NIS-Mediated intermolecular hydroamination of allenamides with imidazole heterocycles: A facile protocol for the synthesis of allylic: N, N -acetals

Article abstract of DOI:10.1039/c8nj03641a

Allylic N,N-acetals are important intermediates in the synthesis of biologically active heterocycles and natural products. Herein, we report a facile protocol for the synthesis of this compound through N-iodosuccinimide-mediated hydroamination of allenamides by imidazole heterocycles. The reaction is regioselective, fast, and tolerant of a broad scope of imidazole and benzimidazole derivatives. The key intermediate is a conjugated sulfimide ion species that undergoes nucleophilic attack by imidazole to form the 1,2-adduct. Mixtures of N¹- and N³-substituted isomers were obtained using asymmetrically substituted imidazoles. However, the 1,4-adduct was obtained using a tri-substituted imidazole. The efficiency of the gram-scale reaction suggests the potential industrial application of this synthetic method.

Full text of DOI:10.1039/c8nj03641a

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NIS-Mediated intermolecular hydroamination of
allenamides with imidazole heterocycles: a facile
protocol for the synthesis of allylic N,N-acetals†
Cite this:DOI: 10.1039/c8nj03641a
Yan Li, Guo Li Luo, Xiao Xiao Li * and Zhi Gang Zhao*
Allylic N,N-acetals are important intermediates in the synthesis of biologically active heterocycles and
natural products. Herein, we report a facile protocol for the synthesis of this compound through
N-iodosuccinimide-mediated hydroamination of allenamides by imidazole heterocycles. The reaction is
regioselective, fast, and tolerant of a broad scope of imidazole and benzimidazole derivatives. The key
intermediate is a conjugated sulfimide ion species that undergoes nucleophilic attack by imidazole to form
the 1,2-adduct. Mixtures of N1- and N3-substituted isomers were obtained using asymmetrically
substituted imidazoles. However, the 1,4-adduct was obtained using a tri-substituted imidazole. The
efficiency of the gram-scale reaction suggests the potential industrial application of this synthetic method.
Received 21st July 2018,
Accepted 18th September 2018
DOI: 10.1039/c8nj03641a
rsc.li/njc
Only a few elegant examples of intramolecular cyclization involving
allenamides have been reported to date.7 At present, the key issue
Introduction
The regioselective functionalization of carbon–carbon double is that iodine-mediated hydroamination of allenamides to produce
bonds has enormous potential in organic synthesis.1 Among allylic N,N-acetals has not been reported except for one case
compounds with CQC bonds, allenamides have recently proven described in our previous report.8
to be important synthetic intermediates that undergo diverse,
Imidazole derivatives have exhibited considerable biological
interesting transformations.2 For instance, the hydroamination activities such as antiinflammatory, antifungal, antiallergic,
of allenamides is a straightforward conversion to form allylic antileishmanial, and analgesic activities.9 Notably, they are also
N,N-acetals, which are key intermediates in the synthesis of useful precursors to N-heterocyclic carbenes, which serve as power-
biologically active heterocycles and natural products.3 Broggini ful ligands in various transition metal complexes.10 Furthermore,
and co-workers reported an Au(III)-catalysed intramolecular chiral imidazole derivatives have been proven to be excellent
hydroamination4 and Pd-catalysed intramolecular carboamin- organocatalysts in enantioselective kinetic resolutions.11 Our
ation5 of allenamides to give allylic-substituted imidazolidine, previous studies on allenamides showed that allylic N,N-acetals
4-quinazolinone, and indoloimidazole derivatives. These reac- can be obtained through regioselective 1,2-addition of N-haloimides,
tions proceed through the coordination of the transition metal which serve as both electrophile and nucleophile in the
complex to the allenyl framework to afford vinyl-gold or palladium reaction, to allenamides (Scheme 1a);12 however, the substrate
p-allyl intermediates. Although effective, these precious rare earth specificity of the reaction limit its broader utility.13 To follow
metals are expensive and scarce; thus, there remains much up on these results, we envisioned that imidazole heterocycles
interest in developing more sustainable and greener protocols would also be of particular interest as reactants in this
to synthesize allylic N,N-acetals.
Reactions with iodine electrophiles have been known for
a long time.6 The reaction with CQC bonds leads to a new
stereogenic centre and that with CRC bonds leads to functiona-
lised alkenes. However, the activation of allenamides by an iodine
electrophile still poses challenges with respect to regioselectivity.
College of Chemistry and Environmental Protection Engineering, Southwest Minzu
University, Chengdu 610041, P. R. China. E-mail: lixiaoxiao.2005@163.com,
zzg63129@163.com
† Electronic supplementary information (ESI) available: NMR spectra. CCDC
1856085 for 4ak0. For ESI and crystallographic data in CIF or other electronic
Scheme 1 Synthesis of allylic N,N-acetals.
format see DOI: 10.1039/c8nj03641a
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Table 2 Substrate scope of allenamidesa,b
hydroamination method to synthesize allylic N,N-acetals
(Scheme 1b).
Results and discussion
Initial studies on the synthesis of heteroaromatic, allylic
N,N-acetals were guided by our previous work on NIS-mediated
iodofunctionalization of allenamides with indoles, pyrroles, and
furans.12g Phenyl allenamide (1a) and imidazole (2a) were used to
optimize the reaction conditions (Table 1). The first attempt using
1.05 equiv. NIS in CH3CN provided the desired product, 4aa as a
single regioisomer in 5 minutes, with a yield of 96%, which is
consistent with our previous report (entry 1).8 The other halogen
electrophiles were then evaluated. NCS, NBS and elemental iodine
gave 4b (16%), 4c (26%) and 4aa (50%), respectively. However,
TCCA was not favoured for this transformation and gave the
degradation product, 4-methyl-N-phenylbenzenesulfonamide, in
43% yield in 1 minute (entry 3). Further solvent optimization
identified CH3CN to be the best reaction medium (entries 6–12).
The yield of 4aa decreased to 73% when the reaction was carried
out at 70 1C (entry 13).
After establishing the optimal reaction conditions for the
present reaction, the reaction was conducted with various
allenamide derivatives, as summarized in Table 2. 4-Me- or
4-MeO-substituted phenyl allenamides were suitable for the
production of the allylic N,N-acetals 4ba, and 4ca, in 71% and
59% yield, respectively. The reaction of allenamides bearing
F, Cl, and Br (i.e., electron-withdrawing groups) at the para
position of the aromatic ring resulted in the corresponding
products, 4da (97%), 4ea (93%), and 4fa (89%), respectively.
Benzyl allenamide (1g) also provided the desired product, 4ga, in
85% yield. Benzyl allenamides with different electron-donating
and electron-withdrawing substituents, such as methyl, methoxy,
a
Conditions: 1 (0.3 mmol), 2a (0.6 mmol), NIS (0.315 mmol), CH3CN
b
(3 mL), rt, within 5 min. Yield of isolated products.
fluoro, chloro, bromo, at the para position were all efficient in
affording the desired products, 4ha–4la, in 55–73% yields.
Furthermore, the reactivity of the aliphatic-substituted allenamide,
1m, was also investigated, and the allylic N,N-acetal, 4ma, was
obtained in 82% yield.
Table 1 Screening of optimal conditionsa
We then examined the NIS-mediated hydroamination of 1a
with different imidazole heterocycles (Table 3). Generally,
the anticipated allylic N,N-acetals, 4ab–4al, were obtained in
modest to good yields. First, 2-substituted imidazoles, such as
imidazole-2-carbaldehyde (2b) and 2-nitroimidazole (2c) were
converted to the allylic N,N-acetals 4ab (36%) and 4ac (40%),
respectively. In the case of asymmetrically substituted imida-
zoles, mixtures of N1 and N3-substituted isomers were obtained.
Thus, complete regioselectivity was achieved for the conversion
of 4-nitroimidazole (2d) to the N1-substituted allylic N,N-acetal,
4ad (65%).14 In contrast, 4-iodoimidazole (2e) and imidazole-3-
carbaldehyde (2f) showed low regioselectivity, yielding the
N1-substituted allylic N,N-acetals, 4ae (16%) and 4af (41%), as
well as the N3-substituted allylic N,N-acetals, 4ae0 (39%) and
4af0 (42%). The di-substituted imidazole (2g) also provided
the product, 4ag, in 44% yield. However, the tri-substituted
imidazole, 2h, only produced the 1,4-adduct, 5ah, in 46% yield,
Entry
Halogen reagent 3
Solvent
Yield of 4b (%)
1
NIS
NCS
TCCA
NBS
I2
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DCM
4aa (96)
4b (16)
NP
2
3c
4
4c (26)
5d
6
4aa (50)
4aa (86)
4aa (84)
4aa (67)
4aa (68)
4aa (76)
4aa (42)
4aa (25)
4aa (63)
7
8
9
10
11
12
13e
DCE
CHCl3
Toluene
Acetone
DMF
DMSO
CH3CN
a
Unless otherwise noted, all reactions were carried out at a 0.1 mmol of
1a, 0.3 mmol of 2a and 0.105 mmol of 3 in 2 mL solvent at rt within
5 min. Isolated yield. NP: no product. 1a was consumed within
15 min. The reaction was carried out at 70 1C.
b
c
d
e
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Table 3 Substrate scope of imidazolesa,b
Scheme 2 Gram-scale reaction of allenamide (1a) with imidazole (2a).
Scheme 3 Proposed reaction pathway for hydroamination of allenamide
(1a) with asymmetrically substituted imidazole (2e).
A scale-up of the reaction was subsequently carried out
(Scheme 2). The reaction was proven to be scalable and
practical because the gram-scale reaction was also efficiently
performed. The reaction of 1a (5 mmol, 1.43 g) and 2a
(10 mmol, 2 equiv.) gave the corresponding product 4aa in
91% yield after 10 minutes under optimal reaction conditions.
On the basis of this and our previous study,8 we propose a
plausible reaction pathway, as shown in Scheme 3. The initial
addition of NIS to 1a is hypothesized to produce the key
intermediate conjugated sulfimide ion II, via a decyclization
reaction of iodiranium intermediate I. Then the N1 or N3 atom
of 2e as the nucleophile that promotes 1,2-addition to give
intermediate III or IV. The proton of III or IV is trapped by the
conjugate base of the imide to produce the allylic N,N-acetals,
4ae and 4ae0.
a
Conditions: 1a (0.3 mmol), 2 (0.6 mmol), NIS (0.315 mmol), CH3CN (3 mL),
rt, within 5 min. b Yield of isolated products. c Yield of 1H NMR of mixture.
possibly because of steric hindrance. Remarkably, benzimida-
zole (2i) was also suitable for the preparation of the allylic
N,N-acetal, 4ai, in 73% yield. On the other hand, 5-chloro-1H-
benzimidazole (2j) and 5-methoxy-1H-benzimidazole (2k) were
converted to the N1-substituted allylic N,N-acetals, 4aj (36%)
and 4ak (16%), as well as the N3-substituted allylic N,N-acetals,
4aj0 (26%) and 4ak0 (24%). The reaction was also efficient with
di-substituted benzimidazole (2l), providing 4al in 48% yield.
Moreover, 4ak0 was a crystalline solid, and single-crystal X-ray
analysis confirmed its structure (Fig. 1).15
Experimental
General information
All reactions were conducted under open air at room tempera-
ture. 1H NMR and 13C NMR spectra were obtained with an
Agilent Technologies 400 spectrometer in CDCl3 with TMS as
an internal standard. Chemical shifts (d) are reported in ppm,
and coupling constants ( J) are in hertz (Hz). The following
abbreviations were used to explain the multiplicities: s = singlet,
Fig. 1 X-ray structure of compound 4ak0.
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d = doublet, t = triplet, q = quartet, m = multiplet, and br = broad. 7.37 (s, 1H), 7.24 (d, J = 8.1 Hz, 2H), 7.00 (d, J = 8.2 Hz, 2H), 6.97
HRMS was performed using a Bruker Daltonics Bio TOF mass (d, J = 7.3 Hz, 2H), 6.75 (s, 1H), 6.69 (s, 1H), 6.64 (d, J = 8.1 Hz, 2H),
spectrometer. Melting points were determined from the solids 6.23 (s, 1H), 2.42 (s, 3H), 2.31 (s, 3H). 13C NMR (100 MHz, CDCl3) d
obtained from column chromatography using a WRS-1B digital 144.45, 140.00, 137.12, 135.66, 132.07, 131.60, 131.24, 129.80,
melting point instrument. All reactions were monitored by 129.58, 128.84, 127.82, 119.13, 102.76, 76.36, 21.61, 21.15. HRMS
TLC. Flash column chromatography was carried out using (ESI) m/z calcd for C20H21IN3O2S [M + H]+ 494.0394; found,
300–400 mesh silica gel at medium pressure. Commercial 494.0391.
reagents were used as supplied or were purified by standard
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-N-(4-methoxyphenyl)-4-
techniques where necessary. Allenamides 1a–1m were prepared methylbenzenesulfonamide (4ca). Purified by flash column
according to the reported method.16
chromatography (hexane/EtOAc = 1/1) in 59% yield (90.1 mg,
0.177 mmol) as a yellow solid. M.p. 103–104 1C. 1H NMR
(400 MHz, CDCl3) d 7.36 (d, J = 8.2 Hz, 2H), 7.23 (s, 1H), 7.11
(d, J = 8.1 Hz, 2H), 6.87 (s, 1H), 6.82 (s, 1H), 6.61 (s, 1H), 6.59–
General procedure for synthesis of compound allylic N,N-acetal
4aa
To a suspension of 1a (0.3 mmol), 2a (0.6 mmol) in CH3CN 6.53 (m, 5H), 6.11 (s, 1H), 3.64 (s, 3H), 2.29 (s, 3H). 13C NMR
(3 mL) was added 3a (0.315 mmol) in one portion. Then the (100 MHz, CDCl3) d 160.15, 144.35, 137.16, 135.53, 133.09,
reaction mixture was stirred at room temperature until com- 131.85, 129.50, 129.12, 127.75, 125.99, 118.97, 114.13, 102.99,
plete consumption of the starting material as monitored by 76.11, 55.29, 21.54. HRMS (ESI) m/z calcd for C20H21IN3O3S
TLC. The concentration of the reaction mixture in vacuo [M + H]+ 510.0343; found, 510.0349.
followed by purification through flash chromatography on a
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-N-(4-fluorophenyl)-4-methyl-
silica gel column (hexane/EtOAc = 1/1 as the eluent) afforded benzenesulfonamide (4da). Purified by flash column chromato-
4aa (138 mg, 96% yield) as a yellow solid.
graphy (hexane/EtOAc = 1/1) in 97% yield (144.7 mg, 0.291 mmol)
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-4-methyl-N-phenylbenzene- as a yellow liquid. 1H NMR (400 MHz, CDCl3) d 7.48 (d, J = 8.3 Hz,
sulfonamide (4aa). Purified by flash column chromatography 2H), 7.39 (s, 1H), 7.25 (d, J = 8.0 Hz, 2H), 7.00 (s, 1H), 6.95 (s, 1H),
(hexane/EtOAc = 1/1) in 96% yield (138 mg, 0.288 mmol) as a 6.91 (d, J = 8.1 Hz, 1H), 6.89 (d, J = 8.1 Hz, 1H), 6.77–6.73 (m, 2H),
1
yellow solid. M.p. 86–87 1C. H NMR (400 MHz, CDCl3) d 7.48 6.71 (dd, J = 2.6, 1.8 Hz, 1H), 6.67 (s, 1H), 6.25 (dd, J = 2.6, 1.6 Hz,
(d, J = 8.1 Hz, 2H), 7.33 (d, J = 9.1 Hz, 2H), 7.24–7.19 (m, 4H), 6.98 1H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3) d 162.89 (d, J = 250.2
(s, 1H), 6.93 (s, 1H), 6.77 (d, J = 8.7 Hz, 2H), 6.74 (s, 1H), 6.65 Hz), 144.76, 137.08, 135.17, 133.86 (d, J = 8.9 Hz), 132.12, 129.78 (d,
(s, 1H), 6.24 (s, 1H), 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3) d J = 3.2 Hz), 129.67, 129.11, 127.76, 118.90, 116.15 (d, J = 22.6 Hz),
144.49, 137.23, 135.57, 134.13, 131.96, 131.89, 129.67, 129.57, 102.51, 76.16, 21.56. HRMS (ESI) m/z calcd for C19H18FIN3O2S
129.27, 129.08, 127.78, 118.98, 102.82, 76.28, 21.58. HRMS (ESI) [M + H]+ 498.0143; found, 498.0142.
m/z calcd for C19H19IN3O2S [M + H]+ 480.0237; found, 480.0234.
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-N-(4-chlorophenyl)-4-
N-(2-Chloro-1-(1H-imidazol-1-yl)allyl)-4-methyl-N-phenyl- methylbenzenesulfonamide (4ea). Purified by flash column
benzenesulfonamide (4b). Purified by flash column chromato- chromatography (hexane/EtOAc = 1/1) in 93% yield (143.2 mg,
graphy (hexane/EtOAc = 2/1) in 16% yield (18.6 mg, 0.048 mmol) 0.279 mmol) as a yellow solid. M.p. 95–96 1C. 1H NMR (400 MHz,
1
as a white solid. M.p. 71–72 1C. H NMR (400 MHz, CDCl3) d CDCl3) d 7.49 (d, J = 8.1 Hz, 2H), 7.42 (s, 1H), 7.26 (d, J = 9.4 Hz,
7.48–7.45 (m, 3H), 7.36 (t, J = 7.4 Hz, 1H), 7.26–7.21 (m, 4H), 7.08 2H), 7.19 (d, J = 8.5 Hz, 2H), 6.99 (d, J = 8.5 Hz, 2H), 6.73–6.69
(s, 1H), 6.98 (s, 1H), 6.85 (d, J = 7.7 Hz, 2H), 6.74 (s, 1H), 5.64 (m, 4H), 6.24 (s, 1H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3) d
(s, 1H), 5.61 (s, 1H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3) d 144.84, 137.07, 136.06, 135.20, 133.22, 132.53, 132.28, 129.74,
144.41, 137.16, 135.74, 135.67, 133.92, 132.08, 129.78, 129.52, 129.40, 129.18, 127.81, 118.98, 102.39, 76.23, 21.62. HRMS (ESI)
129.35, 129.14, 127.80, 119.26, 118.79, 72.66, 21.59. HRMS (ESI) m/z calcd for C19H18ClIN3O2S [M + H]+ 513.9844; found,
m/z calcd for C19H19ClN3O2S [M + H]+ 388.0881; found, 388.0883. 513.9847.
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-4-methyl-N-phenylbenzene-
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-N-(4-bromophenyl)-4-
sulfonamide (4c). Purified by flash column chromatography methylbenzenesulfonamide (4fa). Purified by flash column
(hexane/EtOAc = 1/1) in 26% yield (33.7 mg, 0.078 mmol) as a chromatography (hexane/EtOAc = 1/1) in 89% yield (148.9 mg,
white solid. M.p. 64–65 1C. 1H NMR (400 MHz, CDCl3) d 7.47 0.267 mmol) as a yellow solid. M.p. 116–117 1C. 1H NMR
(d, J = 8.3 Hz, 2H), 7.42 (s, 1H), 7.35 (t, J = 7.4 Hz, 1H), 7.23 (t, J = (400 MHz, CDCl3) d 7.48 (d, J = 8.2 Hz, 2H), 7.38 (s, 1H), 7.35
7.9 Hz, 4H), 7.08 (s, 1H), 6.97 (s, 1H), 6.84 (d, J = 7.4 Hz, 2H), 6.72 (d, J = 8.7 Hz, 2H), 7.26 (d, J = 8.1 Hz, 2H), 6.98 (d, J = 7.4 Hz, 2H),
(s, 1H), 6.13 (dd, J = 3.0, 1.7 Hz, 1H), 5.91 (dd, J = 3.0, 1.5 Hz, 1H), 6.69 (s, 1H), 6.67 (s, 1H), 6.64 (d, J = 8.6 Hz, 2H), 6.24 (s, 1H), 2.43
2.41 (s, 3H). 13C NMR (100 MHz, CDCl3) d 144.43, 137.12, 135.59, (s, 3H). 13C NMR (100 MHz, CDCl3) d 144.82, 137.13, 135.21,
133.95, 132.00, 129.80, 129.56, 129.16, 128.73, 127.83, 126.28, 133.49, 133.09, 132.40, 132.18, 129.73, 129.40, 127.78, 124.30,
123.74, 118.93, 74.00, 21.61. HRMS (ESI) m/z calcd for 118.90, 102.42, 76.13, 21.62. HRMS (ESI) m/z calcd for C19H18BrI-
C19H19BrN3O2S [M + H]+ 432.0376; found, 432.0379.
N3O2S [M + H]+ 557.9342; found, 557.9343.
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-4-methyl-N-( p-tolyl)benzene-
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-N-benzyl-4-methylbenzene-
sulfonamide (4ba). Purified by flash column chromatography sulfonamide (4ga). Purified by flash column chromatography
(hexane/EtOAc = 1/1) in 71% yield (105 mg, 0.213 mmol) as a (hexane/EtOAc = 2/1) in 85% yield (125.8 mg, 0.255 mmol) as a
yellow liquid. 1H NMR (400 MHz, CDCl3) d 7.49 (d, J = 8.1 Hz, 2H), yellow liquid. 1H NMR (400 MHz, CDCl3) d 7.42 (d, J = 8.2 Hz, 2H),
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7.26 (s, 1H), 7.16–7.10 (m, 5H), 6.93 (d, J = 6.9 Hz, 2H), 6.91
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-N-(4-bromobenzyl)-4-
(s, 1H), 6.63 (s, 1H), 6.48 (s, 1H), 6.27 (s, 1H), 6.09 (s, 1H), 4.38 methylbenzenesulfonamide (4la). Purified by flash column
(d, J = 15.7 Hz, 1H), 4.29 (d, J = 15.7 Hz, 1H), 2.34 (s, 3H). 13C NMR chromatography (hexane/EtOAc = 2/1) in 58% yield (97.3 mg,
(100 MHz, CDCl3) d 144.31, 137.13, 136.26, 135.03, 132.37, 129.73, 0.174 mmol) as a white solid. M.p. 103–104 1C. 1H NMR
129.60, 128.75, 128.47, 128.07, 127.34, 118.65, 101.07, 76.37, (400 MHz, CDCl3) d 7.41 (d, J = 8.2 Hz, 2H), 7.40 (s, 1H), 7.22
49.52, 21.55. HRMS (ESI) m/z calcd for C20H20IN3O2S [M + H]+ (d, J = 8.3 Hz, 2H), 7.16 (d, J = 8.1 Hz, 2H), 6.94 (s, 1H), 6.80
494.0394; found, 494.0390.
(d, J = 8.3 Hz, 2H), 6.68 (s, 1H), 6.57 (s, 1H), 6.25 (s, 1H), 6.11
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-4-methyl-N-(4-methyl- (s, 1H), 4.32 (d, J = 16.1 Hz, 1H), 4.28 (d, J = 16.1 Hz, 1H), 2.35
benzyl)benzenesulfonamide (4ha). Purified by flash column (s, 3H). 13C NMR (100 MHz, CDCl3) d 144.59, 136.92, 136.09,
chromatography (hexane/EtOAc = 2/1) in 59% yield (89.8 mg, 134.05, 132.50, 131.50, 130.33, 129.79, 129.50, 127.31,
1
0.177 mmol) as a yellow liquid. H NMR (400 MHz, CDCl3) d 122.13, 118.53, 100.93, 76.43, 48.76, 21.59. HRMS (ESI) m/z
7.50 (d, J = 8.2 Hz, 2H), 7.30 (s, 1H), 7.22 (d, J = 8.1 Hz, 2H), calcd for
7.00 (d, J = 8.1 Hz, 2H), 6.99 (s, 1H), 6.90 (d, J = 7.9 Hz, 2H), 571.9495.
C20H20BrIN3O2S [M +
H]+ 571.9499; found,
6.70 (s, 1H), 6.51 (s, 1H), 6.34 (s, 1H), 6.16 (s, 1H), 4.41 (d, J =
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-N-butyl-4-methylbenzene-
15.5 Hz, 1H), 4.29 (d, J = 15.6 Hz, 1H), 2.42 (s, 3H), 2.30 sulfonamide (4ma). Purified by flash column chromatography
(s, 3H). 13C NMR (100 MHz, CDCl3) d 144.23, 137.93, 137.19, (hexane/EtOAc = 2/1) in 72% yield (99.2 mg, 0.216 mmol) as a
136.30, 132.38, 131.98, 129.68, 129.55, 129.14, 128.78, yellow solid. M.p. 91–92 1C. 1H NMR (400 MHz, CDCl3) d 7.55 (d,
127.36, 118.72, 101.09, 76.34, 49.34, 21.55, 21.07. HRMS J = 8.3 Hz, 2H), 7.39 (s, 1H), 7.22 (d, J = 8.2 Hz, 2H), 6.97 (s, 1H),
(ESI) m/z calcd for C21H23IN3O2S [M + H]+ 508.0550; found, 6.79 (s, 1H), 6.58 (s, 1H), 6.16–6.13 (m, 1H), 6.09–6.08 (m, 1H),
508.0552.
3.19–3.10 (m, 1H), 3.04–2.96 (m, 1H), 2.36 (s, 3H), 1.53–1.42 (m,
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-N-(4-methoxybenzyl)-4- 1H), 1.1–1.01 (m, 2H), 0.98–0.87 (m, 1H), 0.73 (t, J = 7.3 Hz, 3H).
methylbenzenesulfonamide (4ia). Purified by flash column 13C NMR (100 MHz, CDCl3) d 144.30, 136.67, 135.95, 131.58,
chromatography (hexane/EtOAc = 2/1) in 55% yield (86.4 mg, 129.83, 129.68, 127.21, 118.21, 101.58, 76.06, 45.70, 31.79, 21.56,
0.165 mmol) as a yellow solid. M.p. 112–113 1C. 1H NMR 20.24, 13.42. HRMS (ESI) m/z calcd for C17H23IN3O2S [M + H]+
(400 MHz, CDCl3) d 7.42 (d, J = 8.2 Hz, 2H), 7.27 (s, 1H), 7.15 460.0550; found, 460.0555.
(d, J = 8.1 Hz, 2H), 6.93 (s, 1H), 6.86 (d, J = 8.5 Hz, 2H), 6.66
N-(1-(2-Formyl-1H-imidazol-1-yl)-2-iodoallyl)-4-methyl-N-
(s, 2H), 6.65 (d, J = 8.4 Hz, 1H), 6.44 (s, 1H), 6.27 (s, 1H), 6.10 phenylbenzenesulfonamide (4ab). Purified by flash column
(s, 1H), 4.31 (d, J = 15.4 Hz, 1H), 4.21 (d, J = 15.5 Hz, 1H), 3.70 chromatography (hexane/EtOAc = 3/1) in 36% yield (54.8 mg,
(s, 3H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3) d 159.41, 0.108 mmol) as a yellow solid. M.p. 103–104 1C. 1H NMR
144.22, 137.17, 136.38, 132.41, 130.32, 129.71, 129.49, 127.34, (400 MHz, CDCl3) d 9.75 (d, J = 0.9 Hz, 1H), 7.97 (s, 1H), 7.46
126.96, 118.75, 113.83, 101.13, 77.36, 55.24, 49.04, 21.57. (d, J = 8.3 Hz, 2H), 7.26 (t, J = 7.4 Hz, 1H), 7.17–7.11 (m, 4H), 7.00
HRMS (ESI) m/z calcd for C21H23IN3O3S [M + H]+ 524.0499; (d, J = 0.8 Hz, 1H), 6.89 (s, 1H), 6.84 (dd, J = 2.6, 1.7 Hz, 1H), 6.80
found, 524.0498.
(d, J = 7.4 Hz, 2H), 6.17 (dd, J = 2.6, 1.4 Hz, 1H), 2.33 (s, 3H). 13
C
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-N-(4-fluorobenzyl)-4-methyl- NMR (100 MHz, CDCl3) d 182.02, 144.34, 142.45, 135.15, 134.80,
benzenesulfonamide (4ja). Purified by flash column chromato- 132.09, 131.59, 131.29, 129.56, 129.28, 129.17, 128.38, 124.98,
graphy (hexane/EtOAc = 1/1) in 73% yield (109.3 mg, 0.219 mmol) 103.58, 75.67, 21.59. HRMS (ESI) m/z calcd for C20H19IN3O3S
as a yellow liquid. 1H NMR (400 MHz, CDCl3) d 7.49 (d, J = 8.2 Hz, [M + H]+ 508.0186; found, 508.0190.
2H), 7.39 (s, 1H), 7.23 (d, J = 8.2 Hz, 2H), 6.99–6.96 (m, 3H), 6.86
N-(2-Iodo-1-(2-nitro-1H-imidazol-1-yl)allyl)-4-methyl-N-phenyl-
(t, J = 8.6 Hz, 2H), 6.73 (s, 1H), 6.60 (s, 1H), 6.31 (s, 1H), 6.17 benzenesulfonamide (4ac). Purified by flash column chromato-
(s, 1H), 4.39 (s, 2H), 2.41 (s, 3H). 13C NMR (100 MHz, CDCl3) d graphy (hexane/EtOAc = 3/1) in 40% yield (62.9 mg, 0.120 mmol)
162.34 (d, J = 245.9 Hz), 144.44, 136.97, 136.16, 132.36, 130.83 as a white solid. M.p. 93–94 1C. 1H NMR (400 MHz, CDCl3) d 7.75
(d, J = 3.3 Hz), 130.48 (d, J = 8.1 Hz), 129.73, 129.63, 127.26, (s, 1H), 7.43 (d, J = 8.3 Hz, 2H), 7.31–7.27 (m, 1H), 7.18–7.16
118.51, 115.27 (d, J = 21.5 Hz), 101.00, 76.34, 48.62, 21.52. (m, 4H), 6.96 (d, J = 1.2 Hz, 1H), 6.89 (d, J = 1.2 Hz, 1H), 6.85
HRMS (ESI) m/z calcd for C20H20FIN3O2S [M + H]+ 512.0299; (d, J = 7.4 Hz, 2H), 6.79 (dd, J = 2.8, 1.6 Hz, 1H), 6.19 (dd, J = 2.8,
found512.0297.
1.2 Hz, 1H), 2.35 (s, 3H). 13C NMR (100 MHz, CDCl3) d 144.82,
N-(1-(1H-Imidazol-1-yl)-2-iodoallyl)-N-(4-chlorobenzyl)-4-methyl- 134.68, 134.35, 132.53, 131.98, 129.87, 129.52, 129.37, 128.20,
benzenesulfonamide (4ka). Purified by flash column chromato- 127.73, 124.37, 101.79, 78.04, 21.60. HRMS (ESI) m/z calcd for
graphy (hexane/EtOAc = 2/1) in 62% yield (95.8 mg, 0.186 mmol) as C19H18IN4O4S [M + H]+ 525.0088; found, 525.0090.
1
a yellow liquid. H NMR (400 MHz, CDCl3) d 7.42 (d, J = 8.2 Hz,
N-(2-Iodo-1-(4-nitro-1H-imidazol-1-yl)allyl)-4-methyl-N-phenyl-
2H), 7.37 (s, 1H), 7.16 (d, J = 8.1 Hz, 2H), 7.07 (d, J = 8.3 Hz, 2H), benzenesulfonamide (4ad). Purified by flash column chromato-
6.93 (s, 1H), 6.86 (d, J = 8.3 Hz, 2H), 6.67 (s, 1H), 6.56 (s, 1H), 6.25 graphy (hexane/EtOAc = 3/1) in 65% yield (102.2 mg, 0.195 mmol)
(s, 1H), 6.11 (s, 1H), 4.34 (d, J = 15.9 Hz, 1H), 4.29 (d, J = 15.9 Hz, as a yellow solid. M.p. 92–93 1C. 1H NMR (400 MHz, CDCl3) d 7.51
1H), 2.35 (s, 3H). 13C NMR (100 MHz, CDCl3) d 144.56, 136.93, (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.38 (s, 1H), 7.35 (d, J = 7.4 Hz,
136.09, 133.96, 133.56, 132.45, 130.00, 129.78, 129.59, 128.53, 1H), 7.26–7.20 (m, 4H), 6.96 (s, 1H), 6.83 (d, J = 7.7 Hz, 2H), 6.66
127.30, 118.51, 100.96, 76.39, 48.69, 21.57. HRMS (ESI) m/z calcd (s, 1H), 6.26 (s, 1H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3) d
for C20H20ClIN3O2S [M + H]+ 528.0004; found, 528.0009.
147.68, 145.26, 135.98, 134.98, 133.63, 131.83, 130.36, 129.84,
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129.74, 129.63, 127.87, 118.81, 100.35, 77.39, 21.66. HRMS (ESI) column chromatography (hexane/EtOAc = 4/1) in 46% yield
1
m/z calcd for C19H18IN4O4S [M + H]+ 525.0088; found, 525.0085. (96.5 mg, 0.138 mmol) as a white solid. M.p. 97–98 1C. H NMR
N-(2-Iodo-1-(4-iodo-1H-imidazol-1-yl)allyl)-4-methyl-N-phenyl- (400 MHz, CDCl3) d 7.39 (d, J = 8.1 Hz, 2H), 7.29–7.28 (m, 3H),
benzenesulfonamide (4ae). Purified by flash column chromato- 7.25–7.23 (m, 2H), 7.04 (s, 1H), 7.02–7.00 (m, 2H), 4.87 (s, 2H),
graphy (hexane/EtOAc = 4/1) in 16% yield (29.1 mg, 0.048 mmol) 2.42 (s, 3H). 13C NMR (100 MHz, CDCl3) d 144.85, 137.41,
as a white solid. M.p. 77–78 1C. 1H NMR (400 MHz, CDCl3) d 7.46 135.43, 133.76, 129.71, 129.66, 128.95, 128.26, 127.82, 118.92,
(d, J = 8.1 Hz, 2H), 7.37 (t, J = 7.4 Hz, 1H), 7.30–7.22 (m, 5H), 6.92 117.52, 105.54, 84.26, 56.99, 21.65. HRMS (ESI) m/z calcd for
(s, 1H), 6.83 (d, J = 7.9 Hz, 2H), 6.76 (s, 1H), 6.68 (s, 1H), 6.23 C19H15Br3IN3O2SNa [M + Na]+ 737.7352; found, 737.7351.
(s, 1H), 2.43 (s, 3H). 13C NMR (100 MHz, CDCl3) d 144.75, 138.76,
N-(1-(1H-Benzo[d]imidazol-1-yl)-2-iodoallyl)-4-methyl-N-phenyl-
135.43, 134.13, 132.65, 131.86, 129.93, 129.67, 129.27, 128.29, benzenesulfonamide (4ai). Purified by flash column chromato-
127.83, 124.50, 101.57, 76.56, 21.64. HRMS (ESI) m/z calcd for graphy (hexane/EtOAc = 2/1) in 74% yield (117.5 mg, 0.222 mmol)
C19H18I2N3O2S (M + H)+ 605.9204; found, 605.9210.
as a white solid. M.p. 91–92 1C. 1H NMR (400 MHz, CDCl3) d 7.78–
N-(2-Iodo-1-(5-iodo-1H-imidazol-1-yl)allyl)-4-methyl-N-phenyl- 7.72 (m, 1H), 7.47 (d, J = 8.0 Hz, 2H), 7.41 (s, 1H), 7.39–7.35
benzenesulfonamide (4ae0). Purified by flash column chromato- (m, 1H), 7.33–7.22 (m, 4H), 7.17 (d, J = 7.9 Hz, 2H), 7.09 (t, J = 7.7 Hz,
graphy (hexane/EtOAc = 2/1) in 39% yield (70.8 mg, 0.117 mmol) 2H), 7.05 (s, 1H), 6.63 (d, J = 7.6 Hz, 2H), 6.37 (s, 1H), 2.38 (s, 3H).
as a white solid. M.p. 81–82 1C. 1H NMR (400 MHz, CDCl3) d 7.48 13C NMR (100 MHz, CDCl3) d 144.48, 142.98, 142.19, 135.49, 134.15,
(d, J = 8.3 Hz, 2H), 7.28 (t, J = 7.4 Hz, 1H), 7.18–7.15 (m, 4H), 7.03 132.98, 131.98, 131.79, 129.79, 129.52, 129.22, 127.83, 123.86, 123.06,
(s, 1H), 6.99 (s, 1H), 6.96–6.94 (m, 2H), 6.79 (d, J = 7.8 Hz, 2H), 120.61, 110.01, 103.49, 74.80, 21.59. HRMS (ESI) m/z calcd for
6.32–6.29 (m, 1H), 2.37 (s, 3H). 13C NMR (100 MHz, CDCl3) d C23H21IN3O2S [M + H]+ 530.0394; found, 530.0398.
144.45, 139.78, 136.73, 135.33, 134.04, 134.02, 132.11, 131.54,
N-(1-(5-Chloro-1H-benzo[d]imidazol-1-yl)-2-iodoallyl)-4-methyl-
129.83, 129.34, 129.29, 128.34, 103.93, 77.44, 21.64. HRMS (ESI) N-phenylbenzenesulfonamide (4aj). Purified by flash column
m/z calcd for C19H18I2N3O2S (M + H)+ 605.9204; found, 605.9209. chromatography (hexane/EtOAc = 4/1) in 36% yield (60.9 mg,
N-(1-(4-Formyl-1H-imidazol-1-yl)-2-iodoallyl)-4-methyl-N- 0.108 mmol) as a yellow solid. M.p. 80–81 1C. 1H NMR (400 MHz,
phenylbenzenesulfonamide (4af). Purified by flash column CDCl3) d 7.72 (s, 1H), 7.46 (d, J = 8.1 Hz, 2H), 7.43 (s, 1H), 7.28–
chromatography (hexane/EtOAc = 4/1) in 41% yield (62.4 mg, 7.18 (m, 6H), 7.10 (t, J = 7.6 Hz, 2H), 7.04 (s, 1H), 6.62 (d, J =
0.123 mmol) as a yellow solid. M.p. 66–67 1C. 1H NMR (400 MHz, 7.8 Hz, 2H), 6.38 (s, 1H), 2.40 (s, 3H). 13C NMR (100 MHz, CDCl3) d
CDCl3) d 9.74 (s, 1H), 7.44–7.38 (m, 3H), 7.33–7.27 (m, 2H), 7.20– 144.66, 143.86, 143.41, 135.38, 134.05, 132.20, 131.71, 131.61,
7.15 (m, 4H), 6.94 (s, 1H), 6.74 (d, J = 7.8 Hz, 2H), 6.66 (s, 1H), 129.91, 129.58, 129.31, 128.72, 127.80, 124.31, 120.46, 110.93,
6.21 (s, 1H), 2.36 (s, 3H). 13C NMR (100 MHz, CDCl3) d 185.86, 102.98, 74.93, 21.59. HRMS (ESI) m/z calcd for C23H20ClIN3O2S
144.96, 141.83, 138.64, 135.22, 133.83, 132.92, 131.86, 130.13, [M + H]+ 564.0004; found, 564.0008.
129.75, 129.46, 127.83, 124.09, 101.32, 76.90, 21.65. HRMS (ESI)
N-(1-(6-Chloro-1H-benzo[d]imidazol-1-yl)-2-iodoallyl)-4-methyl-
m/z calcd for C20H19IN3O3S [M + H]+ 508.0186; found, 508.0190. N-phenylbenzenesulfonamide (4aj0). Purified by flash column
N-(1-(5-Formyl-1H-imidazol-1-yl)-2-iodoallyl)-4-methyl-N- chromatography (hexane/EtOAc = 3/1) in 26% yield (44 mg,
1
phenylbenzenesulfonamide (4af0). Purified by flash column 0.078 mmol) as a yellow solid. M.p. 97–98 1C. H NMR (400 MHz,
chromatography (hexane/EtOAc = 3/1) in 42% yield (64.0 mg, CDCl3) d 7.63 (d, J = 8.6 Hz, 1H), 7.52 (d, J = 8.3 Hz, 2H), 7.39 (s, 1H),
0.126 mmol) as a white solid. M.p. 55–56 1C. 1H NMR (400 MHz, 7.29–7.23 (m, 4H), 7.17–7.15 (m, 2H), 7.11 (t, J = 7.9 Hz, 2H),
CDCl3) d 9.70 (s, 1H), 7.80 (s, 1H), 7.67 (s, 1H), 7.46 (d, J = 8.0 Hz, 7.08 (s, 1H), 6.61 (d, J = 7.6 Hz, 2H), 6.44–6.41 (m, 1H), 2.42
3H), 7.27 (t, J = 7.4 Hz, 1H), 7.18–7.13 (m, 4H), 6.87 (s, 1H), 6.83 (s, 3H). 13C NMR (100 MHz, CDCl3) d 144.83, 142.91, 141.57,
(d, J = 7.7 Hz, 2H), 6.19 (s, 1H), 2.33 (s, 3H). 13C NMR (100 MHz, 135.30, 134.05, 133.54, 132.33, 131.63, 129.94, 129.77, 129.74,
CDCl3) d 179.23, 144.37, 143.71, 140.08, 135.27, 134.72, 132.08, 129.33, 127.80, 123.84, 121.46, 110.14, 102.91, 74.90, 21.68.
131.99, 129.76, 129.34, 129.27, 128.42, 127.20, 103.71, 75.78, HRMS (ESI) m/z calcd for C23H20ClIN3O2S [M + H]+ 564.0004;
21.62. HRMS (ESI) m/z calcd for C20H19IN3O3S [M + H]+ found, 564.0007.
508.0186; found 508.0185.
N-(2-Iodo-1-(5-methoxy-1H-benzo[d]imidazol-1-yl)allyl)-4-methyl-
N-(1-(4,5-Dicyano-1H-imidazol-1-yl)-2-iodoallyl)-4-methyl-N- N-phenylbenzenesulfonamide (4ak). Purified by flash column
phenylbenzenesulfonamide (4ag). Purified by flash column chromatography (hexane/EtOAc = 2/1) in 16% yield (26.9 mg,
chromatography (hexane/EtOAc = 3/1) in 44% yield (69.9 mg, 0.048 mmol) as a yellow solid. M.p. 70–71 1C. 1H NMR (400 MHz,
0.132 mmol) as a white solid. M.p. 88–89 1C. 1H NMR (400 MHz, CDCl3) d 7.43 (d, J = 8.1 Hz, 2H), 7.31 (s, 1H), 7.20 (d, J = 7.5 Hz,
CDCl3) d 7.66 (s, 1H), 7.49 (d, J = 8.2 Hz, 2H), 7.43 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 8.3 Hz, 5H), 7.05 (t, J = 7.7 Hz, 2H), 7.00 (s, 1H),
1H), 7.34–7.28 (m, 4H), 7.00 (d, J = 1.1 Hz, 1H), 6.93 (s, 1H), 6.90 6.86 (dd, J = 8.8, 1.7 Hz, 1H), 6.58 (d, J = 7.7 Hz, 2H), 6.32 (s, 1H),
(d, J = 7.7 Hz, 2H), 6.40 (d, J = 1.9 Hz, 1H), 2.45 (s, 3H). 13C NMR 3.81 (s, 3H), 2.34 (s, 3H). 13C NMR (100 MHz, CDCl3) d 156.55,
(100 MHz, CDCl3) d 145.55, 141.17, 134.79, 134.30, 133.68, 144.46, 143.89, 142.44, 135.49, 134.13, 131.87, 131.78, 129.75,
131.92, 130.57, 129.96, 129.83, 128.03, 123.53, 111.82, 111.10, 129.51, 129.16, 127.84, 113.83, 110.45, 103.48, 102.60, 74.88,
107.27, 99.67, 76.78, 21.75. HRMS (ESI) m/z calcd for 55.70, 21.56. HRMS (ESI) m/z calcd for C24H23IN3O3S [M + H]+
C21H16IN5O2SNa [M + Na]+ 551.9962; found, 551.9963.
560.0499; found, 560.0500.
(Z)-N-(2-Iodo-3-(2,4,5-tribromo-1H-imidazol-1-yl)prop-1-en-1-yl)-
N-(2-Iodo-1-(6-methoxy-1H-benzo[d]imidazol-1-yl)allyl)-4-methyl-
4-methyl-N-phenylbenzenesulfonamide (5ah). Purified by flash N-phenylbenzenesulfonamide (4ak0). Purified by flash column
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chromatography (hexane/EtOAc = 3/1) in 24% yield (40.3 mg,
0.072 mmol) as a white solid. M.p. 58–59 1C. H NMR (400 MHz,
1
CDCl3) d 7.54 (d, J = 8.8 Hz, 1H), 7.42 (d, J = 8.3 Hz, 2H), 7.22 (s, 1H),
7.18 (d, J = 7.5 Hz, 1H), 7.12 (d, J = 8.4 Hz, 3H), 7.03 (t, J = 7.8 Hz,
2H), 7.00–6.97 (m, 1H), 6.85 (dd, J = 8.8, 2.3 Hz, 1H), 6.75 (d, J =
2.1 Hz, 1H), 6.57 (d, J = 7.7 Hz, 2H), 6.33–6.29 (m, 1H), 3.78 (s, 3H),
2.33 (s, 3H). 13C NMR (100 MHz, CDCl3) d 157.36, 144.50, 141.18,
137.28, 135.55, 134.11, 133.67, 131.84, 129.79, 129.56, 129.20,
127.80, 121.04, 112.48, 103.50, 93.54, 74.75, 55.81, 21.59. HRMS
(ESI) m/z calcd for C24H23IN3O3S [M + H]+ 560.0499; found,
560.0504.
N-(1-(5,6-Dimethyl-1H-benzo[d]imidazol-1-yl)-2-iodoallyl)-4-
methyl-N-phenylbenzenesulfonamide (4al). Purified by flash
column chromatography (hexane/EtOAc = 3/1) in 48% yield
(80.3 mg, 0.144 mmol) as a white solid. M.p. 61–62 1C. 1H NMR
(400 MHz, CDCl3) d 7.49 (d, J = 8.0 Hz, 2H), 7.46 (s, 1H), 7.24–
7.16 (m, 4H), 7.13 (s, 1H), 7.05 (d, J = 8.2 Hz, 3H), 7.02 (s, 1H),
6.58 (d, J = 7.7 Hz, 2H), 6.34 (s, 1H), 2.36 (s, 3H), 2.33 (s, 6H).
13C NMR (100 MHz, CDCl3) d 144.42, 141.48, 141.25, 135.60,
134.09, 133.12, 131.99, 131.77, 131.67, 131.49, 129.73, 129.53,
129.17, 127.89, 120.60, 109.89, 103.82, 74.54, 21.62, 20.55,
20.27. HRMS (ESI) m/z calcd for C25H25IN3O2S [M + H]+
558.0707; found, 558.0705.
Conclusions
In conclusion, we developed a facile protocol for the synthesis
of allylic N,N-acetals through NIS-mediated hydroamination of
allenamides by imidazole derivatives. Regioselective 1,2-addition
and broad substrate specificity were achieved, thereby overcoming
the previous limitations of allenamide activation by an iodine
electrophile. Imidazole acts as the nucleophile, which attacks
the conjugated sulfimide ion intermediate to yield the 1,2-adduct.
This green synthetic method provides an alternative to the corres-
ponding transition-metal-catalysed reaction and shows promise
for large-scale application. The potential utilization and extension
of this interesting synthetic method are currently underway.
Conflicts of interest
There are no conflicts to declare.
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Acknowledgements
This work was financially supported by the Project of Science and
Technology Department of Sichuan Province (No. 2018JY0226)
and the Fundamental Research Funds of Central Universities,
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