Synthesis of N-Substituted 2-Amino-3,4-diiodofurans from Allenes via NIS-Mediated Intramolecular Electrophilic Iodocyclization

Article abstract of DOI:10.1055/s-0036-1588792

A facile and efficient method for the syntheses of N-substituted 2-amino-3,4-diiodofurans from various readily available allenic amides has been developed. The reaction was postulated to proceed via an NIS-mediated electrophilic iodocyclization pathway.

Full text of DOI:10.1055/s-0036-1588792

SYNTHESIS
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© Georg Thieme Verlag Stuttgart · New York
2017, 49, A–K
special topic
A
en
G. Li et al.
Special Topic
Synthesis
Synthesis of N-Substituted 2-Amino-3,4-diiodofurans from Allenes
via NIS-Mediated Intramolecular Electrophilic Iodocyclization
Guangchen Lia
Daisy Zhang-Negrerieb
R2
R1
R2
Yunfei Du*a,b
NIS (2 equiv)
MeCN, rt
O
N
a Tianjin Key Laboratory for Modern Drug Delivery & High-Efficiency,
School of Pharmaceutical Science and Technology, Tianjin University,
Tianjin 300072, P. R. of China
R3
R1
N
R3
O
I
I
b Collaborative Innovation Center of Chemical Science and Engineering
(Tianjin), Tianjin 300072, P. R. of China
R1= H, Me, F, Cl, Br,I
R2 = H, Me, OMe, Cl, Br
R3 = Me, Et, n-Bu, Bn, PMB
19 examples
up to 90% yield
duyunfeier@tju.edu.cn
Published as part of the Special Topic Modern Strategies with Iodine in
Synthesis
Received: 28.02.2017
Accepted after revision: 24.03.2017
Published online: 20.04.2017
a) Yamamoto's work[5]
R1
O
R2
HO
O
IX
DOI: 10.1055/s-0036-1588792; Art ID: ss-2017-c0126-st
(1)
MeOH, rt
X = I, Br
R1
R2
X
I
R1 = Ar, alkyl, H
R2 = Ar, alkyl
Abstract A facile and efficient method for the syntheses of N-substi-
tuted 2-amino-3,4-diiodofurans from various readily available allenic
amides has been developed. The reaction was postulated to proceed via
an NIS-mediated electrophilic iodocyclization pathway.
23–91%
b) This work
R2
R1
Key words diiodofurans, allenes, NIS, electrophilic iodocyclization
R2
O
N
NIS, MeCN
rt
(2)
R3
R1
Substituted furans are an important class of heterocy-
cles that not only exist in a wide range of natural products,
but also are useful building blocks for the assembly of many
pharmaceutical agents.1 Due to their broad utility, a variety
of methods have been developed for the construction of
this class of privileged scaffold;2 however, those that can re-
alize an efficient assembly of specifically substituted furans
is quite limited. Our literature survey found scarce reports
on protocols for forming dihalogenated furans, a special
type of furan derivatives that have the potential for further
functionalization to access versatilely substituted furan de-
rivatives.3–5
To our knowledge, the only example documented is the
construction of 3,4-dihalofurans via electrophilic iodocy-
clization of 4-hydroxybut-2-yn-1-ones by using I2 or IBr as
the electrophile, reported by Yamamoto and co-workers in
2001 (Scheme 1, eq. 1).5 Here, we report an alternative ap-
proach for the facile construction of the N-substituted 2-
amino-3,4-diiodofuran skeleton from readily available al-
lenes under mild reaction conditions (Scheme 1, eq. 2).
Allenes are robust building blocks that have found wide
applications in organic synthesis. In 2013, our group real-
ized the conversion of N-arylcinnamic amides into 3-
arylquinolin-2-ones through phenyliodine(III) bis(trifluo-
roacetate) (PIFA)-mediated C–C bond formation facilitated
N
R3
O
I
I
R1, R2 = H, Me, OMe, F, Cl, Br, I
R3 = Me, Et, n-Bu, Bn, PMB
35–90%
Scheme 1 Formation of 3,4-diiodofurans via electrophilic iodocycliza-
tion
by a concomitant 1,2-aryl shift (Scheme 2, a).6a In 1996
Marshall et al. reported allenic carboxamides to undergo
cyclization to provide iminolactones, which could be fur-
ther converted into aminofurans (Scheme 2, b).6b Inspired
by the above two work, we envisaged two possible path-
ways for the transformation of buta-2,3-dienamide
(Scheme 2, c). In path a, 1a first attacks the iodine of the io-
dine(III) reagent to give the iminium salt 1A, which under-
goes annulation to give the intermediate 1B. Product quino-
lin-2-one 1C is formed with the subsequent conjugate addi-
tion of the L– ion, released from the first step, to
intermediate 1B and along with the release of iodobenzene
(Scheme 2, c). In path b, we expect that dienamide 1a could
be converted into iminium salt 1D, as reported for a similar
case,6b via I(I)-mediated intramolecular cyclization. Then
1D undergoes deprotonation to afford 3-iodofuran 1E,
which could be further converted into diiodofurans 2a via
iodination.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

B
G. Li et al.
Special Topic
Synthesis
a) Known PIFA-mediated C–C bond formation concomitant with a 1,2-aryl shift
R3
Ar
R3
Ar
O
PIFA, TFA, BF3·OEt2
R1
R1
DCE, 0 °C to rt
N
R2
O
N
R2
R
R
1 = H, Me, OMe, F, Cl, Br, CF3, CO2Me
2 = Me, Bn, i-Pr, cyclopropylmethyl; R3 = H, Ar
b) Known cyclization of the allenic carboxamide
I
C7H15
C7H15
I
C7H15
H
IBr
H+, H2O
Me
Me
ArHN
ArN
Me
ArHN
L–
O
O
O
Ar = p-MeO2CC6H4 or p-ClC6H4
c) Two possible pathways proposed
Ph
Ph
L
Ph
path a
PhIL2
– PhI, – L–
Ph
N
O
N
O
I
N
O
L
I
Ph
Ph
I
L
1A
1B
1C
Ph
N
O
I
I
I
1a
L–
N
path b
IL
IL
Ph
Ph
Ph
N
N
– HL
O
O
O
Ph
Ph
Ph
1D
1E
2a
Scheme 2 Two possible pathways based on previous work
Initially, the commercially available N-methyl-N,4-di-
phenylbuta-2,3-dienamide (1a) was selected as a model
substrate for the search of the proposed conversion. Disap-
pointingly, no expected reaction occurred when 1a was
treated with a series of I(III) reagents including PIDA, PIFA,
and PhIO, not even at elevated temperature (see the Sup-
porting Information for details). Further attempts to carry
out the reaction in the presence of various Lewis acids such
as TMSOTf, AlCl3, and BF3·OEt2 were all unsuccessful (see
the Supporting Information for details). To our pleasant
surprise, the reaction of 1 equivalent of 1a with 2 equiva-
lents of N-iodosuccinimide (NIS) in dichloromethane af-
forded 46% yield of a five-membered 3,4-diiodo-N-methyl-
N,5-diphenylfuran-2-amine (2a), the structure of which
was later unambiguously confirmed through X-ray crystal-
lographic analysis (Figure 1, see also Supporting Informa-
tion).7 Further screening of the various reaction parameters
was carried out in order to identify the optimized condi-
tions for this newly discovered reaction.
ing some basic additives such as Et3N and K2CO3 to the reac-
tion, but the yield did not improve (entries 10, 11). Switch-
ing NIS to another electrophile including I2, IBr, NBS, and
NCS did not provide any desired halogenated product in
each case (entries 12–16).
Our next step was to investigate the scope and limita-
tions of this newly established intramolecular iodocycliza-
tion method. A variety of allenes 1a–s were investigated
under the optimized conditions (Scheme 3). The method
was shown to work equally well with substrates bearing an
ethyl, n-butyl, benzyl, and PMB on the N atom (Scheme 3,
2b–e). The highest yield (90%) was obtained from 1e, in
which R3 was a PMB group (Scheme 3, 2e). The electronic
effects of the substituent R1 were evaluated next (Scheme 3,
Results are summarized in Table 1. Solvent-screening
study suggested that MeCN was the most appropriate sol-
vent in comparison to CH2Cl2, EtOH, THF, DMF, CCl4, and
CHCl3 (Table 1, entries 1–7). Reducing the reaction tem-
perature to 0 °C or –20 °C resulted in sluggish reaction and
yields of 77% and 73%, respectively (entries 8, 9). We also
observed that product 2a decomposed completely on acidic
silica gel (200–300 mesh, pH 6–7), but was stable to alumi-
na. We attempted to further improve the yield by introduc-
Figure 1 X-ray crystal structure of 2a
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

C
G. Li et al.
Special Topic
Synthesis
Table 1 Optimization of the Reaction Conditionsa
However, the substrate with both R1 and R2 being Br was
converted into the target compounds in a relatively lower
yield of 62% (Scheme 3, 2s). Unfortunately, the unsubstitut-
ed or ethyl-substituted allene 1u or 1v could not furnish the
desired diiodofuran 2u or 2v under the optimized condi-
tions (Scheme 3, 2u,v).
O
electrophile, solvent
N
additive, temperature
Based on the previous reports,5,8,9 we postulate here a
possible mechanism for the process. As shown in Scheme 4,
the first step is an intramolecular cyclization of the di-
enamide 1a in the presence of NIS leading to the formation
of the iminium salt A, which undergoes deprotonation to
afford the intermediate N-substituted 2-amino-3-iodofu-
ran 3a. Further electrophilic iodination provides iminium
salt B, which was converted into the desired product, N-
substituted 2-amino-3,4-diiodofuran 2a, via deprotonative
aromatization.
A control experiment was carried out to support the
proposed mechanism (Scheme 5). N-(4-Bromophenyl)-N-
methyl-4-(p-tolyl)buta-2,3-dienamide (1q; 5 equiv, 0.5
mmol) was treated with NIS (1 equiv, 0.1 mmol) in MeCN at
room temperature; after 5 seconds the reaction was
quenched with sodium thiosulfate solution. It was found
that the reaction afforded an inseparable mixture of N-sub-
stituted 2-amino-3,4-diiodofuran 2q and N-substituted 2-
amino-4-iodofuran 3q. After treating the above mixture in
MeCN with NIS (0.1 mmol) at room temperature, interme-
diate 3q was completely converted into diiodofuran 2q. This
experiment suggests that the present cyclization proceeds
through the formation of the monoiodonated 3q, with the
subsequent further iodination (Scheme 5).
N
O
I
I
1a
2a
Entry
Solvent
Electrophile Temp
Time
(min)
Yield
(%)b
(2 equiv)
(°C)
1
2
CH2Cl2
EtOH
THF
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
NIS
I2
25
15
6
46
5
25
25
25
25
25
25
0
3
10
5
52
20
78
40
45
77
73
70
68
0e
4
DMF
5
MeCN
CCl4
5
6
5
7
CHCl3
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
5
8
7
9
–20
25
25
25
25
25
50
50
15
5
10c
11d
12
13
14
15
16
5
5
IBr
5
0e
NBS
NBS
NCS
30
30
30
NRf
0e
0e
a Reactions conditions: 1a (0.5 mmol), NIS, in anhyd MeCN (conc. 0.05 M)
at r.t., unless otherwise stated.
b Isolated yield.
The utility of the method extends to converting the re-
sulting diiodofurans into other functional building blocks
through known transformations. For example, N-substitut-
ed 2-amino-3,4-diiodofuran 2a was converted with ease
into the tetrasubstituted furan 2w via Pd-catalyzed
Sonogashira coupling reaction.5 The corresponding product
2w could be even further converted into terminal alkyne 2x
(95% yield) by the removal of the protecting group10
(Scheme 6). In addition, the triphenylfuran 2y could be ob-
tained from diiodofuran 2a via Suzuki coupling reaction.11
In conclusion, we have disclosed a facile and efficient
approach for the synthesis of a series of N-substituted 2-
amino-3,4-diiodofurans from various accessible allenic am-
ides via NIS-mediated electrophilic iodocyclization. This
methodology features simple procedure, mild reaction con-
ditions, and the use of commercially available starting ma-
terials. Furthermore, the corresponding diiodofuran prod-
ucts can be easily converted into tetrasubstituted furans via
transition-metal-catalyzed coupling reactions.
c Et3N (2 equiv).
d K2CO3 (2 equiv).
e No desired product detected.
f No reaction occurred.
1f–l). Yield data showed that the substrate bearing an elec-
tron-donating p-Me group was converted into the expected
product in satisfactory yield of 71% (Scheme 3, 2g). Steric
effect was observed as 2f, with an ortho-methyl group sub-
stituted on the aniline ring, was formed in significantly
lower yield (35%). Substrates bearing electron-withdrawing
halogen groups on the aniline ring gave the desired prod-
ucts 2h–l in 60–75% yields. Concerning the R2 substituents,
electron-withdrawing groups (Cl and Br) were more fa-
vored than electron-donating ones (Me and OMe). The hal-
ogen-substituted substrates were readily converted into the
corresponding desired products in satisfactory yields
(Scheme 3, 2o,p), while much lower yields were obtained
for p-Me- and p-OMe-substituted 2m and 2n (60% and 40%,
respectively). Finally, substrates bearing one electron-with-
drawing substituent (R1 = Br) and one electron-donating
substituent (R2 = Me) were also transformed into the target
compounds in similar satisfactory yields (Scheme 3, 2q,r).
1H NMR and 13C NMR spectra were recorded on a Bruker Avance III
600 MHz or a Bruker Avance III 400 MHz spectrometer at 25 °C.
Chemical shifts values are given in ppm and referred as the internal
standard to TMS: 0.00 ppm. Data are reported as follows: chemical
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

D
G. Li et al.
Special Topic
Synthesis
R2
R1
NIS (2 equiv)
MeCN, rt
O
R2
N
R3
R1
N
R3
1a–s
O
I
I
2a–sb
O
O
O
O
O
N
N
N
N
N
Et
n-Bu
Bn
PMB
I
I
I
I
I
I
I
I
I
I
2a, 78%, 5 min
2b, 68%, 5 min
2c, 70%, 5 min
2d, 81%, 5 min
2e, 90%, 5 min
F
Br
Cl
O
N
O
N
O
N
O
O
N
N
I
I
I
I
I
I
I
I
I
I
2f, 35%, 5 min
2g, 71%, 5 min
2h, 60%, 8 min
2i, 72%, 8 min
2j, 75%, 8 min
I
Br
O
N
Cl
OMe
O
N
O
N
O
N
O
N
I
I
I
I
I
I
I
I
I
I
2k, 73%, 8 min
2l, 65%, 8 min
2m, 60%, 5 min
2n, 40%, 5 min
2o, 72%, 8 min
Br
Br
Br
Br
Br
O
R
O
N
N
O
N
O
N
O
N
I
I
I
I
I
I
I
I
2u: R = H, 0%
2v: R = Et, 0%
I
I
2p, 70%, 8 min
2q, 76%, 8 min
2r, 70%, 8 min
2s, 62%, 20 min
Scheme 3 Substituent effect studies of the NIS-mediated synthesis of N-substituted 2-amino-3,4-diiodofurans from allenic amides. Reagents and con-
ditions: 1 (0.5 mmol), NIS (1.0 mmol), in anhyd MeCN at r.t. Isolated yields are shown.
O
Ph
Ph
I
O
N
Ph
N
NIS
H
N
Ph
Ph
N
O
O
O
I
O
Ph
I
3a
A
N
1a
O
Ph
Ph
O
O
O
N
N
N
Ph
Ph
H
I
I
I
I
B
2a
O
Scheme 4 Proposed mechanism
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

E
G. Li et al.
Special Topic
Synthesis
Br
Br
(a)
O
O
N
N
N
O
I
I
I
Br
1q
3q
2q
(b)
Scheme 5 Control experiment to support the proposed mechanism. Reagents and conditions: (a) 1q (171 mg, 0.5 mmol, 5 equiv), NIS (11 mg, 0.1
mmol, 1 equiv), MeCN (12 mL); (b) NIS (2.7 mg, 0.1 mmol), 5 min.
O
N
O
N
O
N
(1)
(a)
(b)
I
I
HO
OH
2a
2w
2x
O
O
N
N
(c)
(2)
Ph
Ph
I
I
2a
2y
Scheme 6 Reagents and conditions: (a) PdCl2(PPh3)2 (20 mol%), CuI (10 mol%), Et3N, 2-methylbut-3-yn-2-ol (2.5 equiv), N2, 80 °C, 15 h, 76%; (b) NaH
(50 mol%), toluene, 100 °C, 4 h, 95%; (c) PhB(OH)2 (3 equiv), Pd(PPh3)4 (10 mol%), N2, toluene/H2O (20:1),100 °C, in sealed tube, 60 h, 74%.
shift, multiplicity (standard abbreviations), coupling constant (J, in
Hz), and integration. High-resolution mass spectrometry (HRMS) was
obtained on a Bruker 1290 UPLC/micrOTOF-Q II spectrometer. Melt-
ing points were determined with a Micromelting point apparatus.
TLC plates were monitored by exposure to ultraviolet light. Reagents
and solvents were purchased as reagent grade and were used without
further purification. All reactions were performed in standard glass-
ware, heated at 70 °C for 3 h before use. Flash column chromatogra-
phy was performed over silica gel (Yuanli, 200–300 mesh, pH 6–7) or
Al2O3 (Yuanli, 200–300 m, pH 9–10).
1H NMR (600 MHz, CDCl3): δ = 7.40 (t, J = 7.7 Hz, 2 H), 7.32 (t, J = 7.4
Hz, 1 H), 7.29–7.25 (m, 4 H), 7.21 (m, 3 H), 6.42 (d, J = 6.4 Hz, 1 H),
5.98 (d, J = 6.1 Hz, 1 H), 3.37 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 213.1 (s), 164.1 (s), 144.0 (s), 132.0 (s),
129.9 (s), 128.8 (s), 127.9 (s), 127.8 (s), 127.6 (s), 127.5 (s), 98.6 (s),
92.8 (s), 37.9 (s).
HRMS (ESI): m/z calcd for C17H15NONa [M + Na]+: 272.1046; found:
272.1044.
N-Ethyl-N,4-diphenylbuta-2,3-dienamide (1b)
Yield: 379 mg (72%); yellow oil; Rf = 0.33 (EtOAc/PE = 30:70).
2,3-Dienamides 1a–v; General Procedure
1H NMR (600 MHz, CDCl3): δ = 7.40 (t, J = 7.4 Hz, 2 H), 7.33 (t, J = 7.1
Hz, 1 H), 7.28 (d, J = 6.9 Hz, 2 H), 7.21 (m, 5 H), 6.40 (d, J = 5.9 Hz, 1 H),
5.90 (d, J = 4.8 Hz, 1 H), 3.84 (dd, J = 13.1, 6.7 Hz, 2 H), 1.16 (t, J = 7.0
Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 212.8 (s), 163.4 (s), 142.2 (s), 132.0 (s),
129.6 (s), 128.6 (s), 128.5 (s), 127.9 (s), 127.6 (s), 127.4 (s), 98.3 (s),
93.1 (s), 44.7 (s), 13.0 (s).
2,3-Dienamides 1a–v were synthesized by using the procedure re-
ported by Himbert et al.12 A solution of phenylacetyl chloride (371
mg, 2.4 mmol) in CH2Cl2 (40 mL) was transferred slowly by cannula
into a solution of the respective phosphonium ylide (2 mmol) and i-
Pr2NEt (1.03 g, 8 mmol) in CH2Cl2 (20 mL). The mixture was stirred at
r.t. for 12 h and quenched with H2O (50 mL). The organic layer was
separated and washed with H2O, brine, and dried (Na2SO4). After re-
moval of the solvent, the orange residue was purified by column
chromatography on silica gel to afford the desired amide 1.
HRMS (ESI): m/z calcd for C18H17NONa [M + Na]+: 286.1202; found:
286.1200.
N-Methyl-N,4-diphenylbuta-2,3-dienamide (1a)
N-(tert-Butyl)-N,4-diphenylbuta-2,3-dienamide (1c)
Yield: 378 mg (76%); yellow oil; Rf = 0.31 (EtOAc/PE = 30:70).
Yield: 407 mg (70%); yellow oil; Rf = 0.34 (EtOAc/PE = 30:70).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

F
G. Li et al.
Special Topic
Synthesis
1H NMR (600 MHz, CDCl3): δ = 7.39 (t, J = 7.3 Hz, 2 H), 7.32 (t, J = 7.0
Hz, 1 H), 7.29–7.25 (m, 2 H), 7.21 (m, 5 H), 6.39 (d, J = 5.8 Hz, 1 H),
5.90 (d, J = 4.1 Hz, 1 H), 3.83–3.71 (m, 2 H), 1.57–1.49 (m, 2 H), 1.33
(dd, J = 14.6, 7.2 Hz, 2 H), 0.89 (t, J = 7.2 Hz, 3 H).
13C NMR (150 MHz, CDCl3): δ = 212.8 (s), 163.6 (s), 142.5 (s), 132.0 (s),
129.6 (s), 128.6 (s), 128.4 (s), 127.8 (s), 127.6 (s), 127.4 (s), 98.2 (s),
93.0 (s), 49.6 (s), 29.9 (s), 20.1 (s), 13.8 (s).
N-(4-Fluorophenyl)-N-methyl-4-phenylbuta-2,3-dienamide (1h)
Yield: 401 mg (75%); yellow oil; Rf = 0.33 (EtOAc/PE = 30:70).
1H NMR (600 MHz, CDCl3): δ = 7.29 (d, J = 7.2 Hz, 2 H), 7.23–7.20 (m, 3
H), 7.18 (d, J = 7.3 Hz, 2 H), 7.05 (t, J = 8.0 Hz, 2 H), 6.37 (d, J = 5.9 Hz, 1
H), 5.96 (d, J = 3.7 Hz, 1 H), 3.33 (s, 3 H).
13C NMR (151 MHz, CDCl3): δ = 212.8 (s), 164.1 (s), 161.7 (d, J = 258.9
Hz), 139.9 (s), 129.2 (d, J = 8.8 Hz), 127.8 (s), 127.3 (s), 116.7 (s), 116.6
(d, J = 22.7 Hz), 116.6 (s), 98.2 (s), 92.6 (s), 38.0 (s).
HRMS (ESI): m/z calcd for C20H21NONa [M + Na]+: 314.1515; found:
314.1516.
HRMS (ESI): m/z calcd for C17H14FNONa [M + Na]+: 290.0952; found:
290.0955.
N-Benzyl-N,4-diphenylbuta-2,3-dienamide (1d)
Yield: 455 mg (70%); yellow oil; Rf = 0.35 (EtOAc/PE = 30:70).
N-(4-Chlorophenyl)-N-methyl-4-phenylbuta-2,3-dienamide (1i)
Yield: 408 mg (72%); yellow oil; Rf = 0.31 (EtOAc/PE = 30:70).
1H NMR (400 MHz, CDCl3): δ = 7.36–7.26 (m, 4 H), 7.23–7.16 (m, 5 H),
6.36 (d, J = 6.4 Hz, 1 H), 5.97 (d, J = 6.3 Hz, 1 H), 3.33 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.8 (s), 163.9 (s), 142.4 (s), 133.6 (s),
131.7 (s), 129.9 (s), 128.7 (s), 128.7 (s), 127.8 (s), 127.3 (s), 98.3 (s),
92.6 (s), 37.9 (s).
1H NMR (600 MHz, CDCl3): δ = 7.33–7.23 (m, 10 H), 7.21 (m, 3 H), 7.06
(d, J = 7.2 Hz, 2 H), 6.43 (d, J = 6.2 Hz, 1 H), 5.94 (d, J = 5.5 Hz, 1 H), 5.06
(d, J = 14.3 Hz, 1 H), 4.88 (d, J = 14.3 Hz, 1 H).
13C NMR (150 MHz, CDCl3): δ = 213.2 (s), 163.9 (s), 142.2 (s), 137.2 (s),
131.8 (s), 129.5 (s), 129.0 (s), 128.7 (s), 128.5 (s), 128.4 (s), 128.0 (s),
127.7 (s), 127.5 (s), 127.4 (s), 98.5 (s), 92.9 (s), 53.5 (s).
HRMS (ESI): m/z calcd for C23H19NONa [M + Na]+: 348.1359; found:
348.1357.
HRMS (ESI): m/z calcd for C17H14ClNONa [M + Na]+: 306.0656; found:
306.0654.
N-(4-Methoxybenzyl)-N,4-diphenylbuta-2,3-dienamide (1e)
Yield: 483 mg (68%); yellow oil; Rf = 0.30 (EtOAc/PE = 30:70).
1H NMR (600 MHz, CDCl3): δ = 7.32–7.29 (m, 2 H), 7.27 (m, 3 H), 7.20
(m, 3 H), 7.15 (d, J = 8.2 Hz, 2 H), 7.04 (d, J = 7.3 Hz, 2 H), 6.78 (d, J = 8.3
Hz, 2 H), 6.42 (d, J = 6.3 Hz, 1 H), 5.91 (d, J = 5.7 Hz, 1 H), 4.99 (d, J =
14.2 Hz, 1 H), 4.81 (d, J = 14.6 Hz, 1 H), 3.77 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 213.1 (s), 163.8 (s), 159.0 (s), 142.1 (s),
131.9 (s), 130.4 (s), 129.5 (s), 129.4 (s), 128.7 (s), 128.6 (s), 128.0 (s),
127.7 (s), 127.4 (s), 113.7 (s), 98.4 (s), 92.9 (s), 55.2 (s), 52.9 (s).
N-(4-Bromophenyl)-N-methyl-4-phenylbuta-2,3-dienamide (1j)
Yield: 458 mg (70%); yellow oil; Rf = 0.30 (EtOAc/PE = 30:70).
1H NMR (600 MHz, CDCl3): δ = 7.49 (d, J = 7.9 Hz, 2 H), 7.29 (t, J = 7.2
Hz, 2 H), 7.22 (t, J = 7.1 Hz, 1 H), 7.17 (d, J = 7.4 Hz, 2 H), 7.12 (d, J = 7.8
Hz, 2 H), 3.33 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 212.8 (s), 163.9 (s), 142.9 (s), 132.9 (s),
131.7 (s), 129.1 (s), 128.7 (s), 127.8 (s), 127.3 (s), 121.6 (s), 98.3 (s),
92.6 (s), 37.8 (s).
HRMS (ESI): m/z calcd for C17H14BrNONa [M + Na]+: 350.0151; found:
350.0150.
HRMS (ESI): m/z calcd for C24H21NO2Na [M + Na]+: 378.1465; found:
378.1467.
N-(4-Iodophenyl)-N-methyl-4-phenylbuta-2,3-dienamide (1k)
Yield: 510 mg (68%); yellow oil; Rf = 0.31 (EtOAc/PE = 30:70).
1H NMR (600 MHz, CDCl3): δ = 7.68 (d, J = 8.3 Hz, 2 H), 7.29 (t, J = 7.5
Hz, 2 H), 7.22 (t, J = 7.4 Hz, 1 H), 7.17 (d, J = 7.5 Hz, 2 H), 6.99 (d, J = 8.3
Hz, 2 H), 6.36 (d, J = 6.4 Hz, 1 H), 5.98 (d, J = 6.2 Hz, 1 H), 3.33 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 212.8 (s), 163.8 (s), 143.6 (s), 138.9 (s),
131.7 (s), 129.3 (s), 128.7 (s), 127.9 (s), 127. (s), 98.3 (s), 92.6 (s), 37.8
(s).
N-Methyl-4-phenyl-N-(o-tolyl)buta-2,3-dienamide (1f)
Yield: 342 mg (65%); yellow oil; Rf = 0.31 (EtOAc/PE = 30:70).
1H NMR (400 MHz, CDCl3): δ = 7.29–7.23 (m, 4 H), 7.22–7.17 (m, 3 H),
7.17–7.13 (m, 2 H), 6.34 (dd, J = 14.5, 6.4 Hz, 1 H), 5.92–5.78 (m, 1 H),
3.27 (s, 3 H), 2.26 (d, J = 28.5 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.7 (d, J = 17.8 Hz), 164.2 (d, J = 3.1
Hz), 142.4 (d, J = 2.1 Hz), 135.8 (d, J = 20.2 Hz), 131.9 (d, J = 2.4 Hz),
131.4 (d, J = 10.6 Hz), 128.6 (d, J = 1.0 Hz), 128.3 (d, J = 11.3 Hz), 127.7
(d, J = 0.5 Hz), 127.5 (s), 127.4 (s), 127.3 (d, J = 2.3 Hz), 98.1 (d, J = 4.1
Hz), 92.2 (d, J = 4.9 Hz), 36.6 (d, J = 2.8 Hz), 17.6 (d, J = 6.4 Hz).
HRMS (ESI): m/z calcd for C17H14INONa [M + Na]+: 398.0012; found:
398.0010.
HRMS (ESI): m/z calcd for C18H17NONa [M + Na]+: 286.1202; found:
286.1200.
N-(3-Bromophenyl)-N-methyl-4-phenylbuta-2,3-dienamide (1l)
Yield: 458 mg (70%); yellow oil; Rf = 0.33 (EtOAc/PE = 30:70).
N-Methyl-4-phenyl-N-(p-tolyl)buta-2,3-dienamide (1g)
Yield: 373 mg (71%); yellow oil; Rf = 0.33 (EtOAc/PE = 30:70).
1H NMR (400 MHz, CDCl3): δ = 7.30–7.26 (m, 2 H), 7.22–7.17 (m, 5 H),
7.13–7.11 (m, 2 H), 6.40 (d, J = 6.4 Hz, 1 H), 5.99 (d, J = 6.3 Hz, 1 H),
3.34 (s, 3 H), 2.35 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.8 (s), 164.1 (s), 141.3 (s), 137.8 (s),
132.0 (s), 130.3 (s), 128.6 (s), 127.6 (s), 127.3 (s), 127.2 (s), 98.2 (s),
92.7 (s), 37.8 (s), 21.1 (s).
1H NMR (600 MHz, CDCl3): δ = 7.43–7.41 (m, 2 H), 7.28 (t, J = 7.2 Hz, 2
H), 7.25–7.18 (m, 5 H), 6.40 (d, J = 6.2 Hz, 1 H), 5.98 (d, J = 5.7 Hz, 1 H),
3.34 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 213.0 (s), 163.8 (s), 145.1 (s), 131.6 (s),
130.9 (s), 130.6 (s), 128.7 (s), 127.8 (s), 127.4 (s), 126.2 (s), 123.0 (s),
98.5 (s), 92.6 (s), 37.9 (s).
HRMS (ESI): m/z calcd for C17H14BrNONa [M + Na]+: 350.0151; found:
350.0153.
HRMS (ESI): m/z calcd for C18H17NONa [M + Na]+: 286.1202; found:
286.1201.
N-Methyl-N-phenyl-4-(p-tolyl)buta-2,3-dienamide (1m)
Yield: 400 mg (76%); yellow oil; Rf = 0.31 (EtOAc/PE = 30:70).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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G. Li et al.
Special Topic
Synthesis
1H NMR (600 MHz, CDCl3): δ = 7.39 (t, J = 7.7 Hz, 2 H), 7.32 (d, J = 7.3
Hz, 1 H), 7.25 (d, J = 8.2 Hz, 2 H), 7.10–7.07 (m, 4 H), 6.38 (d, J = 6.4 Hz,
1 H), 5.96 (d, J = 6.1 Hz, 1 H), 3.36 (s, 3 H), 2.31 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 212.8 (s), 164.1 (s), 143.9 (s), 137.6 (s),
129.7 (s), 129.4 (s), 128.9 (s), 127.7 (s), 127.4 (s), 127.2 (s), 98.2 (s),
92.6 (s), 37.8 (s), 21.3 (s).
N-(3-Bromophenyl)-N-methyl-4-(p-tolyl)buta-2,3-dienamide (1r)
Yield: 443 mg (65%); yellow oil; Rf = 0.30 (EtOAc/PE = 30:70).
1H NMR (600 MHz, CDCl3): δ = 7.44–7.41 (m, 2 H), 7.25–7.23 (m, 1 H),
7.19–7.18 (m, 1 H), 7.08 (m, 4 H), 6.38 (d, J = 6.4 Hz, 1 H), 5.96 (d, J =
6.3 Hz, 1 H), 3.33 (s, 3 H), 2.32 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 213.0 (s), 164.0 (s), 145.2 (s), 137.7 (s),
130.9 (s), 130.9 (s),130.6 (s), 129.4 (s), 128.6 (s), 127.3 (s), 126.2 (s),
122.9 (s), 98.3 (s), 92.5 (s), 37.8 (s), 21.3 (s).
HRMS (ESI): m/z calcd for C18H17NONa [M + Na]+: 286.1202; found:
286.1200.
HRMS (ESI): m/z calcd for C18H16BrNONa [M + Na]+: 364.0307; found:
364.0304.
4-(4-Methoxyphenyl)-N-methyl-N-phenylbuta-2,3-dienamide
(1n)
Yield: 335 mg (60%); yellow oil; Rf = 0.29 (EtOAc/PE = 30:70).
N-(3-Bromophenyl)-4-(4-bromophenyl)-N-methylbuta-2,3-di-
1H NMR (400 MHz, CDCl3): δ = 7.40 (t, J = 7.6 Hz, 2 H), 7.32 (t, J = 7.4
Hz, 1 H), 7.25 (d, J = 7.5 Hz, 2 H), 7.12 (d, J = 8.6 Hz, 2 H), 6.82 (d, J = 8.7
Hz, 2 H), 6.38 (d, J = 6.4 Hz, 1 H), 5.96 (d, J = 6.3 Hz, 1 H), 3.79 (s, 3 H),
3.36 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 212.8 (s), 164.2 (s), 159.3 (s), 143.9 (s),
129.7 (s), 128.6 (s), 127.7 (s), 127.4 (s), 124.0 (s), 114.2 (s), 97.9 (s),
92.6 (s), 55.3 (s), 37.8 (s).
enamide (1s)
Yield: 493 mg (61%); yellow oil; Rf = 0.31 (EtOAc/PE = 30:70).
1H NMR (600 MHz, CDCl3): δ = 7.44–7.40 (m, 3 H), 7.26–7.24 (m, 2 H),
7.20–7.18 (m, 1 H), 7.05 (d, J = 8.3 Hz, 2 H), 6.35 (d, J = 6.4 Hz, 1 H),
5.98 (d, J = 6.3 Hz, 1 H), 3.34 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 213.0 (s), 164.0 (s), 145.2 (s), 137.7 (s),
131.0 (s), 131.0 (s), 130.6 (s), 129.4 (s), 128.6 (s), 127.3 (s), 126.2 (s),
122.9 (s), 98.3 (s), 92.5 (s), 37.8 (s).
HRMS (ESI): m/z calcd for C18H17NO2Na [M + Na]+: 302.1151; found:
302.1154.
HRMS (ESI): m/z calcd for C17H13Br2NONa [M + Na]+: 427.9256; found:
427.9258.
4-(4-Chlorophenyl)-N-methyl-N-phenylbuta-2,3-dienamide (1o)
Yield: 408 mg (72%); yellow oil; Rf = 0.30 (EtOAc/PE = 30:70).
1H NMR (600 MHz, CDCl3): δ = 7.40 (t, J = 7.7 Hz, 2 H), 7.33 (t, J = 7.5
Hz, 1 H), 7.26–7.22 (m, 4 H), 7.12 (d, J = 8.4 Hz, 2 H), 6.37 (d, J = 6.4 Hz,
1 H), 5.99 (d, J = 6.1 Hz, 1 H), 3.36 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 212.9 (s), 163.7 (s), 143.8 (s), 133.3 (s),
130.5 (s), 129.8 (s), 128.9 (s), 128.5 (s), 127.9 (s), 127.4 (s), 97.5 (s),
93.0 (s), 37.8 (s).
N-Methyl-N-phenylbuta-2,3-dienamide (1u)
Yield: 225 mg (65%); yellow oil; Rf = 0.41 (EtOAc/PE = 30:70).
1H NMR (600 MHz, CDCl3): δ = 7.42 (t, J = 7.5 Hz, 2 H), 7.34 (t, J = 7.3
Hz, 1 H), 7.21 (d, J = 7.8 Hz, 2 H), 5.59 (t, J = 6.1 Hz, 1 H), 5.10 (d, J = 6.5
Hz, 2 H), 3.35 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 214.5 (s), 164.6 (s), 143.8 (s), 129.7 (s),
127.7 (s), 127.4 (s), 88.6 (s), 79.1 (s), 37.7 (s).
HRMS (ESI): m/z calcd for C17H14ClNONa [M + Na]+: 306.0656; found:
306.0659.
HRMS (ESI): m/z calcd for C11H11NONa [M + Na]+: 196.0733; found:
196.0731.
4-(4-Bromophenyl)-N-methyl-N-phenylbuta-2,3-dienamide (1p)
Yield: 432 mg (66%); yellow oil; Rf = 0.32 (EtOAc/PE = 30:70).
1H NMR (600 MHz, CDCl3): δ = 7.40 (m, 4 H), 7.32 (t, J = 7.2 Hz, 1 H),
7.27–7.24 (m, 2 H), 7.06 (d, J = 7.8 Hz, 2 H), 6.35 (d, J = 6.0 Hz, 1 H),
5.98 (d, J = 5.9 Hz, 1 H), 3.36 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 212.9 (s), 163.7 (s), 143.8 (s), 131.8 (s),
131.0 (s), 129.8 (s), 128.8 (s), 127.9 (s), 127.4 (s), 121.5 (s), 97.6 (s),
93.1 (s), 37.8 (s).
N-Methyl-N-phenylhexa-2,3-dienamide (1v)
Yield: 269 mg (67%); yellow oil; Rf = 0.40 (EtOAc/PE = 30:70).
1H NMR (400 MHz, CDCl3): δ = 7.41 (t, J = 7.5 Hz, 2 H), 7.32 (t, J = 7.4
Hz, 1 H), 7.22 (d, J = 7.2 Hz, 2 H), 5.63–5.41 (m, 2 H), 3.34 (s, 3 H),
2.10–2.00 (m, 2 H), 1.01 (t, J = 7.4 Hz, 3 H).
13C NMR (100 MHz, CDCl3): δ = 210.6 (s), 165.2 (s), 144.0 (s), 129.6 (s),
127.5 (s), 127.4 (s), 97.0 (s), 89.5 (s), 37.66 (s), 21.0 (s), 13.2 (s).
HRMS (ESI): m/z calcd for C13H15NONa [M + Na]+: 224.1046; found:
224.1047.
HRMS (ESI): m/z calcd for C17H14BrNONa [M + Na]+: 350.0151; found:
350.0153.
N-Substituted 2-Amino-3,4-diiodofurans 2a–v; General Procedure
N-(4-Bromophenyl)-N-methyl-4-(p-tolyl)buta-2,3-dienamide (1q)
Yield: 477 mg (70%); yellow oil; Rf = 0.33 (EtOAc/PE = 30:70).
1H NMR (600 MHz, CDCl3): δ = 7.47 (d, J = 8.4 Hz, 2 H), 7.10–7.03 (m, 6
H), 6.33 (d, J = 6.3 Hz, 1 H), 5.95 (d, J = 6.1 Hz, 1 H), 3.32 (s, 3 H), 2.32
(s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 212.8 (s), 164.0 (s), 143.0 (s), 137.7 (s),
132.9 (s), 131.6 (s), 129.4 (s), 129.1 (s), 127.2 (s), 121.4 (s), 98.2 (s),
92.5 (s), 37.8 (s), 21.3 (s).
N-Iodosuccinimide (225 mg, 1.0 mmol) was added to a solution of the
appropriate 2,3-dienamide 1 (0.5 mmol) in MeCN (12 mL). The prog-
ress of the reaction was monitored by TLC. Upon completion, the re-
action was quenched with 0.1 M aq Na2S2O3 (20 mL) and then extract-
ed with Et2O (3 × 30 mL). The combined organic phases were washed
with brine (2 × 50 mL) and dried (Na2SO4). The solvent was removed
and the residue was purified by flash column chromatography on
Al2O3 (PE) to afford the desired diiodofuran 2.
HRMS (ESI): m/z calcd for C18H16BrNONa [M + Na]+: 364.0307; found:
364.0305.
3,4-Diiodo-N-methyl-N,5-diphenylfuran-2-amine (2a)
Yield: 195 mg (78%); white solid; mp 102–103 °C; Rf = 0.85 (hexane).
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Synthesis
1H NMR (600 MHz, DMSO-d6): δ = 7.88 (d, J = 7.8 Hz, 2 H), 7.49 (t, J =
7.5 Hz, 2 H), 7.40 (t, J = 7.3 Hz, 1 H), 7.26 (t, J = 7.5 Hz, 2 H), 6.86 (t, J =
7.2 Hz, 1 H), 6.72 (d, J = 8.0 Hz, 2 H), 3.26 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 153.8 (s), 149.0 (s), 146.0 (s), 129.5
(s), 129.2 (s), 128.7 (s), 128.6 (s), 126.0 (s), 119.5 (s), 114.0 (s), 78.1 (s),
77.6 (s), 37.9 (s).
3,4-Diiodo-N-methyl-5-phenyl-N-(o-tolyl)furan-2-amine (2f)
Yield: 90 mg (35%); white solid; mp 92.5–93 °C; Rf = 0.84 (hexane).
1H NMR (600 MHz, DMSO-d6): δ = 7.84 (d, J = 6.4 Hz, 2 H), 7.46 (t, J =
7.3 Hz, 2 H), 7.35–7.3 (m, 1 H), 7.24–7.18 (m, 2 H), 7.16 (d, J = 7.8 Hz, 1
H), 7.08 (t, J = 7.3 Hz, 1 H), 3.32 (s, 3 H), 2.04 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 155.3 (s), 145.3 (s), 144.5 (s), 132.4
(s), 131.1 (s), 129.8 (s), 128.6 (s), 127.7 (s), 126.9 (s), 125.1 (s), 125.1
(s), 124.8 (s), 79.4 (s), 65.5 (s), 17.8 (s), 17.8 (s).
HRMS (ESI): m/z calcd for C17H13I2NOK [M + K]+: 539.8718; found:
539.8715.
HRMS (ESI): m/z calcd for C18H15I2NOK [M + K]+: 553.8875; found:
553.8877.
N-Ethyl-3,4-diiodo-N,5-diphenylfuran-2-amine (2b)
Yield: 175 mg (68%); white solid; mp 80–81 °C; Rf = 0.88 (hexane).
1H NMR (600 MHz, DMSO-d6): δ = 7.88 (d, J = 7.6 Hz, 2 H), 7.49 (t, J =
7.4 Hz, 2 H), 7.40 (t, J = 7.3 Hz, 1 H), 7.24 (t, J = 7.4 Hz, 2 H), 6.84 (t, J =
7.2 Hz, 1 H), 6.70 (d, J = 7.8 Hz, 2 H), 3.70 (q, J = 6.9 Hz, 2 H), 1.22 (t, J =
6.9 Hz, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 153.3 (s), 149.8 (s), 145.6 (s), 130.0
(s), 129.8 (s), 129.2 (s), 129.1 (s), 126.5 (s), 119.9 (s), 114.8 (s), 80.5 (s),
78.0 (s), 45.0 (s), 13.6 (s).
3,4-Diiodo-N-methyl-5-phenyl-N-(p-tolyl)furan-2-amine (2g)
Yield: 183 mg (71%); white solid; mp 113–114 °C; Rf = 0.90 (hexane).
1H NMR (600 MHz, CDCl3): δ = 7.93 (d, J = 7.6 Hz, 2 H), 7.40 (t, J = 7.4
Hz, 2 H), 7.33 (t, J = 7.3 Hz, 1 H), 7.07 (d, J = 7.7 Hz, 2 H), 6.68 (d, J = 7.5
Hz, 2 H), 3.30 (s, 3 H), 2.28 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 154.4 (s), 149.6 (s), 143.9 (s), 130.0 (s),
129.7 (s), 129.4 (s), 128.5 (s), 128.4 (s), 126.3 (s), 114.8 (s), 75.4 (s),
75.1 (s), 38.3 (s), 20.5 (s).
HRMS (ESI): m/z calcd for C18H15I2NOK [M + K]+: 553.8875; found:
291.1126 553.8877.
HRMS (ESI): m/z calcd for C18H15I2NOK [M + K]+: 553.8875; found:
553.8874.
N-Butyl-3,4-diiodo-N,5-diphenylfuran-2-amine (2c)
Yield: 190 mg (70%); white solid; mp 90–90.5 °C; Rf = 0.86 (hexane).
N-(4-Fluorophenyl)-3,4-diiodo-N-methyl-5-phenylfuran-2-amine
1H NMR (600 MHz, DMSO-d6): δ = 7.89 (d, J = 7.7 Hz, 2 H), 7.49 (t, J =
7.6 Hz, 2 H), 7.40 (t, J = 7.3 Hz, 1 H), 7.24 (t, J = 7.6 Hz, 2 H), 6.84 (t, J =
7.2 Hz, 1 H), 6.70 (d, J = 8.0 Hz, 2 H), 3.65 (t, J = 7.3 Hz, 2 H), 1.66–1.57
(m, 2 H), 1.43–1.35 (m, 2 H), 0.90 (t, J = 7.3 Hz, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 153.1 (s), 149.1 (s), 145.5 (s), 129.5
(s), 129.2 (s), 128.7 (s), 128.6 (s), 125.9 (s), 119.5 (s), 114.5 (s), 79.3 (s),
77.6 (s), 49.8 (s), 29.8 (s), 19.5 (s), 13.7 (s).
(2h)
Yield: 155 mg (60%); white solid; mp 109–110 °C; Rf = 0.90 (hexane).
1H NMR (600 MHz, CDCl3): δ = 7.93 (d, J = 7.8 Hz, 2 H), 7.42 (t, J = 7.4
Hz, 2 H), 7.35 (t, J = 7.3 Hz, 1 H), 6.97 (t, J = 8.0 Hz, 2 H), 6.74–6.67 (m,
2 H), 3.30 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 157.3 (d, J = 237 Hz), 154.2 (s), 149.7
(s), 142.5 (s), 129.8 (s), 128.6 (s), 128.5 (s), 126.3 (s), 116.0 (d, J = 7.7
Hz), 115.7 (d, J = 22.43 Hz), 75.4 (s), 75.1 (s), 38.6 (s).
HRMS (ESI): m/z calcd for C20H19I2NOK [M + K]+: 581.9188; found:
581.9189.
HRMS (ESI): m/z calcd for C17H12FI2NOK [M + K]+: 557.8624; found:
557.8622.
N-Benzyl-3,4-diiodo-N,5-diphenylfuran-2-amine (2d)
Yield: 233 mg (81%); white solid; mp 139–140 °C; Rf = 0.86 (hexane).
N-(4-Chlorophenyl)-3,4-diiodo-N-methyl-5-phenylfuran-2-amine
1H NMR (600 MHz, DMSO-d6): δ = 7.85 (d, J = 7.6 Hz, 2 H), 7.48 (m, 4
H), 7.39 (t, J = 7.4 Hz, 1 H), 7.34 (t, J = 7.3 Hz, 2 H), 7.25 (t, J = 7.3 Hz, 1
H), 7.21 (t, J = 7.4 Hz, 2 H), 6.84 (t, J = 7.2 Hz, 1 H), 6.72 (d, J = 7.8 Hz, 2
H), 4.95 (s, 2 H).
13C NMR (150 MHz, DMSO-d6): δ = 153.2 (s), 149.0 (s), 145.2 (s), 137.6
(s), 129.5 (s), 129.2 (s), 128.7 (s), 128.6 (s), 128.4 (s), 127.2 (s), 127.1
(s), 125.9 (s), 120.0 (s), 115.0 (s), 78.8 (s), 77.7 (s), 54.1 (s).
(2i)
Yield: 192 mg (72%); white solid; mp 118–119 °C; Rf = 0.90 (hexane).
1H NMR (400 MHz, CDCl3): δ = 7.93 (d, J = 7.2 Hz, 2 H), 7.42 (t, J = 7.5
Hz, 2 H), 7.35 (t, J = 7.3 Hz, 1 H), 7.21 (d, J = 9.0 Hz, 2 H), 6.67 (d, J = 9.0
Hz, 2 H), 3.29 (s, 3 H).
13C NMR (100 MHz, CDCl3): δ = 153.6 (s), 150.1 (s), 144.8 (s), 129.7 (s),
129.1 (s), 128.7 (s), 128.5 (s), 126.4 (s), 125.0 (s), 115.7 (s), 76.4 (s),
75.0 (s), 38.3 (s).
HRMS (ESI): m/z calcd for C23H17I2NOK [M + K]+: 615.9031; found:
615.9028.
HRMS (ESI): m/z calcd for C17H12ClI2NOK [M + K]+: 573.8328; found:
573.8327.
3,4-Diiodo-N-(4-methoxybenzyl)-N,5-diphenylfuran-2-amine (2e)
Yield: 272 mg (90%); white solid; mp 155–156 °C; Rf = 0.84 (hexane).
N-(4-Bromophenyl)-3,4-diiodo-N-methyl-5-phenylfuran-2-amine
1H NMR (600 MHz, DMSO-d6): δ = 7.85 (d, J = 7.6 Hz, 2 H), 7.49 (t, J =
7.5 Hz, 2 H), 7.39 (m, 3 H), 7.21 (t, J = 7.4 Hz, 2 H), 6.90 (d, J = 7.9 Hz, 2
H), 6.83 (t, J = 7.2 Hz, 1 H), 6.72 (d, J = 7.9 Hz, 2 H), 4.86 (s, 2 H), 3.71 (s,
3 H).
13C NMR (150 MHz, DMSO-d6): δ = 158.4 (s), 153.2 (s), 148.9 (s), 145.2
(s), 129.5 (s), 129.3 (s), 129.1 (s), 128.7 (s), 128.6 (s), 125.9 (s), 125.9
(s), 119.9 (s), 115.0 (s), 113.8 (s), 78.9 (s), 77.8 (s), 55.0 (s), 53.4 (s).
(2j)
Yield: 216 mg (75%); white solid; mp 144–145 °C; Rf = 0.82 (hexane).
1H NMR (600 MHz, CDCl3): δ = 7.93 (d, J = 7.5 Hz, 2 H), 7.42 (t, J = 7.3
Hz, 2 H), 7.37–7.34 (m, 3 H), 6.62 (d, J = 7.9 Hz, 2 H), 3.29 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 153.5 (s), 150.1 (s), 145.2 (s), 132.0 (s),
129.7 (s), 128.8 (s), 128.5 (s), 126.4 (s), 116.1 (s), 112.3 (s), 76.5 (s),
75.0 (s), 38.3 (s).
HRMS (ESI): m/z calcd for C24H19I2NO2K [M + K]+: 645.9137; found:
645.9134.
HRMS (ESI): m/z calcd for C17H12BrI2NOK [M + K]+: 617.7823; found:
617.7820.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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G. Li et al.
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Synthesis
3,4-Diiodo-N-(4-iodophenyl)-N-methyl-5-phenylfuran-2-amine
HRMS (ESI): m/z calcd for C17H12ClI2NOK [M + K]+: 573.8328; found:
(2k)
573.8330.
Yield: 228 mg (73%); white solid; mp 159–160 °C; Rf = 0.86 (hexane).
5-(4-Bromophenyl)-3,4-diiodo-N-methyl-N-phenylfuran-2-amine
(2p)
1H NMR (600 MHz, DMSO-d6): δ = 7.87 (d, J = 7.5 Hz, 2 H), 7.55 (d, J =
8.9 Hz, 2 H), 7.49 (t, J = 7.7 Hz, 2 H), 7.41 (t, J = 7.4 Hz, 1 H), 6.56 (d, J =
8.9 Hz, 2 H), 3.24 (s, 3 H).
Yield: 202 mg (70%); white solid; mp 130–131 °C; Rf = 0.87 (hexane).
13C NMR (150 MHz, DMSO-d6): δ = 153.1 (s), 149.2 (s), 145.8 (s), 137.5
(s), 129.4 (s), 128.7 (s), 128.7 (s), 126.1 (s), 116.6 (s), 82.0 (s), 78.4 (s),
77.7 (s), 37.8 (s).
1H NMR (600 MHz, DMSO-d6): δ = 7.88 (d, J = 8.1 Hz, 2 H), 7.74 (d, J =
8.2 Hz, 2 H), 7.31 (t, J = 7.5 Hz, 2 H), 6.92 (t, J = 7.2 Hz, 1 H), 6.77 (d, J =
7.9 Hz, 2 H), 3.31 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 154.0 (s), 147.8 (s), 145.8 (s), 131.7
(s), 129.2 (s), 128.7 (s), 127.8 (s), 121.7 (s), 119.6 (s), 114.1 (s), 78.7 (s),
78.1 (s), 37.9 (s).
HRMS (ESI): m/z calcd for C17H12I3NOK [M + K]+: 665.7685; found:
665.7683.
N-(3-Bromophenyl)-3,4-diiodo-N-methyl-5-(p-tolyl)furan-2-
HRMS (ESI): m/z calcd for C17H12BrI2NOK [M + K]+: 617.7823; found:
amine (2l)
617.7824.
Yield: 188 mg (65%); white solid; mp 128–129 °C; Rf = 0.87 (hexane).
N-(4-Bromophenyl)-3,4-diiodo-N-methyl-5-(p-tolyl)furan-2-
amine (2q)
1H NMR (600 MHz, CDCl3): δ = 7.94 (d, J = 7.7 Hz, 2 H), 7.43 (t, J = 7.2
Hz, 2 H), 7.36 (t, J = 7.2 Hz, 1 H), 7.10 (t, J = 8.0 Hz, 1 H), 7.02 (d, J = 7.7
Hz, 1 H), 6.90 (s, 1 H), 6.63 (d, J = 8.2 Hz, 1 H), 3.29 (s, 3 H).
Yield: 225 mg (76%); white solid; mp 140–141 °C; Rf = 0.88 (hexane).
1H NMR (600 MHz, DMSO-d6): δ = 7.76 (d, J = 8.2 Hz, 2 H), 7.41 (d, J =
9.0 Hz, 2 H), 7.30 (d, J = 8.1 Hz, 2 H), 6.66 (d, J = 9.0 Hz, 2 H), 3.24 (s, 3
H), 2.34 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 153.2 (s), 150.3 (s), 147.4 (s), 130.4 (s),
129.6 (s), 128.8 (s), 128.5 (s), 126.4 (s), 123.2 (s), 122.8 (s), 117.0 (s),
113.1 (s), 76.9 (s), 74.9 (s), 38.2 (s).
13C NMR (150 MHz, DMSO-d6): δ = 152.8 (s), 149.4 (s), 145.3 (s), 138.3
(s), 131.7 (s), 129.1 (s), 126.6 (s), 126.0 (s), 115.9 (s), 110.9 (s), 78.2 (s),
76.8 (s), 37.9 (s), 20.8 (s).
HRMS (ESI): m/z calcd for C17H12BrI2NOK [M + K]+: 617.7823; found:
617.7821.
3,4-Diiodo-N-methyl-N-phenyl-5-(p-tolyl)furan-2-amine (2m)
Yield: 193 mg (75%); white solid; mp 114–115 °C; Rf = 0.87 (hexane).
HRMS (ESI): m/z calcd for C18H14BrI2NOK [M + K]+: 631.7980; found:
631.7983.
1H NMR (400 MHz, DMSO-d6): δ = 7.76 (d, J = 8.2 Hz, 2 H), 7.29 (d, J =
8.1 Hz, 2 H), 7.27–7.23 (m, 2 H), 6.85 (t, J = 7.3 Hz, 1 H), 6.70 (d, J = 7.9
Hz, 2 H), 3.25 (s, 3 H), 2.34 (s, 3 H).
13C NMR (100 MHz, DMSO-d6): δ = 154.0 (s), 149.8 (s), 146.5 (s), 138.8
(s), 129.7 (s), 129.7 (s), 127.3 (s), 126.5 (s), 120.0 (s), 114.4 (s), 78.5 (s),
77.3 (s), 38.4 (s), 21.4 (s).
N-(3-Bromophenyl)-3,4-diiodo-N-methyl-5-(p-tolyl)furan-2-
amine (2r)
Yield: 207 mg (70%); white solid; mp 128–129 °C; Rf = 0.80 (hexane).
1H NMR (600 MHz, DMSO-d6): δ = 7.77 (d, J = 8.2 Hz, 2 H), 7.30 (d, J =
8.0 Hz, 2 H), 7.19 (t, J = 8.1 Hz, 1 H), 7.03 (d, J = 7.7 Hz, 1 H), 6.89 (t, J =
1.9 Hz, 1 H), 6.65 (dd, J = 8.4, 2.2 Hz, 1 H), 3.25 (s, 3 H), 2.34 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 152.6 (s), 149.6 (s), 147.5 (s), 138.4
(s), 131.0 (s), 129.2 (s), 126.7 (s), 126.1 (s), 122.5 (s), 122.0 (s), 116.0
(s), 113.1 (s), 78.6 (s), 76.9 (s), 38.0 (s), 20.9 (s).
HRMS (ESI): m/z calcd for C18H15I2NOK [M + K]+: 553.8875; found:
553.8875.
3,4-Diiodo-5-(4-methoxyphenyl)-N-methyl-N-phenylfuran-2-
amine (2n)
HRMS (ESI): m/z calcd for C18H14BrI2NOK [M + K]+: 631.7980; found:
631.7977.
Yield: 106 mg (40%); white solid; mp 117–118 °C; Rf = 0.83 (hexane).
1H NMR (600 MHz, CDCl3): δ = 7.93 (d, J = 7.7 Hz, 2 H), 7.41 (t, J = 7.5
Hz, 2 H), 7.33 (t, J = 7.2 Hz, 1 H), 6.84 (d, J = 8.6 Hz, 2 H), 6.76 (d, J = 8.6
Hz, 2 H), 3.77 (s, 3 H), 3.31 (s, 3 H).
13C NMR (150 MHz, CDCl3): δ = 154.8 (s), 153.9 (s), 149.1 (s), 140.1 (s),
129.9 (s), 128.4 (s), 126.2 (s), 116.9 (s), 114.6 (s), 75.3 (s), 73.7 (s), 55.6
(s), 38.7 (s).
N-(3-Bromophenyl)-5-(4-bromophenyl)-3,4-diiodo-N-methylfu-
ran-2-amine (2s)
Yield: 203 mg (62%); white solid; mp 108–109 °C; Rf = 0.81 (hexane).
1H NMR (600 MHz, DMSO-d6): δ = 7.84 (d, J = 8.6 Hz, 2 H), 7.70 (d, J =
8.6 Hz, 2 H), 7.20 (t, J = 8.1 Hz, 1 H), 7.04 (dd, J = 7.8, 1.0 Hz, 1 H), 6.91
(t, J = 2.0 Hz, 1 H), 6.67 (dd, J = 8.3, 2.2 Hz, 1 H), 3.26 (s, 3 H).
13C NMR (150 MHz, DMSO-d6): δ = 153.0 (s), 148.1 (s), 147.2 (s), 131.6
(s), 131.0 (s), 128.5 (s), 127.8 (s), 122.4 (s), 122.3 (s), 121.7 (s), 116.2
(s), 113.3 (s), 78.7 (s), 78.6 (s), 37.8 (s).
HRMS (ESI): m/z calcd for C18H15I2NO2K [M + K]+: 569.8824; found:
569.8822.
5-(4-Chlorophenyl)-3,4-diiodo-N-methyl-N-phenylfuran-2-amine
(2o)
HRMS (ESI): m/z calcd for C17H11Br2I2NOK [M + K]+: 695.6928; found:
695.6929.
Yield: 192 mg (72%); white solid; mp 122–123 °C; Rf = 0.84 (hexane).
1H NMR (600 MHz, DMSO): δ = 7.89 (d, J = 8.6 Hz, 2 H), 7.56 (d, J = 7.4
Hz, 2 H), 7.25 (t, J = 7.8 Hz, 2 H), 6.86 (t, J = 7.2 Hz, 1 H), 6.72 (d, J = 8.3
Hz, 2 H), 3.26 (s, 3 H).
13C NMR (150 MHz, DMSO): δ = 154.0 (s), 147.7 (s), 145.8 (s), 132.9
(s), 129.1 (s), 128.7 (s), 128.2 (s), 127.5 (s), 119.5 (s), 114.0 (s), 78.5 (s),
78.0 (s), 37.8 (s).
4,4′-{2-[Methyl(phenyl)amino]-5-phenylfuran-3,4-diyl}bis(2-
methylbut-3-yn-2-ol) (2w)
This compound was synthesized using the procedure of Mongin et
al.10 Under an atmosphere of N2, 2a (501 mg, 1 mmol, 1 equiv) and 2-
methylbut-3-yn-2-ol (210 mg, 2.5 mmol, 2.5 equiv) were dissolved in
Et3N (15 mL) at r.t. in a flask with a magnetic stirring bar. Then
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

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G. Li et al.
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Synthesis
PdCl2(Ph3P)2 (140 mg, 20 mol%) and CuI (19 mg, 10 mol%) were added
sequentially and the mixture was stirred at 80 °C for 15 h. After the
complete consumption of 2a, the resulting mixture was filtered on a
short pad of silica gel (3 g) and the filtrate was extracted with EtOAc
(3 × 15 mL). The combined organic phases were dried (Na2SO4) and
evaporated under reduced pressure to remove the solvent. The resi-
due was purified by flash chromatography (EtOAc/PE = 30:70) to af-
ford 2w; yield: 322 mg (78%); white solid; mp 124–125 °C; Rf = 0.38
(EtOAc/PE = 30:70).
1H NMR (600 MHz, DMSO-d6): δ = 7.90 (d, J = 7.7 Hz, 2 H), 7.45 (t, J =
7.8 Hz, 2 H), 7.35–7.28 (m, 3 H), 7.01 (d, J = 8.1 Hz, 2 H), 6.97 (t, J = 7.3
Hz, 1 H), 5.58 (s, 1 H), 5.27 (s, 1 H), 3.45 (s, 3 H), 1.53 (s, 6 H), 1.31 (s, 6
H).
13C NMR (150 MHz, DMSO-d6): δ = 153.8 (s), 146.2 (s), 144.8 (s), 129.0
(s), 129.0 (s), 128.8 (s), 127.9 (s), 123.5 (s), 121.3 (s), 117.2 (s), 105.4
(s), 103.1 (s), 103.0 (s), 95.5 (s), 72.1 (s), 70.5 (s), 63.8 (s), 63.6 (s), 38.0
(s), 31.4 (s), 31.4 (s).
HRMS (ESI): m/z calcd for C27H27NO3Na [M + Na]+: 436.1883; found:
436.1882.
13C NMR (100 MHz, CDCl3): δ = 148.8 (s), 147.7 (s), 144.4 (s), 133.6 (s),
131.6 (s), 130.8 (s), 130.5 (s), 129.1 (s), 128.9 (s), 128.6 (s), 128.2 (s),
128.0 (s), 127.3 (s), 127.1 (s), 126.6 (s), 125.9 (s), 122.9 (s), 119.0 (s),
118.6 (s), 113.8 (s), 38.5 (s).
HRMS (ESI): m/z calcd for C29H24NO [M + H]+: 402.1852; found:
402.1851.
Control Experiments to Confirm the Proposed Mechanism
N-Iodosuccinimide (11 mg, 0.1 mmol, 1 equiv) was added to a solu-
tion of 1q (171 mg, 0.5 mmol, 5 equiv) in MeCN (12 mL) at r.t. After 5
seconds, the reaction was quenched with 0.1 M aq Na2S2O3 (30 mL)
and then extracted with Et2O (3 × 40 mL). The combined organic
phases were washed with brine (2 × 80 mL) and dried (Na2SO4). The
solvent was removed and the residue was purified by flash column
chromatography on Al2O3 (PE) to afford a mixture 2q and 3q (13 mg).
N-Iodosuccinimide (2.7 mg, 0.1 mmol) was added to a solution of the
above mixture of 2q and 3q in MeCN (5 mL) at r.t. After 5 min, the
reaction was quenched with 0.1 M aq Na2S2O3 (15 mL) and then ex-
tracted with Et2O (3 × 20 mL). The combined organic phases were
washed with brine (2 × 40 mL) and dried (Na2SO4). The solvent was
removed and the residue was purified by flash column chromatogra-
phy on Al2O3 (PE) to afford 2q (13.5 mg).
3,4-Diethynyl-N-methyl-N,5-diphenylfuran-2-amine (2x)
This compound was synthesized using the procedure of Mongin et
al.11 To a solution of 2w (20 mg, 0.5 mmol, 1 equiv) in anhyd toluene
(10 mL) was added NaH (60% in mineral oil, 0.25 mmol, 0.5 equiv).
After heating at 100 °C for 4 h, the reaction mixture was quenched
with H2O (5 mL), and extracted with EtOAc (3 × 10 mL). The combined
organic phases were dried (Na2SO4) and evaporated under reduced
pressure to remove the solvent. The residue was purified by flash
chromatography on Al2O3 (PE) to give 2x; yield: 160 mg (95%); color-
less oil; Rf = 0.82 (hexane).
Funding Information
National Natural Science Foundation of China (21472136)
National Basic Research Project (2014CB932201)
Tianjin Research Program of Application Foundation and Advanced
Technology (15JCZDJC32900)
1H NMR (600 MHz, DMSO-d6): δ = 7.88 (d, J = 7.6 Hz, 2 H), 7.47 (t, J =
7.8 Hz, 2 H), 7.36 (t, J = 7.4 Hz, 1 H), 7.32 (t, J = 7.9 Hz, 2 H), 7.04 (d, J =
8.0 Hz, 2 H), 7.00 (t, J = 7.3 Hz, 1 H), 4.68 (s, 1 H), 4.28 (s, 1 H), 3.45 (s,
3 H).
Supporting Information
Supporting information for this article is available online at
13C NMR (150 MHz, DMSO-d6): δ = 155.0 (s), 147.6 (s), 144.7 (s), 129.0
(s), 129.9 (s), 128.7 (s), 128.4 (s), 123.8 (s), 121.8 (s), 117.7 (s), 104.6
(s), 94.8 (s), 88.3 (s), 87.7 (s), 75.1 (s), 73.5 (s), 38.3 (s).
http://dx.doi.org/10.1055/s-0036-1588792.
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References
HRMS (ESI): m/z calcd for C21H17NO2Na [M + Na]+: 338.1151; found:
338.1150.
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N-Methyl-N,3,4,5-tetraphenylfuran-2-amine (2y)
This compound was synthesized using the procedure of Maegawa et
al.10 Under an atmosphere of N2, 2a (501 mg, 1 mmol, 1 equiv) and
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297 mg (74%); white solid; mp 149–150 °C; Rf = 0.91 (hexane).
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H), 7.27–7.20 (m, 7 H), 7.13–7.09 (m, 3 H), 7.01 (m, 2 H), 6.85 (d, J =
8.0 Hz, 3 H), 3.19 (s, 3 H).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, A–K

K
G. Li et al.
Special Topic
Synthesis
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