I-MCR-Ullmann cascade toward furo[2,3-b]indole scaffold

Article abstract of DOI:10.1016/j.tet.2011.05.101

An efficient method for the construction of furo[2,3-b]indole derivatives 5 via an isocyanide-based multicomponent reaction (I-MCR) and a copper-catalyzed intramolecular Ullmann reaction sequence was described. This two-step sequence can be performed in a

Full text of DOI:10.1016/j.tet.2011.05.101

Tetrahedron 67 (2011) 6375e6381
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
I-MCR-Ullmann cascade toward furo[2,3-b]indole scaffold
*
*
Xu Zhu, Xiao-Ping Xu , Chang Sun, Tao Chen, Zhi-Liang Shen, Shun-Jun Ji
Key Laboratory of Organic Synthesis of Jiangsu Province, College of Chemistry, Chemical Engineering and Materials Science, Soochow University, Suzhou, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An efficient method for the construction of furo[2,3-b]indole derivatives 5 via an isocyanide-based
multicomponent reaction (I-MCR) and a copper-catalyzed intramolecular Ullmann reaction sequence
was described. This two-step sequence can be performed in a one-pot manner to produce the desired
product 5 in moderate to good yield (up to 90%).
Received 25 March 2011
Received in revised form 17 May 2011
Accepted 24 May 2011
Available online 30 May 2011
Ó 2011 Published by Elsevier Ltd.
Keywords:
Copper catalysis
Furan
Indole
Intramolecular Ullmann coupling
Isocyanide-based multicomponent reaction
(I-MCR)
One-pot reaction
1. Introduction
based multicomponent reaction (I-MCR) has emerged as an effi-
cient method for the synthesis of a wide variety of fused furans.9,10
In recent decades, the searching for more efficient processes,
which allow for the rapid generation of molecular complexity and
diversity from simple and readily accessible starting materials have
attracted much attention of organic chemists.1 Among them, the
strategical use of multicomponent reactions2 (MCRs, especially
isocyanide-based multicomponent reactions of I-MCRs3) followed
by a metal-catalyzed intramolecular cyclization4 has constituted an
efficient method for the construction of complex molecules, such as
indole and furan scaffolds. For an instance, Zhu and co-workers
reported an elegant two-step sequence involving an Ugi four-
component reaction (Ugi-4CR) and a palladium-catalyzed intra-
molecular amidation to construct functionalized oxindoles.5 How-
ever, as stated in their work, cheap copper catalysts (CuI and CuCl2)
failed to effectively catalyze the formation of oxindole (w42%
yield). More recently, Kaim and co-workers also described a novel
access to indole scaffold via a modified UgieSmiles reaction in
For an example, a three-component condensation involving iso-
cyanides, aldehydes, and 1,3-dicarbonyl compounds was developed
for the synthesis of 2-aminofurans in the last decade.9 It was
found that the replacement of 1,3-dicarbonyl compounds by
4-hydroxycoumarin,10a 2-hydroxy-1,4-naphthoquinone,10b and
3-hydroxy-1H-phenalene-1-one10c could also lead to various furan
derivatives. Thus, we envisaged that if the above I-MCRs was car-
ried out using an ortho-halobenzaldehyde as a substrate, the
product can be further manipulated via a metal-catalyzed intra-
molecular Ullmann reaction to generate interesting and highly
fused furo[2,3-b]indole derivatives (5). In continuation of our in-
terest in the application of MCRs11 (especially I-MCRs12) in the
synthesis of indole and furan skeletons, herein, we report an effi-
cient method for the construction of furo[2,3-b]indole derivatives
via an I-MCR and a copper-catalyzed intramolecular Ullmann re-
action sequence. This two-step sequence can be performed in an
one-pot manner to produce the desired products 5 in good yields
(up to 90%).
conjunction with
a
subsequent palladium-mediated Heck-
isomerization.6
Indole and furan moieties are widely featured in a broad range
of pharmacologically and biologically active compounds.7 The
synthesis and functionalization of indole and furan have been the
focuses of research for a long time.8 In this regard, the isocyanide-
2. Results and discussions
Initially, we studied the synthesis of precursor 4 for Ullmann
coupling by using different substrates (Fig. 1). As shown in Table 1,
the isocyanide-based multicomponent reactions (I-MCRs) in-
volving substrate 1 (including 4-hydroxycoumarin 1a, 4-hydroxy-
1-methylquinolinone 1b, and 2-hydroxy-1,4-naphthoquinone 1c),
* Corresponding authors. E-mail addresses: xuxp@suda.edu.cn (X.-P. Xu), shun-
jun@suda.edu.cn (S.-J. Ji).
0040-4020/$ e see front matter Ó 2011 Published by Elsevier Ltd.
doi:10.1016/j.tet.2011.05.101

6376
X. Zhu et al. / Tetrahedron 67 (2011) 6375e6381
Substrate1:
OH
Aldehyde2:
OH
OH
N
O
CHO
CHO
I
F
CHO
Br
O
O
O
1a
O
Br
1b
1c
2a
2b
2c
Isocyanide3:
NC
NC
NC
3a
3b
3c
Fig. 1. Diversity of reagents used in the synthesis of furo[2,3-b]indole derivatives.
obtained when toluene was used as solvent and potassium car-
bonate was employed as a base (entry 4). In addition, various
Table 1
Isocyanide-based multicomponent reaction for the synthesis of precursor 4a
ligands including
thylethane-1,2-diamine (L4), 1,10-phenanthroline (L5) were also
screened and it was observed that -proline was superior to other
L-proline (L1), DABCO (L2), DBU (L3), N,N-dime-
R
OH
NH
X
L
CHO
X
O
ligands in promoting the reaction. Besides, it is worthwhile to note
that the reaction cannot take place in the absence of a ligand (Table
2, entry 12). Moreover, the influence of reaction time and the cat-
alyst loading on the reaction were also investigated (Table 2, entries
13 and 14). It was found that performing the reaction in toluene for
24 h using 10 mol % CuI sufficed to promote this reaction. Under the
toluene
110 oC
R NC
O
O
1
2
3
4
Entry
Substrate
Time (h)
Product
Yield (%)b
optimized reaction conditions (10 mol % CuI, 10 mol % L-proline,
1
2
3
4
5
6
7
8
1a/2a/3a
1a/2a/3b
1a/2a/3c
1b/2a/3a
1b/2a/3b
1b/2a/3c
1c/2a/3a
1c/2a/3b
1a/2c/3a
1b/2c/3a
1a/2b/3a
1b/2b/3c
24
24
24
20
22
24
6
4a
4b
4c
4d
4e
4f
4g
4h
4i
73
77
92
81
85
90
50
60
77
84
75c
77c
K2CO3, toluene, 110 ꢀC), the intramolecular Ullmann reaction pro-
ceeded efficiently to produce the desired product of 5a in 97% yield
(Table 2, entry 4). And its structure was further unambiguously
confirmed by single-crystal X-ray analysis (Fig. 3).
With the success of above reactions, we continued to apply the
optimized conditions to the synthesis of a wide variety of furo[2,3-b]
indole derivatives 5 by using various substrates 4ael. The results are
summarized in Table 3. As depicted in Table 3, in all cases, the intra-
molecular Ullmann coupling reaction occurred efficiently in the
4
9
18
18
48
48
10
11
12
4j
4k
4l
presence of CuI and L-proline. The desired products of furo[2,3-b]in-
a
Reaction condition: 1 (1 mmol), 2 (1 mmol), 3 (1.2 mmol) were stirred at 110 ꢀ
in toluene for a specific time (monitored by TLC) under nitrogen atmosphere.
C
dolederivatives 5were obtained in good to excellent yields (upto 99%).
Unfortunately, the compounds 4i and 4j failed to undergo the coupling
reaction under the present conditions, which might be due to the
electronic effect of fluorine atom attached to the benzene ring. Pre-
viously, Ma and co-workers15c proposed the mechanism of Ulmann
reaction (amino acids were used as the ligands) in detail, which in-
b
Isolated yield.
Temperature: 80 ꢀC.
c
2-halobenzaldehyde 2, and isocyanide 3 proceeded efficiently in
refluxing toluene for a specific time, leading to the desired product
of 4 in moderate to good yields. Both alkyl and aryl isocyanides
were good candidates for the reaction. In addition, the fluorine-
containing benzaldehyde 2c also reacted well to generate the de-
sired product 4 in good yields (Table 1, entries 9 and 10).
volving chelation of the amino acid to the copper species,
p-com-
plexation of copper to the aryl ring, and an intramolecular nucleophilic
substitution step. Because of the high electronic affinity of the fluorine
atom, electronic density of the benzene ring was remarkably reduced.
With the precursor 4 (Fig. 2) in hand, we focused on the feasibility
of the following metal-catalyzed intramolecular Ullmann cyclization
reaction. Although successful examples on the palladium-catalyzed
intramolecular cyclizations have been reported in isocyanide-based
multicomponent reactions,5,6 such reactions promoted by in-
expensive metal catalysts (such as copper species) are still highly
desirable. In recent decades, coupling reactions mediated by copper
catalysts, as economic and powerful strategies for the construction
of CeO and CeN bonds, have been well established.13 For instance,
more recently, Buchwald and Bolm disclosed that CeN bond for-
mation could be effectively catalyzed by ppm-level copper con-
taminant.14 This information encouraged us to perform the
intramolecular Ullmann cyclization with the use of copper species.
The cyclization of 4a was initially investigated in the presence of
the commonly used CuI catalyst.15 As shown in Table 2, the coupling
reaction was surveyed by varying the solvents (entries 1e4), the
bases (entries 4e7), and the ligands (entries 7e11). Among the
various solvents and bases screened, the optimal result was
Consequently, it was difficult for the formation of the
p-complex,
which is an important intermediate of this Ullmann coupling reac-
tion.13a,h We think the results obtained in our cases were consistent
with the known process.
Finally, we envisioned that if the two-step sequence can be carried
out in a one-pot manner without the isolation of the product 4, the
reaction efficiency would be greatly improved. Thus we continued
our task by exploring the extension of this strategy to a more efficient
one-pot procedure. After the three-component I-MCR reaction was
stirred in refluxing toluene for an appropriate time (monitored by
TLC), 0.2 equiv of trifluoroacetic acid6 was added to the reaction
mixture to destroy the remaining isocyanide. Then CuI, L-proline, and
K2CO3 were added to the reaction mixture to initiate the following
intramolecular Ullmann reaction in refluxing toluene. As expected,
thetwo-stepsequencealsoproceededefficientlyinaone-potmanner
to afford the desired products of furo[2,3-b]indoles 5 in moderate to
good yields (Table 4). The one-pot protocol provides great efficiency
in the facile construction of furo[2,3-b]indoles 5 (Table 4).

X. Zhu et al. / Tetrahedron 67 (2011) 6375e6381
6377
NH
O
NH
O
Br
Br
NH
O
NH
O
O
Br
Br
Br
O
O
O
N
O
O
O
4c
4a
4b
4d
NH
O
Br
NH
O
NH
O
NH
O
Br
O
Br
O
O
O
O
O
N
N
4g
4h
4e
4f
NH
O
NH
I
Br
F
NH
O
Br
F
NH
O
I
O
O
O
N
N
O
O
O
O
4k
4i
4j
4l
Fig. 2. The structure of products 4ael.
3. Conclusions
In summary, we have developed an efficient strategy to con-
struct the highly functionalized furo[2,3-b]indole scaffolds from
readily accessible starting materials. The isocyanide-based multi-
component reaction and the subsequent copper-catalyzed intra-
molecular Ullmann reaction can be combined into a one-pot
manner, by destroying the residual isocyanide before perform-
ing the ensuing copper-mediated intramolecular Ullmann
coupling.
Table 2
Optimization of the intramolecular Ullmann reaction conditionsa
CuI (10 mol%)
NH
N
Br
ligand, base
O
O
solvent, 110 oC
24 h
O
O
O
O
5a
4a
4. Experimental section
NHMe
N
N
N
COOH
N
H
N
4.1. General procedure for the synthesis of compound 4
NHMe
L4
N
N
L1
L2
L3
L5
To a mixture of the substrate 1 (1 mmol) and 2-halobenzaldehyde
2 (1 mmol) in anhydrous toluene (3 mL) under nitrogen atmosphere
was added isocyanide 3 (1.2 mmol). The reaction mixture was slowly
heated to 110 ꢀC and then refluxed for a specific time (monitored by
TLC). After reaction, the organic solvent was removed under vacuo
and the residue obtained was purified by silica gel column chroma-
tography to afford the product 4.
Entry
Solvent
Base
Ligand
Yield (%)b
1
2
3
4
5
6
7
8
DMF
DMSO
K2CO3
K2CO3
K2CO3
K2CO3
Cs2CO3
NaOH
Et3N
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
K2CO3
L1
L1
L1
L1
L1
L1
L1
L2
L3
L4
L5
–
80
64
Dioxane
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
82c
97
50
Trace
36
96
79
4.1.1. 3-(2-Bromophenyl)-2-(tert-butylamino)-4H-furo[3,2-c]chro-
men-4-one (4a). Yellow solid; mp: 155e157 ꢀC. IR (KBr)
n
3397,
d 1.25
9
10
11
12
13
14
44
84
2975, 1738, 1615, 1530 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
(s, 9H, 3CH3), 5.33 (s, 1H, NH), 7.28e7.32 (m, 1H, ArH), 7.40e7.53(m,
5H, ArH), 7.67e7.70 (d, J¼7.8 Hz, 1H, ArH), 7.82e7.84 (d, J¼6.6 Hz,
0
L1
L1
78d
80e
1H, ArH). 13C NMR (100 MHz, DMSO-d6):
d 161.8, 160.6, 156.3, 154.8,
a
Unless otherwise noted, the reactions were carried out at 110 ꢀC for 24 h using
-proline (0.025 mmol,
138.5, 138.4, 137.7, 137.0, 134.8, 132.7, 130.8, 130.2, 125.1, 122.1, 117.6,
116.4, 107.3, 58.6, 35.5. HRMS (m/z) calcd for C21H18BrNO3 (Mþ)
411.0470, found 411.0468.
4a (0.25 mmol, 1 equiv), CuI (0.025 mmol, 10 mol %),
L
10 mol %), and K2CO3 (0.5 mmol, 2 equiv) under argon atmosphere.
b
Isolated yield.
Under refluxing conditions.
Reaction time: 12 h.
CuI (5 mol %) was used.
c
d
4.1.2. 3-(2-Bromophenyl)-2-(cyclohexylamino)-4H-furo[3,2-c]chro-
men-4-one (4b). Yellow oil. IR (KBr) n 3299, 2930, 1689, 1604, 1521,
e

6378
X. Zhu et al. / Tetrahedron 67 (2011) 6375e6381
Table 4
One-pot strategy toward the synthesis of compound 5a
CHO
R
N
X
OH
1. toluene, 110 o
C
2
O
+
2. CuI, L-proline, K2CO3
toluene, 110 oC, 24 h
R
NC
O
1
O
5
3
Entry
Substrate
Product
Yield (%)b
1
2
3
4
5
6
7
8
9
10
1a/2a/3a
1a/2b/3a
1a/2a/3b
1a/2a/3c
1b/2a/3a
1b/2a/3b
1b/2a/3c
1b/2b/3c
1c/2a/3a
1c/2a/3b
5a
5a
5b
5c
5d
5e
5f
5f
5g
5h
79
75
80
82
78
71
90
85
49
61
Fig. 3. The X-ray crystal structure of compound 5a.
a
1469 cmꢁ1 1H NMR (400 MHz, CDCl3):
. d 1.17e1.34 (m, 6H, CH2),
See the Supplementary data for detailed reaction conditions.
Isolated yield based on 2-halobenzaldehyde (2a,b) as limiting reagent.
b
1.71e1.74 (m, 2H, CH2), 2.00e2.07 (m, 2H, CH2), 3.50 (s, 1H, CH),
3.96 (s, 1H, NH), 7.19e7.24 (m, 1H, ArH), 7.27e7.3 1(m, 1H, ArH),
7.35e7.41 (m, 4H, ArH), 7.67 (d, J¼8.0 Hz,1H, ArH), 7.77 (d, J¼7.6 Hz,
1H, ArH). 13C NMR (75 MHz, DMSO-d6):
d 157.1, 155.8, 151.1, 148.0,
134.1, 132.7, 132.6, 130.0, 129.2, 127.8, 126.8, 125.3, 119.7, 117.2, 112.9,
93.4, 79.9, 53.1, 33.9, 27.0, 25.5. HRMS (m/z) calcd for C23H20BrNO3
(Mþ) 437.0627, found 437.0624.
Table 3
Construction of furo[2,3-b]indole scaffolds 5 via a copper-catalyzed intramolecular
Ullmann cyclizationa
4.1.3. 3-(2-Bromophenyl)-2-(2,6-dimethylphenylamino)-4H-furo
[3,2-c]chromen-4-one (4c). White solid; mp: 220e222 ꢀC. IR (KBr)
R
N
n
3301, 2959, 1720, 1612, 1585, 1557, 1491 cmꢁ1 1H NMR
.
R
NH
X
(400 MHz, CDCl3):
(m, 3H, ArH), 7.21e7.26 (m, 1H, ArH), 7.33e7.40 (m, 5H, ArH),
7.64e7.68 (m, 2H, ArH). 13C NMR (75 MHz, DMSO-d6):
157.1,
d 2.25 (s, 6H, CH3), 5.77 (s, 1H, NH), 7.03e7.07
O
O
CuI, L-Proline, K2CO3
toluene, 110 oC
24 h
d
O
5
153.8, 151.4, 148.7, 136.6, 135.2, 133.4, 133.3, 132.5, 131.5, 129.8,
128.7, 127.4, 126.3, 126.2, 125.5, 119.9, 117.4, 112.8, 112.7, 96.0, 19.0.
HRMS (m/z) calcd for C25H18BrNO3 (Mþ) 459.0470, found
459.0471.
O
4
Entry
1
Substrate 4
Product 5
Yield (%)b
97
4a
R¼t-Bu
5a
R
N
4.1.4. 3-(2-Bromophenyl)-2-(tert-butylamino)-5-methylfuro[3,2-c]
quinolin-4(5H)-one (4d). Yellow solid; mp: 155e157 ꢀC. IR (KBr)
n
O
3409, 2968, 1708, 1682, 1602, 1522 cmꢁ1
.
1H NMR (400 MHz,
2
3
4b
5b
99
86
DMSO-d6): 1.27 (s, 9H, CH3), 3.61 (s, 3H, NCH3), 5.10 (s, 1H, NH),
d
R¼Cy
4c
5c
7.26e7.30 (m, 1H, ArH), 7.33e7.42 (m, 3H, ArH), 7.52e7.59 (m, 2H,
ArH), 7.67 (d, J¼8.0 Hz, 1H, ArH), 7.87 (d, J¼7.6 Hz, 1H, ArH). 13C
O
O
R¼2,6-Me2C6H3
NMR (75 MHz, DMSO-d6):
d 158.2, 155.1, 148.0, 143.3, 137.2, 133.8,
4d
R¼t-Bu
R
N
4
5d
96
133.5, 132.7, 129.7, 128.9, 127.7, 126.3, 122.9, 120.1, 116.1, 112.7,
103.7, 53.8, 30.8, 29.5. HRMS (m/z) calcd for C22H21BrN2O2 (Mþ)
424.0786, found 424.0791.
O
5
6
4e
5e
82
99
R¼Cy
4f
5f
4.1.5. 3-(2-Bromophenyl)-2-(cyclohexylamino)-5-methylfuro[3,2-c]
N
O
R¼2,6-Me2C6H3
quinolin-4(5H)-one (4e). Yellow oil. IR (KBr)
n
3378, 2954, 1729,
1.20e1.35 (m,
1602, 1537, 1495 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
R
6H, CH2), 1.72e1.76 (m, 2H, CH2), 2.02e2.10 (m, 2H, CH2), 3.52e3.54
(m, 1H, CH), 3.72 (s, 3H, NCH3), 3.86 (s, 1H, NH), 7.22e7.29 (m, 1H,
ArH), 7.38e7.41 (m, 1H, ArH), 7.43e7.45 (m, 4H, ArH), 7.68 (d,
J¼8.0 Hz, 1H, ArH), 7.92 (d, J¼8.0 Hz, 1H, ArH). 13C NMR (75 MHz,
4g
R¼t-Bu
7
5g
89
N
O
O
CDCl3):
d 161.7, 159.1, 154.3, 147.6, 136.7, 133.6, 132.9, 129.2, 127.7,
O
127.3, 125.7, 122.3, 119.9, 115.0, 113.2, 97.3, 53.9, 49.0, 34.4, 29.4,
25.8, 25.2. HRMS (m/z) calcd for C24H23BrN2O2 (Mþ) 450.0943,
found 450.0943.
8
4h
R¼Cy
4i
4j
4k
4l
5h
94
9
5i
5j
5a
5f
d
d
0
0
92
89
10
11
12
4.1.6. 3-(2-Bromophenyl)-2-(2,6-dimethylphenylamino)-5-methylfuro
[3,2-c]quinolin-4(5H)-one(4f). Whitesolid;mp:230e232 ꢀC. IR(KBr)
a
3251, 2916, 1650, 1584, 1561, 1513 cmꢁ1. 1H NMR (400 MHz, CDCl3):
Reaction condition: 4 (0.25 mmol), CuI (0.025 mmol), L-proline (0.025 mmol),
n
and K2CO3 (0.5 mmol) were stirred at 110 ꢀC in toluene for 24 h under nitrogen
atmosphere.
d
2.25 (s, 6H, CH3), 3.74 (s, 3H, NCH3), 5.73 (s, 1H, NH), 7.00e7.05 (m,
b
3H, ArH), 7.21e7.26 (m, 2H, ArH), 7.33e7.37 (m, 1H, ArH), 7.40e7.46
Isolated yield.

X. Zhu et al. / Tetrahedron 67 (2011) 6375e6381
6379
(m, 3H, ArH), 7.67(d, J¼8.0 Hz,1H, ArH), 7.80(d,J¼8.0 Hz,1H, ArH).13
C
ArH), 7.78 (d, J¼8.0 Hz, 1H, ArH), 7.94 (d, J¼8.0 Hz,1H, ArH). 13C NMR
NMR (75 MHz, DMSO-d6):
d
158.1, 153.2, 146.5, 137.4, 136.9, 134.9,
(75 MHz, CDCl3): d 159.0, 151.2, 148.1, 139.0, 137.2, 136.7, 133.2, 132.1,
133.4, 132.8, 132.3, 129.3, 128.7, 128.6, 127.2, 126.6, 125.9, 122.9, 119.6,
117.1, 116.1, 112.5, 97.4, 29.5, 19.0. HRMS (m/z) calcd for C26H21BrN2O2
(Mþ) 472.0786, found 472.0784.
129.5, 128.9, 128.5, 128.2, 128.2, 125.3, 122.3, 120.5, 116.2, 115.0, 113.1,
104.4, 102.2, 29.4, 19.0. HRMS (m/z) calcd for C26H21IN2O2 (Mþ)
520.0648, found 520.0644.
4.1.7. 3-(2-Bromophenyl)-2-(tert-butylamino)naphtho[2,3-b]furan-
4.2. General procedure for the synthesis of compound 5
4,9-dione (4g). Red solid; mp: 170e173 ꢀC. IR (KBr)
n
3265, 2973,
1673, 1642, 1597, 1545 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d
1.42
The compound 4 (0.25 mmol) was added to a pre-dried round-
(s, 9H, CH3), 7.13 (s, 1H, NH), 7.32e7.35 (m, 1H, ArH), 7.41e7.42
(m, 2H, ArH), 7.69e7.71 (m, 2H, ArH), 7.78e7.82 (m, 1H, ArH), 7.86
(d, J¼6.4 Hz, 1H, ArH), 8.02 (d, J¼6.4 Hz, 1H, ArH). 13C NMR
bottomed flask, then CuI (0.025 mmol), L-proline (0.025 mmol), and
K2CO3 (0.5 mmol) was sequentially added to the flask under
nitrogen atmosphere. The mixture was refluxed in anhydrous tol-
uene for 24 h. After reaction, the organic solvent was removed
under vacuo and the residue obtained was purified by re-
crystallization from acetone or by silica gel column chromatogra-
phy to afford the product 5.
(75 MHz, CDCl3):
d 181.8, 169.6, 159.2, 143.9, 134.3, 134.0, 133.6,
133.5, 133.2, 132.5, 131.6, 131.1, 130.2, 127.9, 126.5, 126.4, 125.1,
99.2, 54.4, 30.2. HRMS (m/z) calcd for C22H18BrNO3 (Mþ)
423.0470, found 423.0473.
4.1.8. 3-(2-Bromophenyl)-2-(cyclohexylamino)naphtho[2,3-b]furan-
4.2.1. 11-(tert-Butyl)chromeno[30,40:4,5]furo[2,3-b]indol-6(11H)-one
4,9-dione (4h). Red solid; mp: 127e129 ꢀC. IR (KBr)
n
3179, 2932,
1.20e1.35
(5a). Purified by recrystallization in acetone. Yellow solid; mp:
1676, 1647, 1596, 1546 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
264e267 ꢀC. IR (KBr) 2977, 1728, 1621, 1535, 1487 cmꢁ1. 1H NMR
n
(m, 6H, CH2), 1.72e1.75 (m, 2H, CH2), 2.02e2.09 (m, 2H, CH2),
3.74e3.81 (m, 1H, CH), 4.56 (d, J¼8.8 Hz, 1H, NH), 7.28e7.30 (m, 1H,
ArH), 7.39e7.40 (m, 2H, ArH), 7.57e7.60 (m, 1H, ArH), 7.66e7.71 (m,
2H, ArH), 7.97 (d, J¼7.6 Hz, 1H, ArH), 8.16 (d, J¼7.6 Hz, 1H, ArH). 13C
(400 MHz, CDCl3): d 1.98 (s, 9H, CH3), 7.26e7.29 (m, 2H, ArH),
7.31e7.35 (m, 1H, ArH), 7.43e7.47 (m, 2H, ArH), 7.70e7.72 (m, 1H,
ArH), 7.84 (d, J¼7.6 Hz, 1H, ArH), 8.14 (d, J¼5.2 Hz, 1H, ArH). Due to
the low solubility of 5a in all commercially available deuterium
solvents, the 13C NMR spectra of the compound 5a was not
obtained, but the authenticity of 5a can be unambiguously con-
firmed by single-crystal X-ray analysis. HRMS (m/z) calcd for
C21H17NO3 (Mþ) 331.1208, found 331.1208.
NMR (75 MHz, CDCl3): d 181.9,169.6,158.9,143.1,134.0,133.6,133.5,
133.4, 133.1, 132.4, 131.1, 130.1, 127.8, 126.6, 126.4, 125.3, 97.6, 52.7,
34.3, 34.1, 25.5, 25.0. HRMS (m/z) calcd for C24H20BrNO3 (Mþ)
449.0627, found 449.0629.
4.1.9. 3-(2-Bromo-5-fluorophenyl)-2-(tert-butylamino)-4H-furo[3,2-
4.2.2. 11-Cyclohexylchromeno[30,40:4,5]furo[2,3-b]indol-6(11H)-one
c]chromen-4-one (4i). Yellow solid; mp: 197e199 ꢀC. IR (KBr)
n
(5b). Purified by recrystallization in acetone. Yellow solid; mp:
3368, 2959, 1754, 1601, 1534, 1478 cmꢁ1. 1H NMR (400 MHz, CDCl3):
1.41 (s, 9H, CH3), 3.86 (s,1H, NH), 7.01e7.06 (m,1H, ArH), 7.14e7.17
223e225 ꢀC. IR (KBr) 2960, 1720, 1618, 1542, 1473 cmꢁ1. 1H NMR
n
d
(400 MHz, CDCl3): d 1.42e1.55 (m, 3H, CH2), 1.86e1.90 (m, 1H, CH2),
(m, 1H, ArH), 7.36e7.40 (m, 1H, ArH), 7.45e7.52 (m, 2H, ArH),
7.66e7.70 (m, 1H, ArH), 7.85 (d, J¼7.6 Hz, 1H, ArH). 13C NMR
2.03e2.06 (m, 2H, CH2), 2.14e2.22 (m, 4H, CH2), 4.38e4.44 (m, 1H,
CH), 7.28e7.3 9(m, 3H, ArH), 7.44e7.48 (m, 3H, ArH), 7.94 (d,
J¼7.6 Hz, 1H, ArH), 8.12 (d, J¼8.0 Hz, 1H, ArH). Due to the low sol-
ubility of 5b in all commercially available deuterium solvents, the
13C NMR spectra of the compound 5b was not obtained. HRMS (m/z)
calcd for C23H19NO3 (Mþ) 357.1365, found 357.1359.
(75 MHz, CDCl3):
d 163.5, 160.2, 157.6, 155.0, 151.9, 151.0, 134.5,
134.4, 133.6, 133.5, 129.5, 124.6, 120.1, 119.8, 119.4, 117.3, 117.0, 113.0,
111.2, 101.1, 54.5, 30.6. HRMS (m/z) calcd for C21H17BrFNO3 (Mþ)
429.0376, found 429.0373.
4.1.10. 3-(2-Bromo-5-fluorophenyl)-2-(tert-butylamino)-5-methylfuro
[3,2-c]quinolin-4(5H)-one (4j). Yellow solid; mp: 163e165 ꢀC. IR
4.2.3. 11-(2,6-Dimethylphenyl)chromeno[30,40:4,5]furo[2,3-b]indol-
6(11H)-one (5c). Yellow solid; mp: 235e237 ꢀC. IR (KBr)
n
2920,
(KBr)
n
3382, 2943, 1727, 1620, 1544, 1480 cmꢁ1. 1H NMR (400 MHz,
1746, 1621, 1544, 1462 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d 2.06 (s,
CDCl3):
d
1.37 (s, 9H, CH3), 3.73 (s, 4H, NH and NCH3), 6.95e7.00 (m,
6H, CH3), 7.01 (d, J¼8.0 Hz, 1H, ArH), 7.32e7.41 (m, 5H, ArH),
7.44e7.55 (m, 3H, ArH), 7.86 (d, J¼8.0 Hz, 1H, ArH), 8.24 (d,
1H, ArH), 7.13e7.16 (m, 1H, ArH), 7.29e7.32 (m, 1H, ArH), 7.41e7.51
(m, 2H, ArH), 7.61e7.65 (m, 1H, ArH), 7.94 (d, J¼8.0 Hz, 1H, ArH). 13C
J¼7.6 Hz, 1H, ArH). 13C NMR (75 MHz, CDCl3):
d 158.6, 156.0, 154.9,
NMR (75 MHz, CDCl3):
d
163.4, 160.1, 158.9, 154.4, 148.9, 137.2, 134.9,
151.9, 138.4, 137.8, 132.5, 129.9, 129.5, 129.1, 124.7, 123.3, 122.0,
121.5, 120.3, 119.2, 117.5, 113.9, 111.3, 108.8, 100.0, 18.0. HRMS (m/z)
calcd for C25H17NO3 (Mþ) 379.1208, found 379.1208.
134.7, 134.1, 134.0, 128.4, 122.4, 120.4, 120.0, 116.9, 116.6, 115.5, 115.1,
113.1, 102.2, 102.2, 54.3, 30.7, 29.4. HRMS (m/z) calcd for
C22H20BrFN2O2 (Mþ) 442.0692, found 442.0689.
4.2.4. 11-(tert-Butyl)-5-methyl-5H-indolo[30,20:4,5]furo[3,2-c]quino-
4.1.11. 2-(tert-Butylamino)-3-(2-iodophenyl)-4H-furo[3,2-c]chro-
lin-6(11H)-one (5d). Yellow solid; mp: 251e252 ꢀC. IR (KBr)
n
2977,
men-4-one (4k). Yellow solid; mp: 157e159 ꢀC. IR (KBr)
n
3390,
1.39
1651, 1618, 1580, 1532 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d 1.94
2973,1738, 1612,1558,1485 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d
(s, 9H, CH3), 3.80 (s, 3H, NCH3), 7.24e7.26 (m, 2H, ArH), 7.39e7.43
(m, 1H, ArH), 7.58e7.62 (m, 1H, ArH), 7.69e7.71 (m, 1H, ArH),
7.87e7.89 (m, 1H, ArH), 7.80e8.03 (m, 2H, ArH). 13C NMR (75 MHz,
(s, 9H, CH3), 3.77 (s, 1H, NH), 7.11e7.14 (m, 1H, ArH), 7.35e7.38 (m,
2H, ArH), 7.46e7.50 (m, 3H, ArH), 7.85 (d, J¼7.2 Hz, 1H, ArH), 8.01
(d, J¼8.0 Hz, 1H, ArH). 13C NMR (75 MHz, CDCl3):
d
152.9, 150.0,
CDCl3): d 160.0, 155.4, 153.4, 137.4, 137.2, 128.1, 122.4, 121.9, 121.6,
147.2, 146.0, 134.9, 131.1, 127.3, 125.2, 124.6, 123.8, 119.8, 115.3, 112.5,
108.4, 106.6, 101.1, 97.1, 49.7, 26.0. HRMS (m/z) calcd for C21H18INO3
(Mþ) 459.0331, found 459.0327.
120.6, 120.6, 120.2, 115.2, 114.2, 114.1, 112.7, 101.0, 58.6, 30.2, 29.7.
HRMS (m/z) calcd for C22H20N2O2 (Mþ) 344.1525, found 344.1522.
4.2.5. 11-Cyclohexyl-5-methyl-5H-indolo[30,20:4,5]furo[3,2-c]quino-
4.1.12. 2-(2,6-Dimethylphenylamino)-3-(2-iodophenyl)-5-methylfuro
lin-6(11H)-one (5e). Yellow solid; mp: 214e216 ꢀC. IR (KBr)
n
2934,
[3,2-c]quinolin-4(5H)-one (4l). White solid, mp: 185e187 ꢀC. IR (KBr)
1656,1625,1584,1542 cmꢁ1. 1H NMR (400 MHz, CDCl3):
d 1.65e1.70
n
3248, 2920, 1678, 1566, 1559, 1519 cmꢁ1
.
1H NMR (400 MHz,
(m, 2H, CH2), 1.93e1.97 (m, 1H, CH2), 2.01e2.13 (m, 2H, CH2),
2.22e2.30 (m, 5H, CH2), 3.97 (s, 3H, NCH3), 4.44e4.52 (m, 1H, CH),
7.36e7.44 (m, 3H, ArH), 7.51e7.53 (m, 1H, ArH), 7.56e7.61 (m, 2H,
CDCl3):
d 2.26 (s, 6H, 2CH3), 3.74 (s, 3H, NCH3), 5.61 (s, 1H, NH),
7.02e7.05 (m, 4H, ArH), 7.21e7.26 (m, 1H, ArH), 7.38e7.48 (m, 4H,

6380
X. Zhu et al. / Tetrahedron 67 (2011) 6375e6381
ArH), 8.15 (d, J¼7.6 Hz, 1H, ArH), 8.29 (d, J¼8.8 Hz, 1H, ArH). 13C
Education (No. 10KJB150016), and Key Project in Science and
Technology Innovation Cultivation Program of Soochow University.
NMR (75 MHz, CDCl3): d 159.5, 155.1, 153.9, 137.4, 137.1, 128.1, 122.4,
121.8, 121.6, 120.7, 120.3, 119.6, 115.2, 114.2, 113.2, 110.4, 100.8, 55.6,
32.4, 29.7, 26.2, 25.7. HRMS (m/z) calcd for C24H22N2O2 (Mþ)
370.1681, found 370.1682.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tet.2011.05.101.
4.2.6. 11-(2,6-Dimethylphenyl)-5-methyl-5H-indolo[30,20:4,5]furo
[3,2-c]quinolin-6(11H)-one (5f). Yellow solid; mp: 152e155 ꢀC. IR
(KBr)
DMSO-d6):
n .
2921, 1651, 1582, 1549, 1495 cmꢁ1 1H NMR (400 MHz,
References and notes
d
1.93 (s, 6H, CH3), 3.80 (s, 3H, NCH3), 6.93 (d, J¼8.4 Hz,
1H, ArH), 7.24e7.34 (m, 3H, ArH), 7.37e7.40 (m, 2H, ArH), 7.45e7.48
(m, 1H, ArH), 7.54e7.58 (m, 1H, ArH), 7.68 (d, J¼8.4 Hz, 1H, ArH),
7.88 (d, J¼7.6 Hz, 1H, ArH), 8.05 (d, J¼7.6 Hz, 1H, ArH). 13C NMR
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(75 MHz, DMSO-d6):
d 158.8, 154.8, 154.2, 138.1, 137.5, 132.5, 130.4,
129.7,129.4,129.4,123.4,123.2,122.1,121.2,120.5,119.4,116.4,113.4,
113.2, 111.6, 100.2, 30.0, 17.8. HRMS (m/z) calcd for C26H20N2O2 (Mþ)
392.1525, found 392.1528.
4.2.7. 5-(tert-Butyl)-5H-naphtho[20,30:4,5]furo[2,3-b]indole-7,12-
dione (5g). Red solid; mp: 190e193 ꢀC. IR (KBr)
n
2932, 1675, 1649,
1.75 (s, 9H, CH3),
1576, 1523 cmꢁ1. 1H NMR (400 MHz, DMSO-d6):
d
7.13e7.23 (m, 2H, ArH), 7.63e7.71 (m, 2H, ArH), 7.76 (d, J¼8.4 Hz,
3. (a) Domling, A.; Ugi, I. Angew. Chem., Int. Ed. 2000, 39, 3168; (b) Domling, A.
Chem. Rev. 2006, 106, 17; (c) Ramon, D. J.; Yus, M. Angew. Chem., Int. Ed. 2005, 44,
1602.
1H, ArH), 7.85 (d, J¼7.2 Hz, 1H, ArH), 7.89e7.93 (m, 2H, ArH). 13C
NMR (75 MHz, CDCl3): d 181.9, 171.7, 158.8, 149.7, 140.1, 134.1, 133.6,
4. (a) Cuny, G.; Bois-Choussy, M.; Zhu, J. J. Am. Chem. Soc. 2004, 126, 14475; (b)
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Coffinier, D.; Kaim, L. E.; Grimaud, L. Org. Lett. 2009, 11, 995; (e) Spatz, J. H.;
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11, 1078; (g) Fontaine, P.; Masson, G.; Zhu, J. Org. Lett. 2009, 11, 1555; (h) Pirali,
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2284; (j) Ohno, H.; Ohta, Y.; Oishi, S.; Fujii, N. Angew. Chem., Int. Ed. 2007, 46,
2295; (k) Barluenga, J.; Jimenez-Aquino, A.; Valdes, C.; Aznar, F. Angew. Chem.,
Int. Ed. 2007, 46, 1529; (l) Pinto, A.; Neuville, L.; Zhu, J. Angew. Chem., Int. Ed.
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133.0, 132.7, 130.2, 127.0, 126.8, 124.1, 122.8, 121.7, 120.0, 114.8, 103.1,
59.5, 30.0. HRMS (m/z) calcd for C22H17NO3 (Mþ) 343.1208, found
343.1203.
4.2.8. 5-Cyclohexyl-5H-naphtho[20,30:4,5]furo[2,3-b]indole-7,12-
dione (5h). Red solid; mp: 245e248 ꢀC. IR (KBr)
n
2918, 1670, 1634,
1587, 1530 cmꢁ1 1H NMR (400 MHz, CDCl3):
. d 1.42e1.54 (m, 3H,
CH2), 1.81e1.84 (m, 1H, ArH), 2.01e2.04 (m, 2H, CH2), 2.17e2.22 (m,
4H, CH2), 4.33e4.40 (m, 1H, CH), 7.31e7.46 (m, 3H, ArH), 7.67e7.77
(m, 2H, ArH), 8.18e8.25 (m, 3H, ArH). 13C NMR (75 MHz, CDCl3):
d
181.8, 171.8, 158.5, 150.1, 140.1, 134.1, 133.5, 133.0, 132.7, 127.6,
126.8, 126.8, 124.4, 122.6, 121.9, 119.0, 111.1, 102.8, 56.0, 31.9, 26.1,
25.3. HRMS (m/z) calcd for C24H19NO3 (Mþ) 369.1365, found
369.1367.
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4.3. General procedure for the one-pot synthesis of 5
The mixture of substrate 1 (0.5 mmol), aldehyde 2 (0.5 mmol),
and isocyanide 3 (0.6 mmol) was stirred at 110 ꢀC in anhydrous
toluene. Upon completion of the reaction as monitored by TLC,
CF3COOH (8
mL, 0.2 equiv) was added to the reaction mixture at
room temperature. After that, CuI (0.05 mmol),
L-proline
(0.05 mmol), and K2CO3 (1 mmol) was added sequentially under
nitrogen atmosphere and the mixture was refluxed for 24 h. After
reaction, the organic solvent was removed under vacuo and the
residue obtained was purified by recrystallization from acetone or
by silica gel column chromatography to afford the pure products 5.
The compound 4 (0.25 mmol) was added to a pre-dried round-
bottomed flask, then CuI (0.025 mmol), L-proline (0.025 mmol), and
K2CO3 (0.5 mmol) was sequentially added to the flask under
nitrogen atmosphere. The mixture was refluxed in anhydrous tol-
uene for 24 h. After reaction, the organic solvent was removed
under vacuo and the residue obtained was purified by re-
crystallization from acetone or by silica gel column chromatogra-
phy to afford the product 5.
Acknowledgements
11. (a) Zhu, S. L.; Ji, S. J.; Su, X. M.; Liu, Y. Tetrahedron Lett. 2008, 49, 1777; (b) Zhu, S.
L.; Ji, S. J.; Liu, Y. Tetrahedron Lett. 2008, 49, 2578; (c) Zhu, S. L.; Ji, S. J.; Zhang, Y.
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The work was partially supported by the National Natural Sci-
ence Foundation of China (No. 20672079, 20910102041, 21042007),
Nature Science Basic Research of Jiangsu Province for Higher

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