New Efficient Synthesis of 1,2,4-Trisubstituted Furans by a Sequential Passerini/Wittig/Isomerization Reaction Starting from Baylis-Hillman β-Bromo Aldehydes

Article abstract of DOI:10.1055/s-0036-1588564

A new and efficient synthesis of 1,2,4-trisubstituted furans from a Baylis-Hillman β-bromo aldehyde, an acid, an isocyanide, and methyl(diphenyl)phosphine, by a sequential Passerini condensation, Wittig reaction, and isomerization in the presence of triethylamine is reported.

Full text of DOI:10.1055/s-0036-1588564

SYNLETT
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© Georg Thieme Verlag Stuttgart · New York
2017, 28, A–E
letter
A
en
Z.-L. Ren et al.
Letter
Synlett
New Efficient Synthesis of 1,2,4-Trisubstituted Furans by a
Sequential Passerini/Wittig/Isomerization Reaction Starting from
Baylis–Hillman β-Bromo Aldehydes
Zhi-Lin Ren
CHO
Br
Ar
R2HN
O
O
1. Ph2MeP,
toluene
Ar
Mei Sun
O
CH2Cl2
Zhi-Rong Guan
Ming-Wu Ding*
O
Ar
R1
R1
R1 = alkyl, aryl;
R1COOH
R2NC
r.t., 3 d
2. NEt3
O
NHR2
reflux, 3–12 h
63–87%
53–85%
Br
Key Laboratory of Pesticide & Chemical Biology of
Ministry of Education, Central China Normal Uni-
versity, Wuhan 430079, P. R. of China
mwding@mail.ccnu.edu.cn
R2 = alkyl; Ar = aryl
24 examples
Received: 12.06.2017
Accepted after revision: 26.07.2017
Published online: 25.08.2017
ase 1 inhibitory activity,6 and cyclooxygenase-1 inhibitory
activity.7 Owing to the broad range of activities of furan de-
rivatives, many attractive methods for their synthesis have
been developed in the past few decades. Conventional
methods such as the Paal–Knorr8 and Feist–Benary9 reac-
tions have found wide application in furan synthesis. Poly-
substituted furan derivatives have also been recently pre-
pared by numerous metal-free intramolecular approach-
es,10 or transition-metal-catalyzed synthetic strategies11
involving, for example, copper, palladium, gold, silver, ytter-
bium, or ruthenium, with remarkable improvements.
The Wittig reaction has been recognized as one of the
most powerful methods for constructing C=C double bonds,
and it has become an efficient tool in organic chemistry for
the preparation of alkenes.12 The intramolecular Wittig re-
action has been extensively used in the preparation of vari-
ous heterocycles through intramolecular cyclization.13 The
combination of an Ugi or Passerini condensation with a
subsequent Wittig reaction provides an efficient method
for the synthesis of a series of biologically useful heterocy-
cles. For example, Dömling and co-workers reported the
synthesis of highly substituted butenolides, pyrrolidinones,
and pyridones by sequential Ugi/Horner or Passerini/Horner
reactions.14 In our previous work, an Ugi or Passerini/Wittig
sequence was used to prepare polysubstituted 1H-2-benz-
azepin-1-ones, 1H-isochromenes, isoquinolin-1(2H)-ones
and indoles, starting from the corresponding phosphonium
precursors.15 Here, we report a new efficient synthesis of 1,2,4-
trisubstituted furans by a sequential Passerini/Wittig/isomeri-
zation reaction sequence starting from Baylis–Hillman β-
bromo aldehydes.
DOI: 10.1055/s-0036-1588564; Art ID: st-2017-w0460-l
Abstract A new and efficient synthesis of 1,2,4-trisubstituted furans
from a Baylis–Hillman β-bromo aldehyde, an acid, an isocyanide, and
methyl(diphenyl)phosphine, by a sequential Passerini condensation,
Wittig reaction, and isomerization in the presence of triethylamine is
reported.
Key words Passerini reaction, Wittig reaction, Baylis–Hillman
reaction, furans, isomerization
Isocyanide-based multicomponent reactions (IMCRs)
have become powerful tools in organic and medicinal
chemistry for diversity-oriented and complexity-generat-
ing syntheses of drug-like small molecules.1 Among various
IMCRs, the Passerini reaction and the Ugi reaction are two
main examples which have been widely used in preparing
various α-acyloxy or α-acylamino amide adducts in one op-
erational step.2 The so-called post-Passerini modifications
have emerged as useful tools for the preparation of struc-
turally diverse molecules, especially heterocyclic com-
pounds.3 For example, a domino Passerini/aldol reaction
was recently used to prepare bicyclic isocoumarins with
various substituted patterns through solvent-dependent
pathways.3a An oxidation/Passerini/hydrolysis/alkylation
strategy has been developed for the construction of triazo-
lo-fused benzoxazepines with high operational simplicity.3b
γ-Lactams and γ-lactones have also been obtained by se-
quential Passerini/ring-opening/cyclization reactions under
acidic or basic conditions.3c
Furans are an important class of heterocycles that are
present in many natural products and biologically active
molecules. Some derivatives of this heterocycle were re-
cently reported to show good anticancer activity,4 antia-
moebic activity,5 selective protein arginine methyltransfer-
There are few reports on Baylis–Hillman reactions be-
tween acrylaldehyde and other aldehydes.16 Our experi-
mental results revealed that only reactive aromatic alde-
hydes ArCHO (Ar = 4-O2NC6H4, 2-O2NC6H4, 4-F3CC6H4) gave
the corresponding Baylis–Hillman adducts in 60–75% yields
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

B
Z.-L. Ren et al.
Letter
Synlett
(Scheme 1). Other aromatic aldehydes (Ar = 4-FC6H4, 4-ClC6H4,
3-ClC6H4, 4-BrC6H4, 3-BrC6H4, 2-BrC6H4, Ph, 4-Tol, 4-MeOC6H4)
gave only traces of the product, probably due to the prefer-
ential self-polymerization of acrylaldehyde under the reac-
tion condition. The Baylis–Hillman β-bromo aldehydes 1a–
c were then obtained in 87–92% yield by further bromina-
tion of the corresponding Baylis–Hillman adducts.
We initially examined the reaction of the Passerini
product 4a with triphenylphosphine, and we found that it
readily gave the corresponding phosphonium salt at room
temperature. Triethylamine was then added to the reaction
mixture in an attempt to induce a further intramolecular
Wittig reaction without isolation of the phosphonium salt
intermediate. When the reaction mixture was stirred at
room temperature, no product was detected (Table 1,
entry 1). However, at reflux, a mixture of furan 5a (38%,
Table 1, entry 2) and furan-2(3H)-one 6a (43%) was unex-
pectedly obtained. Changing the base from NEt3 to DABCO,
NaHCO3, K2CO3, or Cs2CO3 gave lower yields of furan 5a as
the major product (Table 1, entry 3–6). No product was ob-
tained when NEt3/MeOH or NEt3/DMSO was used (Table 1,
entries 7 and 8), probably due to decomposition of the
phosphonium salt intermediate in the more-polar solvent.
A lower yield was also obtained when the NEt3/THF system
was used at the reflux (Table 1, entry 9). Adding an external
oxidant to the reaction mixture had no obvious effect on
the product ratios (Table 1, entries 10 and 11). When the re-
action mixture was carried out under a nitrogen atmo-
sphere, the furan 5a was obtained exclusively in moderate
yield (53%, Table 1, entry 12).
OH
CHO
DABCO (5%)
THF
CHO
ArCHO
+
Ar
CHO
Ar
HBr
CH2Cl2
Br
1a: Ar = 4-O2NC6H4
b: Ar = 2-O2NC6H4
c: Ar = 4-F3CC6H4
Scheme 1 Preparation of bromides 1a–c by the Baylis–Hillman
reaction
Although the 3-phenyl-substituted β-bromo aldehyde
1d could not be obtained by a Baylis–Hillman reaction, it
was successfully prepared by another synthetic route, start-
ing from commercially available 2-methyl-3-phenylacryl-
aldehyde (Scheme 2).
The structure of the unexpected product, the furan-
2(3H)-one 6a, was confirmed from its spectral data. Fur-
thermore, a single crystal of 6a was grown from the
CH2Cl2/petroleum ether solution, and its proposed struc-
ture was verified by X-ray crystal analysis (Figure 1).18
OAc
CHO
CH3
Ac2O
NBS
CCl4
Ph
Ph
OAc
Ph
H2SO4
CH3
OAc
OAc
CHO
HCl
Ph
THF
Br
Br
1d
Scheme 2 Preparation of bromide 1d
With the β-bromo aldehydes 1a–d in hand, we investi-
gated their Passerini reactions. A mixture of the β-bromo
aldehyde 1, acid 2, and isocyanide 3 was stirred in dichloro-
methane at room temperature for three days (Scheme 3).
The Passerini reaction occurred smoothly, and the bro-
mides 1 were found to be compatible with the reaction con-
dition. The corresponding products 4 were finally obtained
in 53–85% yields.17
Figure 1 ORTEP drawing of 6a with 50% probability thermal ellipsoids
CHO
Ar
R2HN
O
O
The formation of the furan-2(3H)-one 6 (Scheme 4)
might involves: (i) air oxidation of the sp3-C–H bond of
phosphonium salt 7 in the presence of NEt3 to afford the
key intermediate 8, as reported in similar cases;19 (ii) re-
arrangement of the intermediate 8 to 9 through migration
of the carboxamide group to the vinyl carbon under the ba-
sic condition, in a manner similar to the rearrangement of
benzilic acid with migration of the phenyl group to the car-
Br
O
CH2Cl2
r.t.
1
Ar
R1
R1COOH (2)
R2NC (3)
Br
4
Scheme 3 Passerini reaction for preparation of the bromides 4
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

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Z.-L. Ren et al.
Letter
Synlett
Table 1 Investigation of the Reaction Conditions
O2N
O2N
t-BuNH
O
O
O
O
1. Ph2PR
2. Base
+
NH-t-Bu
Ph
O
O2N
Br
Ph
Ph
O
O
O
NH-t-Bu
4a
5a
6a
Entry
Phosphine
Ph3P
Solvent
Temp
r.t.
Time (h)
Base
Additive
Yield (%)a
5a
6a
1
2
toluene
toluene
toluene
toluene
toluene
toluene
MeOH
12
8
8
8
8
8
6
6
8
8
8
8
4
2
NEt3
NEt3
–
0
38
37
25
35
27
0
0
43
30
10
14
10
0
reflux
reflux
reflux
reflux
reflux
reflux
90 °C
reflux
reflux
reflux
refluxb
reflux
reflux
–
3
DABCO
NaHCO3
K2CO3
Cs2CO3
NEt3
–
4
–
5
–
6
–
7
–
8
DMSO
NEt3
–
0
0
9
THF
NEt3
–
28
31
30
53
82
45
25
34
33
0
10
11
12
13
14
toluene
toluene
toluene
toluene
toluene
NEt3
CrO3
H2O2
–
NEt3
NEt3
Ph2PMe
Me3P
NEt3
–
0
NEt3
–
0
a Isolated yield based on the bromide 4a.
b Under N2.
bonyl carbon;20 (iii) proton transfer of 9 to produce phos-
phonium salt 10; and (iv) an intramolecular Wittig reaction
of 10 in the presence of NEt3, through the reactive anhy-
dride carbonyl group, to give furan-2(3H)-one 6.
R2HN
O
O
R2HN
O
O
O
O2
NEt3
Ph3P
Ar
Ar
R1
Ph3P+
Br–
O
R1
We speculated that if the phosphine reagent was
changed from Ph3P to Ph2MeP, a more reactive Wittig re-
agent might result, and furans 5 might be formed predomi-
nately. Indeed, as shown in Table 1, entry 13, furan 5a was
produced exclusively in a good yield (82%) when Ph2MeP
was utilized as the phosphine reagent, even without the
protection of a N2 atmosphere. However, when Me3P was
used, the reaction mixture became more complex, and a
moderate yield (45%) of the product was obtained probably
due to the presence of side reactions (Table 1, entry 14).
Having determined the optimal conditions (entry 13),
we examined the reactions of various Passerini products 4
with Ph2MeP as the phosphine reagent (Table 2). All reac-
tions proceeded smoothly in refluxing toluene to give mod-
erate to good yields (63–87%) of furans 5 with various sub-
stituents (Table 2).21 Good yields of compounds 5a–s (71–
87%) were obtained with R1 being an aromatic group with
Br
4
7
R2HN
O
O
O
R2HN
+
O
O
H
NEt3
HNEt3
-
Ar
O
Ar
Ph3P+
Br–
O
R1
Ph3P+
Br–
O
R1
8
9
O
O
O
R2HN
Ar
Ar
O
NEt3
O
NHR2
Ph3P+
Br–
R1
R1
O
O
10
6
Scheme 4 A possible mechanism for the formation of 6
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

D
Z.-L. Ren et al.
Letter
Synlett
Table 2 One-Pot Preparation of Furans 5 by Using Ph2MeP as the
Phosphine Reagent. Preparation and Yields of Compounds 5a–x
terms of an initial reaction of bromide 4 with Ph2MeP to
give the phosphonium salt 11. Further intramolecular
Wittig reaction of 11 produces dihydrofuran 12, which
isomerizes through a 1,3-H shift in the presence of NEt3 to
give furan 5.
R2HN
O
O
R2HN
O
O
O
NEt3
Ph2PMe
Ar
In conclusion,
a Passerini/Wittig/isomerization se-
Ar
R1
quence, starting from Baylis-Hillman β-bromo aldehydes,
for preparing 1,2,4-trisubstituted furans is reported. The
method was adapted to the synthesis of various substituted
furans under mild reaction condition, which makes it useful
in synthetic and medicinal chemistry. The unexpected for-
mation of furan-2(3H)-one 6a was observed when Ph3P was
used as the phosphine reagent.
Ph2MeP+
Br–
O
R1
Br
11
4
R2HN
R2HN
O
O
Ar
Ar
O
O
R1
R1
Funding Information
12
5
We gratefully acknowledge the financial support of this work by the
National Natural Science Foundation of China (No. 21572075) and the
Product Ar
R1
R2
Yielda (%)
111 Project B17019.
N
oaitn
a
l
N
a
utarl
Secince
F
o
u
n
d
oaitn
of
C
h
n
i
a
2(
1
5
7
2
0
7
5)
5a
5b
5c
5d
5e
5f
4-O2NC6H4
4-F3CC6H4
4-O2NC6H4
2-O2NC6H4
4-O2NC6H4
4-O2NC6H4
4-O2NC6H4
Ph
Ph
Ph
Ph
Ph
t-Bu
Bu
82
87
76
84
75
77
83
85
77
74
71
75
78
72
70
77
85
78
86
75
81
71
63
75
Supporting Information
Bu
Supporting information for this article is available online at
https://doi.org/10.1055/s-0036-1588564.
t-Bu
t-Bu
Bu
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
4-ClC6H4
4-ClC6H4
4-FC6H4
4-FC6H4
4-Tol
References and Notes
5g
5h
5i
Bu
(1) (a) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev.
2014, 114, 8323. (b) Dömling, A.; Wang, W.; Wang, K. Chem. Rev.
2012, 112, 3083.
t-Bu
t-Bu
Bu
4-O2NC6H4
2-O2NC6H4
4-O2NC6H4
2-O2NC6H4
4-F3CC6H4
4-O2NC6H4
4-O2NC6H4
Ph
5j
4-Tol
(2) (a) Zhang, J.; Lin, S.-X.; Cheng, D.-J.; Liu, X.-Y.; Tan, B. J. Am.
Chem. Soc. 2015, 137, 14039. (b) Ponra, S.; Nyadanu, A.; El Kaïm,
L.; Grimaud, L.; Vitale, M. R. Org. Lett. 2016, 18, 4060.
(c) Yugandhar, D.; Kuriakose, S.; Nanubolu, J. B.; Srivastava, A. K.
Org. Lett. 2016, 18, 1040. (d) Miranda, L. D.; Hernández-Vázquez,
E. J. Org. Chem. 2015, 80, 10611. (e) Wu, R.; Gao, S.; Chen, X.;
Yang, G.; Pan, L.; Hu, G.; Jia, P.; Zhong, W.; Yu, C. Eur. J. Org.
Chem. 2014, 3379.
(3) (a) Ma, G.-H.; Jiang, B.; Tu, X.-J.; Ning, Y.; Tu, S.-J.; Li, G. Org. Lett.
2014, 16, 4504. (b) De Moliner, F.; Bigatti, M.; Banfi, L.; Riva, R.;
Basso, A. Org. Lett. 2014, 16, 2280. (c) Alcaide, B.; Almendros, P.;
Aragoncillo, C.; Callejo, R.; Ruiz, M. P. J. Org. Chem. 2013, 78,
10154. (d) Moni, L.; Banfi, L.; Basso, A.; Carcone, L.; Rasparini,
M.; Riva, R. J. Org. Chem. 2015, 80, 3411. (e) Martinand-Lurin, E.;
El Kaïm, L.; Grimaud, L. Tetrahedron Lett. 2014, 55, 5144.
(f) Cordier, M.; Dos Santos, A.; El Kaïm, L.; Narboni, N. Chem.
Commun. 2015, 51, 6411. (g) Martinand-Lurin, E.; Dos Santos,
A.; El Kaïm, L.; Grimaud, L.; Retailleau, P. Chem. Commun. 2014,
50, 2214.
(4) Alnabulsi, S.; Santina, E.; Russo, I.; Hussein, B.; Kadirvel, M.;
Chadwick, A.; Bichenkova, E. V.; Bryce, R. A.; Nolan, K.;
Demonacos, C.; Stratford, I. J.; Freeman, S. Eur. J. Med. Chem.
2016, 111, 33.
(5) Ansari, M. F.; Siddiqui, S. M.; Ahmad, K.; Avecilla, F.; Dharavath,
S.; Gourinath, S.; Azam, A. Eur. J. Med. Chem. 2016, 124, 393.
(6) Yan, L.; Yan, C.; Qian, K.; Su, H.; Kofsky-Wofford, S. A.; Lee, W.-C.;
Zhao, X.; Ho, M.-C.; Ivanov, I.; Zheng, Y. G. J. Med. Chem. 2014,
57, 2611.
5k
5l
4-Tol
Bu
4-Tol
t-Bu
t-Bu
t-Bu
Cy
5m
5n
5o
5p
5q
5r
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-MeOC6H4
4-F3CC6H4
2-FC6H4
3-O2NC6H4
Et
t-Bu
Bu
2-O2NC6H4
2-O2NC6H4
2-O2NC6H4
Ph
t-Bu
t-Bu
t-Bu
t-Bu
t-Bu
Bu
5s
5t
5u
5v
5w
5x
2-O2NC6H4
2-O2NC6H4
4-O2NC6H4
4-O2NC6H4
Et
i-Pr
t-Bu
4-ClC6H4CH2
t-Bu
a Isolated yield based on bromide 4.
electron-donating (MeO or Me) or electron-withdrawing
substituent (F, Cl, CF3, or NO2) on the benzene ring. When R1
was an alkyl group, moderate to good yields of products 5t–
x (63–81%) were obtained. It is noteworthy that a 63% yield
of compound 5w was obtained when R1 was a bulky t-Bu
group. The formation of furans 5 can be rationalized in
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E

E
Z.-L. Ren et al.
Letter
Synlett
(7) Vitale, P.; Tacconelli, S.; Perrone, M. G.; Malerba, P.; Simone, L.;
Scilimati, A.; Lavecchia, A.; Dovizio, M.; Marcantoni, E.; Bruno,
A.; Patrignani, P. J. Med. Chem. 2013, 56, 4277.
(8) (a) Khaghaninejad, S.; Heravi, M. M. Adv. Heterocycl. Chem.
2014, 111, 95. (b) Minetto, G.; Raveglia, L. F.; Sega, A.; Taddei, M.
Eur. J. Org. Chem. 2005, 5277.
(17) 1-(Aminocarbonyl)-3-aryl-2-(bromomethyl)prop-2-en-1-yl
Esters 4; General Procedure
The appropriate acid 2 (2 mmol) and isocyanide 3 (2 mmol)
were added to a solution of the Baylis–Hillman β-bromo alde-
hyde 1 (2 mmol) in CH2Cl2 (4 mL), and the mixture was stirred
at r.t. for 3 d until the reaction was complete (TLC). The solvent
was removed under reduced pressure, and the residue was puri-
fied by flash chromatography [silica gel, EtOAc/PE (1:10)].
(2Z)-2-(Bromomethyl)-1-[(tert-butylamino)carbonyl]-3-(4-
nitrophenyl)prop-2-en-1-yl Benzoate(4a)
(9) (a) Feist, F. Ber. Dtsch. Chem. Ges. 1902, 35, 1537. (b) Calter, M.
A.; Zhu, C.; Lachicotte, R. J. Org. Lett. 2002, 4, 209.
(10) (a) Zhou, Q.-F.; Zhang, K.; Cai, L.; Kwon, O. Org. Lett. 2016, 18,
2954. (b) Mal, K.; Das, I. J. Org. Chem. 2016, 81, 932. (c) Yang, Y.;
Ni, F.; Shu, W.-M.; Wu, A.-X. Tetrahedron 2014, 70, 6733.
(11) (a) Manna, S.; Antonchick, A. P. Org. Lett. 2015, 17, 4300. (b) Yu,
J.-T.; Shi, B.; Peng, H.; Sun, S.; Chu, H.; Jiang, Y.; Cheng, J. Org.
Lett. 2015, 17, 3643. (c) Lu, B.; Wu, J.; Yoshikai, N. J. Am. Chem.
Soc. 2014, 136, 11598. (d) Rajesh, M.; Puri, S.; Kant, R.; Reddy, M.
S. Org. Lett. 2016, 18, 4332. (e) Shiroodi, R. K.; Koleda, O.;
Gevorgyan, V. J. Am. Chem. Soc. 2014, 136, 13146. (f) Hosseyni,
S.; Su, Y.; Shi, X. Org. Lett. 2015, 17, 6010. (g) Lee, E.; Bang, J.;
Kwon, J.; Yu, C.-M. J. Org. Chem. 2015, 80, 10359. (h) Li, M.; Kong,
X.-J.; Wen, L.-R. J. Org. Chem. 2015, 80, 11999. (i) Matsui, K.;
Shibuya, M.; Yamamoto, Y. ACS Catal. 2015, 5, 6468. (j) Lin, M.-H.;
Kuo, C.-K.; Huang, Y.-C.; Tsai, Y.-T.; Tsai, C.-H.; Liang, K.-Y.; Li, Y.-S.;
Chuang, T.-H. Tetrahedron 2014, 70, 5513.
(12) (a) Chen, Z.; Nieves-Quinones, Y.; Waas, J. R.; Singleton, D. A. J.
Am. Chem. Soc. 2014, 136, 13122. (b) Ma, J.; Yuan, Z.-Z.; Kong,
X.-W.; Wang, H.; Li, Y.-M.; Xiao, H.; Zhao, G. Org. Lett. 2016, 18,
1450. (c) Bruckner, S.; Bilitewski, U.; Schobert, R. Org. Lett.
2016, 18, 1136. (d) Chen, L.; Du, Y.; Zeng, X.-P.; Shi, T.-D.; Zhou,
F.; Zhou, J. Org. Lett. 2015, 17, 1557.
(13) (a) Zhang, K.; Cai, L.; Jiang, X.; Garcia-Garibay, M. A.; Kwon, O. J.
Am. Chem. Soc. 2015, 137, 11258. (b) Lee, C.-J.; Chang, T.-H.; Yu,
J.-K.; Reddy, G. M.; Hsiao, M.-Y.; Lin, W. Org. Lett. 2016, 18, 3758.
(c) Wang, J.; Yao, J.; Wang, H.; Chen, H.; Dong, J.; Zhou, H. J. Org.
Chem. 2016, 81, 5250. (d) Saleh, N.; Voituriez, A. J. Org. Chem.
2016, 81, 4371.
White solid; yield: 664 mg (70%); mp 118–120 °C. 1H NMR (600
MHz, CDCl3): δ = 8.24 (d, J = 7.2 Hz, 2 H, Ar-H), 8.13 (d, J = 5.4
Hz, 2 H, Ar-H), 7.62–7.51 (m, 5 H, Ar-H), 7.07 (s, 1 H, =CH), 6.27
(s, 1 H, NH), 6.03 (s, 1 H, CH), 4.26 (d, J = 10.8 Hz, 1 H, CH2a), 4.16
(d, J = 10.2 Hz, 1 H, CH2b), 1.41 (s, 9 H, 3CH3). 13C NMR (150 MHz,
CDCl3): δ = 166.0, 164.5, 147.1, 141.5, 135.4, 133.9, 133.3, 129.8,
129.6, 128.7, 123.8, 75.8, 51.8, 28.5, 27.1. HRMS: m/z [M + H]+
calcd for C22H24BrN2O5: 475.0863; found: 475.0860.
(18) CCDC 1545270 contains the supplementary crystallographic
data for compound 6a. The data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via
www.ccdc.cam.ac.uk/getstructures.
(19) Trang, T. T. T.; Peshkov, A. A.; Jacobs, J.; Van Meervelt, L.;
Peshkov, V. A.; Van der Eycken, E. V. Tetrahedron Lett. 2015, 56,
2882.
(20) Lowry, T. H.; Richardson, K. S. Mechanism and Theory in Organic
Chemistry; Harper & Row: New York, 1987, 3rd ed. 486.
(21) Furans 5; General Procedure
In an oven-dried flask, bromide 4 (1 mmol) and Ph2MeP (0.20 g,
1 mmol) were dissolved in toluene (5 mL) at r.t. After two hours,
the white phosphonium salt solid 11 formed. Without isolation
of the phosphonium salt intermediate, NEt3 (0.20 g, 2 mmol)
was added and the mixture was stirred at reflux for 3–12 h until
the reaction was complete (TLC). The solution was then concen-
trated under reduced pressure and the residue was purified by
flash chromatography [silica gel, EtOAc/PE (1:12 to 1:1)].
N-(tert-Butyl)-3-(4-nitrobenzyl)-5-phenyl-2-furamide (5a)
Light-yellow oil; yield: 309 mg (82%). 1H NMR (600 MHz,
CDCl3): δ = 8.04 (d, J = 8.4 Hz, 2 H, Ar-H), 7.53 (d, J = 7.2 Hz, 2 H,
Ar-H), 7.39–7.23 (m, 5 H, Ar-H), 6.37 (s, 1 H, furan-4-H), 6.21 (s,
1 H, NH), 4.31 (s, 2 H, CH2), 1.43 (s, 9 H, 3CH3). 13C NMR
(150 MHz, CDCl3): δ = 158.8, 153.5, 147.9, 146.4, 142.0, 130.1,
129.5, 129.2, 128.7, 128.6, 124.3, 123.6, 109.0, 51.4, 31.3, 29.0.
HRMS: m/z [M + H]+ calcd for C22H23N2O4: 379.1652; found:
379.1653.
(14) (a) Beck, B.; Magnin-Lachaux, M.; Herdtweck, E.; Dömling, A.
Org. Lett. 2001, 3, 2875. (b) Beck, B.; Picard, A.; Herdtweck, E.;
Dömling, A. Org. Lett. 2004, 6, 39.
(15) (a) Wang, L.; Ren, Z.-L.; Ding, M.-W. J. Org. Chem. 2015, 80, 641.
(b) Wang, L.; Guan, Z.-R.; Ding, M.-W. Org. Biomol. Chem. 2016,
14, 2413. (c) Duan, Z.; Gao, Y.; Yuan, D.; Ding, M.-W. Synlett
2015, 26, 2598. (d) Yan, Y.-M.; Rao, Y.; Ding, M.-W. J. Org. Chem.
2017, 82, 2772.
(16) (a) Tang, X.; Zhang, B.; He, Z.; Gao, R.; He, Z. Adv. Synth. Catal.
2007, 349, 2007. (b) Reddy, M. V. R.; Rudd, M. T.;
Ramachandran, P. V. J. Org. Chem. 2002, 67, 5382.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2017, 28, A–E