryl Stannane
(7−10).25 t-Butyl 2-[2-(Trimethylstannyl)phenyl]ethylcarbamate (7).
A solution of N-(t-butoxycarbonyl)-2-(2-iodophenyl)ethyl amine 6a
(770 mg, 2.21 mmol) in anhydrous toluene (12 mL) at rt under N2 was
treated with tetrakis(triphenylphospine)palladium(0) (229 mg, 0.31
mmol) and hexamethylditin (0.9 mL, 2.80 mmol). The reaction
mixture was warmed at 120 °C for 1 h, cooled to rt, and filtered
through a pad of Celite. The filtrate was concentrated under reduced
pressure and subjected to flash column chromatography (SiO2, 10%
EtOAc/hexanes) to afford 7 (715 mg, 84%) as a white solid: mp 77−
80 °C; 1H NMR (400 MHz, CDCl3) δ 0.33 (s, 9H), 1.45 (s, 9H), 2.82
(t, J = 3.4 Hz, 2H), 3.38−3.39 (m, 2H), 4.55 (s, 1H), 7.19−7.32 (m,
3H), 7.44 (d, J = 7.2 Hz, 1H); 13C NMR (50 MHz, CDCl3) δ −8.15,
28.4, 39.1, 42.1,79.2, 125.9, 128.4, 128.8, 136.4, 142.4, 145.5, 155.7;
MS ESI m/z 385 [M + H]+, 249 (100). Anal. Calcd. For
C16H27NO2Sn: C, 50.03; H, 7.09; N, 3.65. Found: C, 50.03; H,
7.09; N, 3.65.
White solid (215 mg, 70%): mp 158−160 °C; 1H NMR (400 MHz, CD3OD-
d4) δ 1.42 (s, 9H), 2.36 (s, 3H), 3.07−3.10 (m, 2H), 3.29−3.31 (m, 2H), 7.22
(d, J = 8.0 Hz, 2H), 7.28−7.30 (m, 2H), 7.31−7.40 (m, 1H), 7.56 (d, J =
7.6 Hz, 1H), 7.63−7.65 (m, 1H), 7.69 (d, J = 8.0 Hz, 2H), 8.21−8.24 (m, 2H),
8.31 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ 21.3, 28.7, 40.2,
42.0, 80.3, 109.6, 120.5 (d, J =23.4Hz),121.3,127.0,129.8,131.5,133.2,134.6,
138.9, 139.0 (d, J = 8.6 Hz), 141.7, 143.2, 143.5, 158.5, 166.3 (d, J = 252.6 Hz);
MS ESI m/z 442 (M+), 164 (100). Anal. Calcd. For C26H29FINO5S: C, 50.90;
H, 4.76; N, 2.28; S, 5.23. Found: C, 50.88; H, 4.72; N, 2.39; S, 5.14.
(2-(2-(t-Butoxycarbonylaminoethyl)phenyl)(4-chlorophenyl)-
iodonium p-Toluenesulfonate (11b).
Benzyl 2-(Trimethylstannyl)phenylethylcarbamate (8).
White solid, 726 mg, 86%: mp 73−76 °C; 1H NMR (400 MHz, CDCl3)
δ 0.28 (s, 9H), 2.81 (t, J = 7.2 Hz, 2H), 3.39−3.44 (m, 2H), 4.7 (s, 1H),
5.06 (s, 2H), 7.14−7.32 (br m, 8H), 7.39 (d, J = 7.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ −8.0, 39.1, 42.7, 66.9, 126.2, 128.3, 128.3, 128.6,
128.7, 129.0, 136.65, 136.71, 142.6, 145.3, 156.4; MS ESI m/z 442
([M + Na]+, 100). Anal. Calcd. For C19H25NO2Sn: C, 54.58; H, 6.03; N,
3.35. Found: C, 54.55; H, 6.06; N, 3.34.
1
White solid (226 mg, 72%): mp 163−165 °C; H NMR (400 MHz,
DMSO-d6) δ 1.39 (s, 9H), 2.28 (s, 3H), 2.97−3.01 (m, 2H), 3.13−3.18
(m, 2H), 7.10−7.15 (m, 3H), 7.35 (t, J = 7.2 Hz, 1H), 7.46 (d, J = 8.0 Hz,
2H), 7.52 (d, J = 7.6 Hz, 1H), 7.58−7.64 (m, 3H), 8.22 (d, J = 8.8 Hz,
2H), 8.44 (d, J = 8.0 Hz, 1H); 13C NMR (100 MHz, DMSO-d6) δ 21.3,
23.4, 28.7, 41.2, 78.4, 114.5, 122.1, 126.0, 128.5, 130.5, 131.8, 132.2,
133.5, 137.2, 137.8, 138.1, 142.0, 146.2, 156.2, 175.0; MS ESI m/z 458
(M+), 164 (100). Anal. Calcd. For C26H29ClINO5S: C, 49.57; H, 4.64;
N, 2.22; S, 5.09. Found: C, 49.47; H, 4.53; N, 2.25; S, 5.12.
2-(Trimethylstannylphenyl)ethylacetamide (9).
(2-(2-(t-Butoxycarbonylamino)ethyl)phenyl)(4-bromophenyl)-
iodonium p-Toluenesulfonate (11c).
White solid, 660 mg, 76%: mp 74−77 °C; 1H NMR (400 MHz, CDCl3)
δ 0.34 (s, 9H), 1.97 (s, 3H), 2.85 (t, J = 7.0 Hz, 2H), 3.49−3.54 (m, 2H),
5.56 (s, 1H), 7.21−7.34 (m, 3H), 7.46 (d, J = 7.2 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 8.0, 23.5, 38.6, 41.1, 126.2, 128.5, 129.0, 136.7,
142.6, 145.5, 170.1; MS ESI m/z 350 ([M + Na]+, 100). Anal. Calcd.
For C13H21NOSn: C, 47.89; H, 6.49; N, 4.30. Found: C, 47.90; H, 6.35;
N, 4.23.
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White solid (219 mg, 65%): mp 162−164 °C; 1H NMR (400 MHz,
DMSO-d6) δ 1.39 (s, 9H), 2.28 (s, 3H), 2.97−3.01 (m, 2H), 3.13−
3.16 (m, 2H), 7.10−7.12 (m, 3H), 7.35−7.39 (m, 1H), 7.47 (d, J =
8.4 Hz, 2H), 7.51−7.53 (m, 1H), 7.64 (t, J = 7.2 Hz, 3H), 8.15 (d, J =
8.8 Hz, 2H), 8.44 (d, 1H, J = 8.0 Hz); 13C NMR (100 MHz, DMSO-
d6) δ 21.3, 23.4, 28.7, 41.2, 78.4, 115.2, 122.0, 126.0, 126.6, 128.5,
130.5, 131.8, 133.5, 135.1, 137.3, 138.1, 142.0, 146.2, 156.2, 174.9;
MS ESI, m/z 504 (M+), 502 (M+), 164 (100). Anal. Calcd. For
C26H29BrINO5S: C, 46.31; H, 4.33; N, 2.08; S, 4.75. Found: C, 46.38;
H, 4.53; N, 2.01; S, 4.77.
(2-(2-(Benzyloxycarbonylamino)ethyl)phenyl)(4-chlorophenyl)-
iodonium p-Toluenesulfonate (12b).
1
White solid (248 mg, 75%): mp 84−86 °C; H NMR (400 MHz,
(2-(2-(t-Butoxycarbonylamino)ethyl)phenyl)(4-methoxyphenyl)-
iodonium p-Toluenesulfonate (11d).
CD3OD) δ 2.36 (s, 3H), 3.10 (t, J = 6.8 Hz, 2H), 3.34−3.36 (m, 2H),
5.07 (s, 2H), 7.20 (d, J = 7.6 Hz, 2H), 7.23−7.39 (m, 7H), 7.45
(d, J = 7.2 Hz, 2H), 7.54−7.69 (m, 4H), 8.11 (d, J = 7.2 Hz, 2H), 8.29
(d, J = 7.6 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ 21.3, 40.0,
42.4, 67.5, 113.1, 121.2, 126.9, 128.8, 129.0, 129.5, 129.8, 131.6, 133.1,
133.2, 134.7, 137.7, 138.3, 139.0, 140.2, 141.7, 143.1, 143.5, 158.9; MS
ESI m/z 492 (M+), 91 (100). Anal. Calcd. For C29H27ClINO5S:
C, 52.46; H, 4.10; N, 2.11; S, 4.83. Found: C, 52.52; H, 4.36; N, 2.10;
S, 4.79.
White solid (234 mg, 75%): mp 162−165 °C; 1H NMR (400 MHz,
DMSO-d6) δ 1.41 (s, 9H), 2.28 (s, 3H), 2.98−3.02 (m, 2H), 3.14−
3.17 (m, 2H), 3.78 (s, 3H), 7.05 (d, J = 8.8 Hz, 2H), 7.10 (d, J =
7.6 Hz, 2H), 7.13−7.19 (m, 1H), 7.34 (t, J = 8.8 Hz, 1H), 7.46−7.51
(m, 3H), 7.60 (t, J = 7.2 Hz, 1H), 8.18 (d, J = 8.8 Hz, 2H), 8.41 (d,
J = 8.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 20.8, 28.3,
38.4, 40.8, 55.7, 78.0, 105.1, 117.5, 121.9, 125.5, 128.0, 129.9,
131.1, 132.8, 136.1, 137.3, 137.6, 141.2, 145.8, 155.7, 161.9; MS ESI
m/z 454 (M+), 164 (100). Anal. Calcd. For C27H32INO6S: C,
51.84; H, 5.16; N, 2.24; S, 5.13. Found: C, 51.92; H, 5.01; N, 2.00; S,
5.11.
(2-(2-(Benzyloxycarbonylamino)ethyl)phenyl)(4-bromophenyl)-
iodonium p-Toluenesulfonate (12c).
1
White solid (254 mg, 72%): mp 88−91 °C; H NMR (400 MHz,
CD3OD) δ 2.36 (s, 3H), 3.08−3.12 (m, 2H), 3.34−3.36 (m, 2H), 5.07
(s, 2H), 7.21 (d, J = 7.2 Hz, 2H), 7.33−7.38 (m, 6H), 7.55−7.72 (m,
6H) 8.02−8.04 (m, 2H), 8.29 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz,
CD3OD) δ 21.3, 40.0, 42.4, 67.5, 113.9, 121.1, 126.9, 128.5, 128.8, 129.1,
129.5, 129.8, 131.6, 133.1, 134.7, 136.2, 137.8, 138.3, 139.0, 141.7, 143.2,
143.5, 158.9; MS ESI m/z 538 (M+), 536 (100). Anal. Calcd. For
C29H27BrINO5S: C, 49.17; H, 3.84; N, 1.98; S, 4.53. Found: C, 49.20; H,
3.98; N, 1.90; S, 4.76.
(2-(2-(t-Butoxycarbonylamino)ethyl)phenyl)(p-tolyl)iodonium
p-Toluenesulfonate (11e).
(2-(2-(Benzyloxycarbonylamino)ethyl)phenyl)(4-methoxyphenyl)-
iodonium p-Toluenesulfonate (12d).
1
White solid (204 mg, 67%): mp 163−166 °C; H NMR (400 MHz,
DMSO-d6) δ 1.41 (s, 9H), 2.28 (s, 3H), 2.32 (s, 3H), 2.98−3.01 (m,
2H), 3.16−3.17 (m, 2H), 7.11(d, J = 7.6 Hz, 2H), 7.12−7.19 (m, 1H),
7.30−7.35 (m, 2H), 7.46−7.63 (br m, 5H), 8.11 (d, J = 8.0 Hz, 2H), 8.42
(d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, DMSO-d6) δ 20.80, 20.82,
28.3, 38.5, 40.8, 77.9, 112.6, 121.5, 125.5, 128.1, 128.8, 129.9, 131.1,
131.4, 132.4, 132.8, 135.0, 137.5, 141.4, 142.5, 155.7; MS ESI m/z 438
(M+), 164 (100). Anal. Calcd. For C27H32INO5S: C, 53.20; H, 5.29; N,
2.30; S, 5.26. Found: C, 53.28; H, 5.38; N, 2.15; S, 5.29.
1
White solid (221 mg, 67%): mp 84−86 °C; H NMR (400 MHz,
CD3OD) δ 2.35 (s, 3H), 3.11 (t, J = 7.4 Hz, 2H), 3.35−3.39 (m, 2H),
3.81 (s, 3H), 5.08 (s, 2H), 6.99 (d, J = 8.0 Hz, 2H), 7.21 (d, J = 8.0 Hz,
2H), 7.28−7.39 (m, 6H), 7.50−7.55 (m, 1H), 7.56−7.62 (m, 1H),
7.69 (d, J = 7.6 Hz, 2H), 8.07 (d, J = 8.0 Hz, 2H), 8.24 (d, J = 8.0 Hz,
1H); 13C NMR (125 MHz, CD3OD) δ 21.3, 39.9, 42.5, 56.3, 67.5, 104.2,
106.2, 118.8, 121.4, 127.0, 128.8, 129.0, 129.5, 129.8, 131.4,
132.9, 134.4, 138.3, 138.6, 141.8, 142.8, 143.4, 157.9, 164.4; MS ESI
m/z 488 (M+), 91 (100). Anal. Calcd. For C30H30INO6S: C,
54.63; H, 4.58; N, 2.12; S, 4.86. Found: C, 54.53; H, 4.91; N, 1.92;
S, 4.95.
(2-(2-(Benzyloxycarbonylamino)ethyl)phenyl)(4-fluorophenyl)-
iodonium p-Toluenesulfonate (12a).
(2-(2-(Benzyloxycarbonylamino)ethyl)phenyl)(p-tolyl)-
iodonium p-Toluenesulfonate (12e).
1
White solid (226 mg, 70%): mp 78−81 °C; H NMR (400 MHz,
CD3OD) δ 2.37 (s, 3H), 3.08−3.13 (m, 2H), 3.33−3.38 (m, 2H), 5.08
(s, 2H), 7.22−7.24 (m, 4H), 7.29−7.40 (m, 6H), 7.53−7.65 (m, 4H),
7.69 (d, J = 7.6 Hz, 2H), 8.18−8.26 (m, 2H), 8.32 (d, J = 7.6 Hz, 1H);
13C NMR (125 MHz, CD3OD) δ 20.1, 38.8, 41.3, 66.3, 108.3, 119.4
(d, J = 23.7 Hz), 120.2, 125.8, 127.7, 127.9, 128.4, 128.7, 130.4, 131.9,
133.5, 137.2, 137.8, 137.9 (d, J = 9.1 Hz), 140.5, 141.9, 142.3, 157.7,
165.2 (d, J = 252.1 Hz); MS ESI m/z 476 (M+), 91 (100). Anal. Calcd.
For C29H27FINO5S: C, 53.79; H, 4.20; N, 2.16; S, 4.95. Found: C, 53.82;
H, 4.27; N, 2.11; S, 5.00.
1
White solid (225 mg, 70%): mp 81−83 °C; H NMR (400 MHz,
CD3OD) δ 2.36 (s, 3H), 2.37 (s, 3H), 3.09−3.13 (m, 2H), 3.34−3.38
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(m, 2H), 5.08 (s, 2H), 7.21 (d, J = 7.2 Hz, 2H), 7.29−7.33 (m, 8H),
7.51−7.54 (m, 1H), 7.56−7.61 (m, 1H), 7.69 (d, J = 7.6 Hz, 2H), 8.01
(d, J = 6.8 Hz, 2H), 8.25 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz,
CD3OD) δ 21.3 (2 CH3−C), 40.0, 42.4, 67.5, 112.0, 121.0, 127.0, 128.8,
129.0, 129.5, 129.8, 131.4, 133.0, 133.9, 134.5, 136.2, 138.4, 138.8, 141.6,
143.0, 143.5, 145.0, 158.9; MS ESI m/z 472 (M+), 91 (100). Anal. Calcd.
For C30H30INO5S: C, 55.99; H, 4.70; N, 2.18; S, 4.98. Found: C, 55.98;
H, 4.89; N, 2.19; S, 4.97.
(2-(2-Acetamidoethyl)phenyl)(4-methoxyphenyl)iodonium
p-Toluenesulfonate (13d).
(2-(2-Acetamidoethyl)phenyl)(4-fluorophenyl)iodonium
p-Toluenesulfonate (13a).
1
White solid (204 mg, 72%): mp 176−178 °C; H NMR (400 MHz,
CD3OD) δ 1.95 (s, 3H), 2.37 (s, 3H), 3.12−3.15 (m, 2H), 3.40−3.43
(m, 2H), 3.84 (s, 3H), 7.05 (d, J = 9.2 Hz, 2H), 7.22 (d, J = 8.0 Hz, 2H),
7.32−7.39 (m, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.61−7.66 (m, 1H), 7.70
(d, J = 8.0 Hz, 2H), 8.10 (d, J = 9.2 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H); 13C
NMR (125 MHz, CD3OD) δ 21.3, 22.6, 39.5, 41.1, 56.3, 104.2, 118.9,
121.5, 127.0, 129.8, 131.4, 132.8, 134.4, 138.3, 138.8, 141.7, 142.8, 143.5,
164.4, 173.6; MS ESI m/z 396 (M+, 100); HRMS FAB (Double focusing
analyzer (DFA)) m/z calcd. for C17H19INO2+ [M − OTs]− 396.0455,
found 396.0462.
Pale yellow solid (194 mg, 70%): mp 170−173 °C; 1H NMR
(400 MHz, CD3OD) δ 1.94 (s, 3H), 2.37 (s, 3H), 3.12 (t, J = 7.6 Hz,
2H), 3.38−3.42 (m, 2H), 7.21−7.31 (m, 4H), 7.34−7.40 (m, 1H),
7.56−7.58 (m, 1H), 7.64 (d, 1H, J = 7.6 Hz), 7.69 (d, J =
6.8 Hz, 2H), 8.23−8.27 (m, 2H), 8.35 (d, J = 1.2 Hz, 1H);
13C NMR (125 MHz, CD3OD) δ 21.3, 22.6, 39.5, 41.1, 109.5, 120.5
(d, J = 23.8 Hz), 121.4, 127.0, 129.8, 131.6, 133.0, 134.7, 139.0,
139.1 (d, J = 7.5 Hz), 141.8, 143.0, 143.4, 166.3 (d, J = 251.3 Hz),
173.7; MS ESI m/z 384 (M+, 100). Anal. Calcd. For C23H23FINO4S:
C, 49.74; H, 4.17; N, 2.52; S, 5.77. Found: C, 49.67; H, 4.05; N,
2.47; S, 5.77.
(2-(2-Acetamidoethyl)phenyl)(p-tolyl)iodonium p-Toluene-
sulfonate (13e).
1
White solid (179 mg, 65%): mp 174−175 °C; H NMR (400 MHz,
(2-(2-Acetamidoethyl)phenyl)(4-chlorophenyl)iodonium
CD3OD) δ 1.93 (s, 3H), 2.36 (s, 3H), 2.39 (s, 3H), 3.09−3.13 (m, 2H),
3.38−3.41 (m, 2H), 7.22−7.24 (m, 2H), 7.32−7.36 (m, 3H), 7.55 (d, J =
7.6 Hz, 1H), 7.62−7.70 (m, 3H), 8.03−8.06 (m, 2H), 8.30 (d, J = 6.8 Hz,
1H); 13C NMR (125 MHz, CD3OD) δ 21.3 (2 CH3−C), 22.6, 39.5,
41.1, 112.1, 121.1, 127.0, 129.8, 131.5, 132.9, 133.9, 134.5, 136.2, 139.0,
141.7, 143.0, 143.5, 145.0, 173.6; MS ESI m/z 380 (M+, 100). Anal.
Calcd. For C24H26INO4S: C, 52.27; H, 4.75; N, 2.54; S, 5.81. Found: C,
52.32; H, 4.58; N, 2.42; S, 5.77.
p-Toluenesulfonate (13b).
(2-(2-(3,3-Diethylureido)ethyl)phenyl)(4-fluorophenyl)-
iodonium p-Toluenesulfonate (14a).
White solid (208 mg, 73%): mp 172−174 °C; 1H NMR (400 MHz,
CD3OD) δ 1.93 (s, 3H), 2.37 (s, 3H), 3.10−3.13 (m, 2H), 3.38−
3.42 (m, 2H), 7.22 (d, J = 7.2 Hz, 2H), 7.24−7.37 (m, 1H), 7.51−
7.54 (m, 2H), 7.57−7.59 (m, 1H), 7.64−7.70 (m, 3H), 8.14−8.17
(m, 2H), 8.34 (dd, J = 8.0, 1.2 Hz, 1H); 13C NMR (125 MHz,
CD3OD) δ 21.3, 22.6, 39.6, 41.1, 113.2, 121.3, 127.0, 129.8, 131.6,
133.0, 133.3, 134.7, 137.8, 139.1, 140.3, 141.7, 143.1, 143.4, 173.7;
MS ESI m/z 400 (M+), 399 (100). Anal. Calcd. For C23H23ClINO4S:
C, 48.31; H, 4.05; N, 2.45; S, 5.61. Found: C, 48.32; H, 3.85; N, 2.46;
S, 5.66.
1
White solid (229 mg, 73%): mp 179−182 °C; H NMR (400 MHz,
CD3OD) δ 1.08 (t, J = 5.6 Hz, 6H), 2.37 (s, 3H), 3.15−3.17 (m, 2H),
3.26 (q, J = 5.6 Hz, 4H), 3.42−3.46 (m, 2H), 7.22−7.37 (m, 5H), 7.57
(dd, J = 6.0, 1.2 Hz, 1H), 7.58−7.63 (m, 1H), 7.70 (d, J = 6.4 Hz, 2H),
8.23−8.31 (m, 3H); 13C NMR (125 MHz, CD3OD) δ 14.0, 21.3, 40.7,
42.1, 42.2, 109.8, 120.5 (d, J = 23.8 Hz), 121.6, 127.0, 129.8, 131.4,
133.3, 134.5, 138.7, 139.1 (d, J = 8.8 Hz), 141.7, 143.4, 143.5, 159.6,
166.3 (d, J = 252.5 Hz); MS ESI m/z 441 (M+), 219 (100). Anal. Calcd.
For C26H30FIN2O4S: C, 50.98; H, 4.94; N, 4.57; S, 5.24. Found: C,
50.84; H, 5.00; N, 4.49; S, 5.33.
(2-(2-Acetamidoethyl)phenyl)(4-bromophenyl)iodonium
p-Toluenesulfonate (13c).
(2-(2-(3,3-Diethylureido)ethyl)phenyl)(4-chlorophenyl)-
iodonium p-Toluenesulfonate (14b).
Pale yellow solid (209 mg, 68%): mp 178−181 °C (decomposed);
1H NMR (400 MHz, CD3OD) δ 1.93 (s, 3H), 2.37 (s, 3H), 3.11−
3.13 (m, 2H), 3.38−3.40 (m, 2H), 7.22 (d, J = 8.0 Hz, 2H), 7.36−
7.41 (m, 1H), 7.56−7.61 (m, 1H), 7.68−7.70 (m, 5H), 8.08 (d, J =
8.4 Hz, 2H), 8.34 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CD3OD)
δ 21.3, 22.6, 39.6, 41.1, 113.2, 121.3, 127.0, 129.8, 131.6, 133.0, 133.3,
134.8, 137.8, 139.1, 140.3, 141.7, 143.1, 143.4, 173.7; MS ESI m/z
446 (M+), 444 (M+), 162 (100). Anal. Calcxd. For C23H23BrINO4S:
C, 44.82; H, 3.76; N, 2.27; S, 5.20. Found: C, 44.75; H, 3.90; N, 2.39;
S, 5.21.
1
White solid (221 mg, 69%): mp 188−192 °C; H NMR (400 MHz,
CD3OD) δ 1.07 (t, J = 7.2, Hz, 6H), 2.36 (s, 3H), 3.13−3.17 (m, 2H),
3.24 (q, J = 7.2, Hz, 4H), 3.42−3.46 (m, 2H), 7.22 (d, J = 7.6 Hz, 2H),
7.31−7.37 (m, 1H), 7.52 (d, J = 7.6, Hz, 2H), 7.56−7.65 (m, 2H), 7.69
(d, J = 8.0 Hz, 2H), 8.15 (d, J = 8.0 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H); 13C
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NMR (125 MHz, CD3OD) δ 14.0, 21.3, 40.6, 42.0, 42.2, 113.4, 121.5,
127.0, 129.8, 131.4, 133.2, 133.3, 134.5, 137.8, 138.8, 140.2, 141.7, 143.4,
143.5, 159.6; MS ESI m/z 457 (M+), 219 (100). Anal. Calcd. For
C26H30ClIN2O4S: C, 49.65; H, 4.81; N, 4.45; S, 5.10. Found: C, 49.71;
H, 4.68; N, 4.33; S, 5.23.
column chromatography (SiO2, EtOAc/hexanes) afforded the corre-
sponding N-protected indoline.
N-t-Butoxycarbonylindoline (15).
(2-(2-(3,3-Diethylureido)ethyl)phenyl)(4-bromophenyl)-
iodonium p-Toluenesulfonate (14c).
White solid (91 mg, 84%): mp 45−48 °C; 1H NMR (400 MHz,
DMSO-d6) δ 1.50 (s, 9H), 3.05 (t, J = 8.8 Hz, 2H), 3.89 (t, J = 8.8 Hz,
2H), 6.90 (t, J = 7.6 Hz, 1H), 7.12 (t, J = 8.4, Hz, 1H), 7.18 (d, J = 7.6 Hz,
1H), 7.67 (br s, 1H); 13C NMR (125 MHz, CDCl3) δ 27.4, 28.7, 47.9,
80.7, 114.7, 122.7, 125.5, 127.7, 132.0, 143.1, 152.4; MS ESI(GC) m/z
219 (M+), 117 (100). Anal. Calcd. For C13H17NO2: C, 71.21; H, 7.81;
N, 6.39. Found: C, 71.20; H, 7.92; N, 6.39.
N-Benzyloxycarbonylindoline (16).
1
White solid (248 mg, 72%): mp 184−186 °C; H NMR (400 MHz,
CD3OD) δ 1.07 (t, J = 7.2, m Hz, 6H), 2.36 (s, 3H), 3.14 (t, J = 7.2 Hz,
2H), 3.24 (q, J = 7.2 Hz, 4H), 3.42−3.46 (m, 2H), 7.22 (d, J = 8.4 Hz,
2H), 7.32−7.38 (m, 1H), 7.56−7.59 (m, 1H), 7.62−7.70 (m, 5H), 8.08
(d, J = 8.0 Hz, 2H), 8.28 (d, J = 8.4 Hz, 1H); 13C NMR (125 MHz,
CD3OD) δ 14.0, 21.3, 40.7, 42.0, 42.2, 114.2, 121.4, 127.0, 128.4, 129.8,
131.4, 133.4, 134.5, 136.2, 137.8, 138.8, 141.7, 143.48, 143.52, 159.6;
MS ESI m/z 503 (M+), 501 (M+), 219 (100). Anal. Calcd. For
C26H30BrIN2O4S: C, 46.37; H, 4.49; N, 4.16; S, 4.76. Found: C, 46.26;
H, 4.41; N, 4.21; S, 4.71.
1
Brown solid (102 mg, 80%): mp 62−65 °C; H NMR (400 MHz,
DMSO-d6) δ 3.09 (t, J = 8.8 Hz, 2H), 3.99 (t, J = 8.0 Hz, 2H), 5.23 (s,
2H), 6.95 (t, J = 7.6 Hz, 1H), 7.15 (t, J = 8.0 Hz, 1H), 7.21 (d, J = 7.2 Hz,
1H), 7.32−7.45 (m, 5H), 7.73 (br s, 1H); 13C NMR (125 MHz,
DMSO-d6) δ 27.7, 47.5, 66.9, 114.9, 122.7, 124.8, 127.6, 128.1, 128.2,
128.7, 131.0, 133.3, 142.7, 153.0. 27.7, 47.9, 66.9, 114.7, 123.2, 125.6,
127.8, 128.4, 128.7, 129.2, 132.0, 137.3, 142.9, 153.0; MS ESI(GC) m/z
253 (M+), 91(100). Anal. Calcd. For C16H15NO2: C, 75.87; H, 5.97; N,
5.53. Found: C, 75.89; H, 6.02; N, 5.45.
(2-(2-(3,3-Diethylureido)ethyl)phenyl)(4-methoxyphenyl)-
iodonium p-Toluenesulfonate (14d).
N-Acetylindoline (17).
Brown solid (58 mg, 72%): mp 96−99 °C; 1H NMR (400 MHz, CDCl3)
δ 2.22 (s, 3H), 3.20 (t, J = 6.8 Hz, 2H), 4.05 (t, J = 6.8 Hz, 2H), 7.00 (d,
J = 6.0 Hz, 1H), 7.03−7.18 (m, 2H), 8.20 (d, J = 6.4 Hz, 1H); 13C NMR
(125 MHz, CDCl3) δ 24.4, 28.1, 48.9, 117.1, 123.7, 124.6, 127.7, 131.2,
143.0, 168.9; MS ESI m/z 184 ([M + Na]+, 100); HRMS EI (DFA) m/z
calcd. for C10H11NO [M+] 161.0841, found 161.0840.
1
White solid (217 mg, 68%): mp 178−183 °C; H NMR (400 MHz,
CD3OD) δ 1.08 (t, J = 6.8 Hz, 6H), 2.36 (s, 3H), 3.14−3.17 (m, 2H),
3.25 (q, J = 6.8 Hz, 4H), 3.43−3.46 (m, 2H), 3.83 (s, 3H), 7.04 (d, J = 8.8
Hz, 2H), 7.22 (d, J = 8.4 Hz, 2H), 7.28−7.35 (m, 1H), 7.52−7.57 (m,
1H), 7.58−7.63 (m, 1H), 7.69 (d, J = 8.0 Hz, 2H), 8.10 (d, J = 8.8 Hz,
2H), 8.23 (d, J = 8.0 Hz, 1H); 13C NMR (125 MHz, CD3OD) δ 14.0,
21.3, 40.6, 42.1, 42.2, 56.3, 104.5, 118.8, 121.7, 127.0, 129.8, 131.3,
133.2, 134.2, 138.3, 138.4, 141.7, 143.2, 143.5, 159.6, 164.4; MS ESI m/z
N,N-Diethylindoline-1-carboxamide (18).
+
453 (M+), 219 (100); HRMS FAB (DFA) calcd. for C20H26IN2O2
[M − OTs−]+ 453.1033, found 453.1041.
1
(2-(2-(3,3-Diethylureido)ethyl)phenyl)(p-tolyl)iodonium
p-Toluenesulfonate (14e).
Yellow oil (76 mg, 70%): H NMR (400 MHz, CDCl3) δ 1.18 (t, J =
7.2 Hz, 6H), 3.02 (t, J = 8.0 Hz, 2H), 3.34 (q, J = 7.2 Hz, 4H), 3.88 (d, J =
8.0 Hz, 2H), 6.82−6.90 (m, 1H), 6.95 (d, J = 8.0 Hz, 1H), 7.09−7.17 (m,
2H); 13C NMR (125 MHz, CDCl3) δ 13.7, 28.3, 42.0, 50.5, 113.0, 121.3,
125.0, 127.1, 131.5, 144.9, 159.8; MS ESI m/z 241 ([M + Na]+, 100);
HRMS EI (DFA) calcd. for C13H18N2O [M+] 218.1419, found
218.1420.
ASSOCIATED CONTENT
1
■
White solid (230 mg, 74%): mp 188−192 °C; H NMR (400 MHz,
S
* Supporting Information
CD3OD) δ 1.09 (t, J = 7.2 Hz, 6H), 2.38 (s, 3H), 2.40 (s, 3H), 3.15−3.18
(m, 2H), 3.26 (q, 7.2 Hz, 4H), 3.44−3.48 (m, 2H), 7.23 (d, J = 7.6 Hz,
2H), 7.33 (d, J = 8.0 Hz, 3H), 7.55−7.64 (m, 2H), 7.71 (d, J = 8.0 Hz,
2H), 8.05 (d, J = 8.4 Hz, 2H), 8.26 (d, J = 8.0 Hz, 1H); 13C NMR (125
MHz, CD3OD) δ 14.0, 21.3 (2 CH3−C), 40.6, 42.1, 42.2, 112.2, 121.2
127.0, 129.8, 131.3, 133.2, 133.8, 134.3, 136.2, 138.6, 141.7, 143.4, 143.5,
144.9, 159.6; MS ESI m/z 437 (M+), 219 (100). Anal. Calcd. For
C27H33IN2O4S: C, 53.29; H, 5.47; N, 4.60; S, 5.27. Found: C, 53.17; H,
5.21; N, 4.61; S, 5.32.
1H and 13C NMR spectra of compounds. This material is
available free of charge via the Internet at http://pubs.acs.org/.
AUTHOR INFORMATION
Corresponding Author
*Tel.: 82-10-9077-7686. E-mail: dychi@sogang.ac.kr.
Notes
■
General Procedure for Metal-Free Synthesis of N-Protected
Indoline. A solution of diaryliodonium salt (0.5 mmol) in DMF (1 mL)
was treated with Cs2CO3 (3.0 equiv) and TEMPO (0.1 equiv) at rt.
After the reaction mixture was warmed to 80 °C under Ar for 1 h, the
mixture was cooled to rt and treated with water (5 mL). The resulting
mixture was extracted with EtOAc (10 mL × 3). The combined organic
extracts were washed with saturated aq NaCl, dried (Na2SO4), and
concentrated under reduced pressure to provide crude product. Flash
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This research was supported by the Converging Research
Program (2011K00705) through the Ministry of Education,
Science and Technology. High resolution mass spectra were
carried out at the Korea Basic Science Institute (Daegu, Korea).
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REFERENCES
■
(1) (a) Ontoria, J. M.; Di Marco, S.; Conte, I.; Di Francesco, M. E.;
Gardelli, C.; Koch, U.; Matassa, V. G.; Poma, M.; Steinkuhler, C.;
Volpari, C.; Harper, S. J. Med. Chem. 2004, 47, 6443−6446. (b) Horton,
D. A.; Bourne, G. T.; Smythe, M. L. Chem. Rev. 2003, 103, 893−930.
(c) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg, J. A. Chem.
Rev. 1997, 97, 787−828. (d) Bermudez, J.; Dabbs, S.; Joiner, K. A.; King,
F. D. J. Med. Chem. 1990, 33, 1929−1932. (e) Glennon, R. A. J. Med.
Chem. 1987, 30, 1−12.
(2) Kuang, D.; Uchida, S.; Humphry-Baker, R.; Zakeeruddin, S. M.;
Gratzel, M. Angew. Chem., Int. Ed. 2008, 47, 1923−1927.
̈
(3) (a) Omar-Amrani, R.; Schneider, R.; Fort, Y. Synthesis 2004, 2257−
2534. (b) Yang, B. H.; Buchwald, S. L. Org. Lett. 1999, 1, 35−37.
(c) Wolfe, J. P.; Rennels, R. A.; Buchwald, S. L. Tetrahedron 1996, 52,
7525−7546.
(4) (a) Johnston, J. N.; Plotkin, M. A.; Viswanathan, R.; Prabhakaran,
E. N. Org. Lett. 2001, 3, 1009−1011. (b) Viswanathan, R.; Smith, C. R.;
Prabhakaran, E. N.; Johnston, J. N. J. Org. Chem. 2008, 73, 3040−3046.
(5) Houlden, C. E.; Bailey, C. D.; Ford, J. G.; Gagne, M. R.; Lloyd-
́
Jones, G. C.; Booker-Milburn, K. I. J. Am. Chem. Soc. 2008, 130, 10066−
10067.
(6) Ganton, M. D.; Kerr, M. A. Org. Lett. 2005, 7, 4777−4779.
(7) Thansandote, P.; Raemy, M.; Rudolph, A.; Lautens, M. Org. Lett.
2007, 9, 5255−5258.
(8) (a) Padwa, A.; Brodney, M. A.; Dimitroff, M. J. Org. Chem. 1998,
63, 5304−5305. (b) Padwa, A.; Brodney, M. A.; Liu, B.; Satake, K.; Wu,
T. J. Org. Chem. 1999, 64, 3595−3607.
(9) (a) Mei, T.-S.; Wang, X.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131,
10806−10807. (b) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew. Chem., Int. Ed.
2008, 47, 6452−6455.
(10) Gilmore, C. D.; Allan, K. M.; Stoltz, B. M. J. Am. Chem. Soc. 2008,
130, 1558−1559.
(11) Nicolaou, K. C.; Roecker, A. J.; Pfefferkorn, J. A.; Cao, G.-Q. J. Am.
Chem. Soc. 2000, 122, 2966−2967.
(12) (a) Gruenfeld, N.; Stanton, J. L.; Yuan, A. M.; Ebetino, F. H.;
Browne, L. J.; Gude, C.; Huebner, C. F. J. Med. Chem. 1983, 26, 1277−
1282. (b) Natesh, R.; Schwager, S. L. U.; Evans, H. R.; Sturrock, E. D.;
Acharya, K. R. Biochemistry 2004, 43, 8718−8724.
(13) Boger, D. L.; Boyce, C. W.; Garbaccio, R. M.; Goldberg,
J. A. Chem. Rev. 1997, 97, 787−828. (b) Sunazuka, T.; Hirose, T.;
Shirahata, T.; Harigaya, Y.; Hayashi, M.; Komiyama, K.; Omura, S.;
Smith, A. B., III J. Am. Chem. Soc. 2000, 122, 2122−2123. (c) Dounay, A.
B.; Overman, L. E.; Wrobleski, A. D. J. Am. Chem. Soc. 2005, 127,
10186−10187.
(14) Kuwano, R.; Kashiwabara, M. Org. Lett. 2006, 8, 2653−2655.
(15) Wang, Z.; Wan, W.; Jiang, H.; Hao, J. J. Org. Chem. 2007, 72,
9364−9367.
(16) Correa, A.; Tellitu, I.; Dominguez, E.; SanMartin, R. J. Org. Chem.
2006, 71, 8316−8319.
(17) Carroll, M. A.; Wood, R. A. Tetrahedron 2007, 63, 11349−11354.
(18) Kang, S. K.; Lee, S.-H.; Lee, D. H. Synlett 2000, 1022−1024.
(19) (a) Stang, P. J.; Zhdankin, V. V. Chem. Rev. 1996, 96, 1123−1178.
(b) Wirth, T.; Hirt, U. H. Synthesis 1999, 1271−1287.
(20) Baldwin, J. E.; Thomas, R. C.; Kruse, L. I.; Silberman, L. J. Org.
Chem. 1977, 42, 3846−3852.
(21) Kazmierczak, P.; Skulski, L.; Kraszkiewicz, L. Molecules 2001, 6,
́
881−891.
(22) Pike, V. W.; Butt, F.; Shah, A.; Widdowson, D. A. J. Chem. Soc.,
Perkin Trans. 1 1999, 245−248.
(23) (a) Wadsworth, H. J.; Widdowson, D. A.; Wilson, E.; Carroll, M.
A. WO 2005/061415, 2005. (b) Carroll, M. A.; Nairne, J.; Smith, G.;
Widdowson, D. A. J. Fluorine Chem. 2007, 128, 127−132.
(24) Leffler, J. E.; Story, L. J. J. Am. Chem. Soc. 1967, 89, 2333−
2338.
(25) Chun, J.-H.; Pike, V. W. J. Org. Chem. 2012, 77, 1931−1938.
5713
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