Phosphorus-containing Lewis base catalyzed highly regioselective cyclization of isatin derived electron-deficient alkenes with but-3-yn-2-one

Article abstract of DOI:10.1016/j.tet.2012.01.036

In this paper, we reported that phosphorus-containing Lewis bases catalyzed [4+2] cyclization of N-protected isatin derived electron-deficient alkenes with but-3-yn-2-one could proceed smoothly to give the corresponding dihydropyrano[2,3-b]indoles in good

Full text of DOI:10.1016/j.tet.2012.01.036

Tetrahedron 68 (2012) 2401e2408
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journal homepage: www.elsevier.com/locate/tet
Phosphorus-containing Lewis base catalyzed highly regioselective cyclization
of isatin derived electron-deficient alkenes with but-3-yn-2-one
*
Zhong Lian, Yin Wei, Min Shi
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Science, 345 Lingling Road, Shanghai 200032 China
a r t i c l e i n f o
a b s t r a c t
Article history:
In this paper, we reported that phosphorus-containing Lewis bases catalyzed [4þ2] cyclization of N-
protected isatin derived electron-deficient alkenes with but-3-yn-2-one could proceed smoothly to give
the corresponding dihydropyrano[2,3-b]indoles in good to excellent yields under mild conditions. The
substrate scope has been carefully examined and the plausible reaction mechanism has been also
proposed.
Received 17 November 2011
Received in revised form 31 December 2011
Accepted 7 January 2012
Available online 20 January 2012
Ó 2012 Elsevier Ltd. All rights reserved.
Keywords:
But-3-yn-2-one
[4þ2] Cyclization
Lewis bases
PPh3
Electron-deficient alkenes
1. Introduction
annulations of isatin with but-3-yn-2-one, giving the corre-
sponding spiro[indoline-3,20-pyran]-2,40(30H)-dione and spiro[fu-
Heterocyclic compounds hold a special place in organic chem-
istry because of their abundance in natural products and the di-
verse biological properties associated with them. Many
heterocycles have received an enormous amount of attention from
synthetic chemists, and among them indole and pyran ring systems
are of particular importance.1 The benzopyran or chromene core
containing chemicals are prevalent in compounds with proven
pharmacological properties.2 Fused chromenes (polycyclic pyrans)
are also of great interest because of their well-documented anti-
bacterial and novobiocin activities.3 Thus, the need for the de-
velopment of efficient and practical syntheses of novel heterocycles
with these ring systems is of great significance. The hetero-Diel-
seAlder reaction is one of the most important reactions for the
construction of heterocyclic six-membered rings.4e8 Over the past
few years, syntheses of several complex annulated dihydropyrans
have been achieved using the hetero-DielseAlder reaction.9,10 Re-
cently, our group reported a novel phosphorus-containing Lewis
base catalyzed highly geometric selective [3þ2] annulation of isatin
ran-2,30-indoline]-20,4(5H)-dione in good to excellent yields under
mild conditions (Scheme 1).12 Herein, we wish to present an in-
teresting phosphorus-containing Lewis base PPh3-catalyzed
highly regioselective [4þ2] cyclization of isatin derived electron-
deficient alkenes with but-3-yn-2-one, providing dihydropyrano
[2,3-b]indoles in good to excellent yields under mild conditions
(Scheme 2).
2. Results and discussion
Initially, we utilized diethyl 2-(1-benzyl-2-oxoindolin-3-
ylidene)malonate 1a and but-3-yn-2-one 2 as the substrates to
investigate their cyclization behaviors in the presence of various
Lewis bases, such as nitrogen and phosphorus-containing Lewis
bases (for example, PPh3, PPh2Me, DABCO, DBU, and so on) at room
temperature. To our disappointment, no reactions occurred under
various reaction conditions (Scheme 3). Using isatin derived
electron-deficient alkene 3a as the substrate in which the alkenyl
moiety should be more electron-deficient than that of 1a, we found
that the [4þ2] cyclization took place smoothly to give the corre-
sponding cyclic product 4a in good yield in the presence of PPh3
(Scheme 3). Moreover, using more electron-deficient alkene, such
as isatylidene malononitrile 5a as the substrate did not give an ideal
reaction outcome, affording complex product mixtures (Scheme 3).
The general procedure for the preparation of isatin derived
electron-deficient alkene 3a is shown in the Supplementary data.
derived a,b-unsaturated diesters with a-allenic ester, affording the
functionalized spirocyclic products in good to excellent yields
(Scheme 1).11 Subsequently, we also reported novel nitrogen and
phosphorus-containing Lewis bases catalyzed [4þ2] and [3þ2]
* Corresponding author. Fax: þ86 21 64166128; e-mail address: mshi@mail.sio-
c.ac.cn (M. Shi).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.036

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Z. Lian et al. / Tetrahedron 68 (2012) 2401e2408
Previous work:
EtO2C
EtO2C
EtO2C
EtO2C
CO2Et
EtO2C
EtO2C
4
CO2Et
5
PBu3 (20 mol %)
•
CO2Et
O
+
O
+
O
toluene, rt, 2 h
6
N
N
N
R2
R2
7
R2
R3
R3
R3
minor
major
74-90% total yields (3:1 ~>20:1)
O
CO2
Et
CO2
Et
O
O
O
R1
PBu3
R1
R1
•
CO2Et
+
+
R2
O
toluene, rt
R2
R2
O
N
N
N
Bn
Bn
Bn
(cis, trans)
(trans, trans)
up to 90% yield, (cis, trans):(trans, trans)>20:1
O
4
O
5
6
R1
DABCO (100 mol %)
THF
O
N
7
R2
64-98% yields
O
4
5
6
O
R1
O
+
N
O
7
R2
O
4
5
6
PPh2Me (20 mol %)
THF
R1
O
N
7
R2
64-87% yields
Scheme 1. Nitrogen and phosphorus-containing Lewis bases mediated/catalyzed [4þ2] and [3þ2] annulations in our previous work.
This work
O
CN
EtO2C
EtO2C
CN
O +
O
PPh3 (20 mol %)
THF
R1
R1
O
N
N
2
R2
R2
, up to 91% yield
3
4
Scheme 2. PPh3-catalyzed cycloaddition of isatin derived electron-deficient alkenes with but-3-yn-2-one.
Moreover, the E-configuration of 3a has been determined by X-ray
diffraction (see Supplementary data for the details).13
cyclic product ethyl 3-acetyl-9-benzyl-4-cyano-4,9-dihydropyrano
[2,3-b]indole-4-carboxylate 4a was obtained in 50% yield (Table 1,
entry 1). The structure of product 4a was assigned on the basis of
spectroscopic analyses. Its structure has been further un-
ambiguously determined by X-ray diffraction of single crystals of its
analogue 4j (see Table 2, entry 9). Its ORTEP drawing is shown in
Fig. 1 and the CIF data are presented in the Supplementary data.14
The examination of various phosphorus containing catalysts, such
as PPh2Me, PPhMe2, and PBu3 for this reaction indicated that PPh3
was the best catalyst for this reaction (Table 1, entries 2e4). Using
Subsequently, we attempted to optimize the reaction conditions
in cyclization of isatin derived electron-deficient alkene 3a with
but-3-yn-2-one 2 in the presence of various Lewis bases. The initial
investigation aroused from the reaction of (E)-ethyl 2-(1-benzyl-2-
oxoindolin-3-ylidene)-2-cyanoacetate 3a (1.0 equiv) and but-3-yn-
2-one
2 (1.5 equiv) in the presence of triphenylphosphine
(PPh3) (20 mol %) in tetrahydrofuran (THF) at room temperature
(20 ꢀC). We found that oxygen atom-containing six-membered

Z. Lian et al. / Tetrahedron 68 (2012) 2401e2408
2403
Having identified the optimal reaction conditions, we next set
out to examine the substrate scope of this [4þ2] cyclization cata-
lyzed by PPh3 using various isatin derived electron-deficient alkene
derivatives 3 with different substituents on their benzene rings and
the results are summarized in Table 2. As can be seen from Table 2,
the reactions proceeded smoothly to give the corresponding
products 4beh in moderate to good yields whether electron-
withdrawing or electron-donating groups were introduced at the
5-, 6-, or 7-position of their benzene rings of N-Bn protected isatins
3, suggesting that the electronic property of the substituents on the
benzene rings did not have significant impact on the reaction
outcomes (Table 2, entries 1e7). It should be also noted that, in the
case of other isatin derivatives 3iem bearing different N-protecting
groups, the reactions also proceeded efficiently to produce the
corresponding oxa-cycloadducts 4iem in moderate to good yields
(Table 2, entries 8e12). We also found that these products 4aem
are quite stable during the isolation by silica gel column
chromatography.
EtO2C
CO2Et
O
Lewis base
+
N. R.
O
N
Bn
2
1a
O
CN
EtO2C
CN
O
EtO2C
O
PPh3
O
+
N
N
Bn
Bn
2
4a
3a
NC
CN
O
O
Lewis base
+
Complex product mixtures
N
Bn
5a
2
A plausible reaction mechanism for the formation of 4a shown
in Scheme 4 may be invoked to rationalize the reaction outcome.
Initially, the reaction of PPh3 with but-3-yn-2-one 2 generates the
zwitterionic intermediate A.15 Then nucleophilic addition of in-
termediate A to the alkenyl group of 3a produces intermediate B.
The intramolecular Michael addition of Oꢁ anion to the olefin
moiety in intermediate B gives ylide-type intermediate C, which
subsequently undergoes the elimination of phosphine to give the
final product 4a and regenerates PPh3 to complete the catalytic
cycle.16
An unexpected finding is that during our preparation of N-Bn
protected isatin derived electron-deficient alkene derivative 3 us-
ing 5-Cl substituted isatin as the substrate under the standard
procedure, we found that compound 6 was formed rather than the
desired isatylidene derivative 3, presumably due to the electronic
effect.17 Using compound 6 (1.0 M) in THF as the substrate in the
reaction with but-3-yn-2-one 2 (3 equiv) in the presence of PPh3
(0.2 equiv) under the standard conditions, it was found that the
corresponding product 7 was formed in the yield of 91% as a single
diastereoisomer via a similar mechanism shown in Scheme 4
(Scheme 5). The structure of product 7 has been assigned on the
basis of spectroscopic analyses. Its structure has been also further
unambiguously determined by X-ray diffraction of its single crys-
tals. The ORTEP drawing is shown in Fig. 2 and the CIF data are
presented in the Supplementary data.18
Scheme 3. Cycloaddition of isatin derived electron-deficient alkenes with but-3-yn-2-
one 2 catalyzed by Lewis base.
Table 1
Optimization of the reaction conditionsa
O
CN
EtO2C
EtO2C
CN
O
O
cat. (x mol%)
solvent
+
O
N
N
Bn
Bn
3a
2
4a
Entry
3a/2
Cat.
ꢂ (mol %)
Solvent
Yieldb (%)
4a
1
2
3
4
5
6
7
8
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:1.5
1:2
1:3
1:3
1:3
1:3
PPh3
20
20
20
20
20
20
20
20
20
20
10
5
20
20
20
20
20
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
THF
CH3CN
Et2O
DCM
Toluene
DMF
50
44
31
22
Trace
Trace
Trace
Trace
58
93
45
28
25
79
31
55
48
PPh2Me
PPhMe2
PBu3
DM AP
DABCO
DBU
Et3N
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
PPh3
9
10
11
12
13
14
15
16
17
3. Conclusion
1:3
1:3
1:3
1:3
In summary, we have disclosed a facile synthetic protocol for the
preparation of functionalized dihydropyrano[2,3-b]indole de-
rivatives in good to excellent yields by phosphorus-containing
Lewis bases catalyzed cyclization of N-protected isatin derived
electron-deficient alkene 3 with but-3-yn-2-one 2 under mild
conditions. These cyclizations are suitable to a variety of isatin
derived electron-deficient alkenes. Efforts are underway to eluci-
date the mechanistic details of this cyclization and to explore some
other interesting annulation reactions using N- and P-containing
Lewis bases.
Italic values represents the best reaction conditions.
a
Compound 3a (0.1 mmol) and catalyst were dissolved in solvent (1 mL), then
compound 2 was added and the reaction mixture was stirred for about 5 h.
b
Isolated yields.
nitrogen-containing Lewis bases as the catalysts, we found that
only trace product 4a was formed in the presence of 4-N,N-dime-
thylpyridine (DMAP), 1,4-diazabicyclo[2,2,2]octane (DABCO), 1,8-
diazabicyclo[5,4,0]-7-undecene (DBU) or triethylamine (TEA) in
THF (Table 1, entries 5e8). Delightfully, increasing the employed
amount of but-3-yn-2-one 2 to 2.0 equiv and 3.0 equiv afforded
product 4a in 58% and 93% yields, respectively (Table 1, entries 9
and 10). However, we found that decreasing the employed amounts
of PPh3 to 0.1 or 0.05 equiv led to a dramatic drop in the yield of
product 4a (Table 1, entries 11 and 12). The examination of solvent
effects revealed that THF is the solvent of choice for this novel cy-
clization (Table 1, entries 13e17).
4. Experimental section
4.1. General remarks
Mps were obtained with a Yanagimoto micro melting point
apparatus and are uncorrected. 1H NMR and 13C NMR spectra were
recorded for a solution in CDCl3 with tetramethylsilane (TMS) as
internal standard. J-values are in 300 M or 400 MHz. Mass spectra
were recorded with an HP-5989 instrument and HRMS was

2404
Z. Lian et al. / Tetrahedron 68 (2012) 2401e2408
Table 2
Substrate scope of PPh3-catalyzed [4þ2] cycloaddition reactiona
O
CN
EtO2C
4
EtO2C
CN
O
5
PPh3 (20 mol%)
THF
R1
O
R1
+
O
N
N
6
R2
R2
7
3
2
4
Entry
R1
R2
Yieldb (%)
4
1
2
3
4
5
6
7
8
5-F
Bn, 3b
Bn, 3c
Bn, 3d
Bn, 3e
Bn, 3f
Bn, 3g
Bn, 3h
Me, 3i
Allyl, 3j
4b, 91
4c, 89
4d, 81
4e, 75
4f, 73
4g, 81
4h, 88
4i, 71
4j, 77
4k, 90
41, 76
4m, 79
5-Me
5-Br
6-Br
6-CH3
5,7-Me2
5-MeO
H
H
H
H
H
9
10
11
12
Anthracen-10-ylmethyl, 3k
Boc, 3l
Mom, 3m
a
Compound 3 (0.1 mmol) and PPh3 (0.02 mmol) were dissolved in solvent (1 mL), then compound 2 (0.3 mmol) was added and the reaction
mixture was stirred for about 5 h.
b
Isolated yields.
measured by a Finnigan MAþ mass spectrometer. The solid com-
pounds reported in this paper gave satisfactory CHN microanalyses
with a Carlo-Erba 1106 analyzer. Commercially obtained reagents
were used without further purification. All reactions were moni-
tored by TLC with Huanghai GF254 silica gel coated plates. Flash
column chromatography was carried out using 300e400 mesh
silica gel at increased pressure. Reaction experiments were per-
formed under argon condition.
column chromatography on silica gel eluted with ethyl acetate/
petroleum ether (1:5, v/v) to afford the products 3 mainly as E-
configuration.
4.1.1.1. (E)-Ethyl 2-(1-benzyl-2-oxoindolin-3-ylidene)-2-
cyanoacetate (3a). Mp 147e149 ꢀC; 1H NMR (CDCl3, 400 MHz,
TMS)
d
1.42 (t, 3H, J¼7.2 Hz, CH3), 4.45 (q, 2H, J¼7.2 Hz, CH2), 4.90 (s,
2H, CH2), 6.70 (d, 1H, J¼8.0 Hz, ArH), 7.05 (t, 1H, J¼8.0 Hz, ArH),
7.24e7.35 (m, 6H, ArH), 8.28 (d, 1H, J¼8.0 Hz, ArH); 13C NMR (CDCl3,
4.1.1. Typical reaction procedure for the preparation of 3.
100 MHz, TMS)
d
13.9, 43.9, 63.4, 106.5, 109.7, 114.0, 118.7, 123.1,
EtO2C
EtO2C
CN
C
CN
O
O
C
N
H
BnBr
K2CO3
O
O + NC
CO2Et
EtOH, reflux
N
N
H
N
Bn
H
3a
9
8
10 (E/Z= 1.5:1~ 6:1)
To a solution of the appropriate isatins 8 (10 mol) in dry ethanol
(20.0 mL), ethyl 2-cyanoacetate 9 (10 mol) was added, as well as
two drops of piperidine as catalyst. Then the reaction mixture was
refluxed for nearly 2 h, and after allowing the mixture to cool to
room temperature, crystalline products of 10 precipitated. The
precipitated solids of compound 10 were filtered off and washed
several times with cold ethanol (10 mL) to afford analytically pure
compounds.
125.2, 127.4, 128.9, 129.9, 134.5, 135.6, 139.8, 145.6, 161.5, 164.4; IR
(CH2Cl2): n ;
3032, 2982, 2213, 1720, 1583, 1380, 1059, 821, 599 cmꢁ1
MS (%) (EI) m/z 332 (Mþ, 20.6), 303 (9.7), 258 (17.5), 230 (5.6), 92
(10.4), 91 (100), 65 (12.4). HRMS (EI) calcd for C20H16N2O3 requires
332.1161, found: 332.1164.
4.1.1.2. (E)-Ethyl 2-(1-benzyl-5-fluoro-2-oxoindolin-3-ylidene)-2-
cyanoacetate (3b). 1H NMR (CDCl3, 400 MHz, TMS)
d 1.45 (t, 3H,
K2CO3 (1.2 mmol) was added to a solution of ethyl 2-cyano-2-
(2-oxoindolin-3-ylidene)acetate 10 (1.0 mmol) and benzyl bro-
mide (1.2 mmol) in DMF (15 mL) at room temperature and the
mixture was stirred overnight at room temperature. The reaction
mixture was diluted with CH2Cl2 and washed with water. The or-
ganic layer was dried over anhydrous MgSO4, filtered, the solvent
was removed under vacuum and the residue was purified by flash
J¼7.2 Hz, CH3), 4.47 (q, 2H, J¼6.8 Hz, CH2), 4.93 (s, 2H, CH2), 6.65
(dd, 1H, J1¼4.0 Hz, J2¼8.4 Hz, ArH), 7.06e7.11 (m, 1H, ArH),
7.26e7.36 (m, 5H, ArH), 8.16 (dd, 1H, J1¼2.4 Hz, J2¼9.2 Hz, ArH); 13
C
NMR (CDCl3, 100 MHz, TMS)
d 13.9, 44.1, 63.7, 108.0, 110.3 (d,
J¼8.2 Hz), 113.7, 117.4 (d, J¼27.2 Hz), 119.5 (d, J¼8.8 Hz), 122.0 (d,
J¼24.3 Hz), 127.4, 128.1, 129.0, 134.4, 141.9, 144.2, 158.5 (d,
J¼239.6 Hz), 161.2, 164.2; 19F NMR (CDCl3, 282 MHz, CFCl3)

Z. Lian et al. / Tetrahedron 68 (2012) 2401e2408
2405
Fig. 2. ORTEP drawing of 7.
d
ꢁ118.8; IR (CH2Cl2):
n 2952, 2851, 1733, 1716, 1608, 1574, 1464,
Fig. 1. ORTEP drawing of 4j.
1347, 1285, 1190, 1105, 775, 759, 734 cmꢁ1; MS (%) (EI) m/z 350 (Mþ,
14.3), 321 (3.6), 276 (8.5), 248 (3.3), 92 (8.6), 91 (100), 65 (8.0).
HRMS (EI) calcd for C20H15N2O3F requires 350.1067, found:
350.1064.
O
4.1.1.3. (E)-Ethyl 2-(1-benzyl-5-methyl-2-oxoindolin-3-ylidene)-
O
2-cyanoacetate (3c). Mp 140e143 ꢀC; 1H NMR (CDCl3, 400 MHz,
+
Ph3P
2
PPh3
TMS)
d
1.42 (t, 3H, J¼7.2 Hz, CH3), 2.32 (s, 3H, CH3), 4.47 (q, 2H,
A
EtO2C
CN
O
J¼7.2 Hz, CH2), 4.85 (s, 2H, CH2), 6.59 (d, 1H, J¼8.4 Hz, ArH),
7.13e7.15 (m, 1H, ArH), 7.27e7.33 (m, 5H, ArH), 7.89 (s, 1H, ArH); 13C
NMR (CDCl3, 100 MHz, TMS)
d 13.8, 20.9, 43.7, 63.2, 106.0, 109.4,
N
114.0, 118.6, 125.4, 127.3, 128.7, 130.1, 132.5, 134.7, 136.1, 143.4, 144.6,
Bn
3a
161.4, 164.3; IR (CH2Cl2): n 2957, 2925, 2856, 1718, 1560, 1340, 1124,
2
O
CN
1011, 820, 698 cmꢁ1; MS (%) (EI) m/z 346 (Mþ, 17.4), 272 (10.5), 91
(100), 65 (8.7). HRMS (EI) calcd for C21H18N2O3 requires 346.1317,
found: 346.1320.
EtO2C
PPh3
PPh3
O
N
4.1.1.4. (E)-Ethyl 2-(1-benzyl-5-bromo-2-oxoindolin-3-ylidene)-
Bn
2-cyanoacetate (3d). Mp 173e174 ꢀC; 1H NMR (CDCl3, 400 MHz,
B
TMS)
d
1.46 (t, 3H, J¼7.2 Hz, CH3), 4.48 (q, 2H, J¼7.2 Hz, CH2), 4.92 (s,
O
CN
O
CN
2H, CH2), 6.61 (d, 1H, J¼8.0 Hz, ArH), 7.24e7.35 (m, 5H, ArH),
EtO2C
7.44e7.48 (m, 1H, ArH), 8.51 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz,
EtO2C
TMS)
d
13.9, 44.1, 63.8, 108.1, 111.1, 115.8, 120.2, 127.4, 128.2, 129.0,
3026,
O
PPh3
132.7, 134.2, 138.0, 143.4, 144.5, 161.1, 163.9; IR (CH2Cl2):
n
N
O
Bn
N
2926, 2872, 2218, 1716, 1621, 1455, 1380, 1253, 1125, 1011, 937, 821,
699, 599 cmꢁ1; MS (%) (EI) m/z 410 (Mþ, 6.4), 336 (3.4), 91 (100), 65
(8.2). HRMS (EI) calcd for C20H15N2O3Br requires 410.0266, found:
410.0271.
4a
Bn
C
Scheme 4. A plausible mechanism of the formation of 4a.
4.1.1.5. (E)-Ethyl 2-(1-benzyl-6-bromo-2-oxoindolin-3-ylidene)-
2-cyanoacetate (3e). Mp 167e170 ꢀC; 1H NMR (CDCl3, 400 MHz,
TMS)
d
1.44 (t, 3H, J¼7.2 Hz, CH3), 4.45 (q, 2H, J¼7.2 Hz, CH2), 4.91 (s,
Cl
Bn
N
2H, CH2), 6.89 (d, 1H, J¼2.0 Hz, ArH), 7.16 (dd, 1H, J1¼2.0 Hz,
O
BnN
O
J2¼8.8 Hz, ArH), 7.30e7.35 (m, 5H, ArH), 8.26 (d, 1H, J¼8.8 Hz, ArH);
O
Me
13C NMR (CDCl3, 100 MHz, TMS)
d 14.0, 44.1, 63.6, 113.1, 114.0, 117.7,
O
PPh3 (20 mol%)
THF, 5 h
Cl
Cl
+
Cl
126.3, 127.4, 128.3, 129.0, 129.1, 130.6, 131.2, 134.2, 143.6, 146.6,
161.5, 164.4; IR (CH2Cl2): 2989, 2981, 2925, 2207, 1791, 1760, 1734,
1683, 1621, 1600, 1506, 1464, 1350, 1253, 1150, 1011, 774, 734,
699 cmꢁ1; MS (%) (EI) m/z 410 (Mþ, 6.7), 338 (5.7), 336 (5.3), 139
(4.7), 92 (8.2), 91 (100), 65 (10.3). HRMS (EI) calcd for C20H15N2O3Br
requires 410.0266, found: 410.0264.
O
O
N
2
n
N
Bn
Bn
6
7
, 91% yield
Scheme 5. A control experiment.

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Z. Lian et al. / Tetrahedron 68 (2012) 2401e2408
4.1.1.6. (E)-Ethyl 2-(1-benzyl-6-methyl-2-oxoindolin-3-ylidene)-
2-cyanoacetate (3f). Mp 141e143 ꢀC; 1H NMR (CDCl3, 400 MHz,
TMS)
J¼8.0 Hz, ArH), 6.89 (t, 1H, J¼8.0 Hz, ArH), 7.51 (t, 2H, J¼8.0 Hz,
ArH), 7.62 (t, 2H, J¼8.0 Hz, ArH), 8.04 (d, 2H, J¼8.0 Hz, ArH), 8.14 (d,
d
1.35 (t, 3H, J¼6.8 Hz, CH3), 2.24 (s, 3H, CH3), 4.36 (q, 2H,
1H, J¼8.0 Hz, ArH), 8.38 (d, 2H, J¼8.0 Hz, ArH), 8.50 (s, 1H, ArH); 13
C
J¼6.8 Hz, CH2), 4.82 (s, 2H, CH2), 6.45 (s, 1H, ArH), 6.78 (d, 1H,
NMR (CDCl3, 100 MHz, TMS) d 14.0, 37.9, 63.4, 106.6, 110.8, 114.4,
J¼8.4 Hz, ArH), 7.18e7.29 (m, 5H, ArH), 8.15 (d, 1H, J¼8.4 Hz, ArH);
118.8, 122.8, 123.4, 124.5, 125.2, 127.3, 129.3, 129.5, 129.7, 130.8,
131.3, 135.5, 144.4, 145.9, 161.5, 164.5; IR (CH2Cl2): 2978, 2845,
13C NMR (CDCl3, 100 MHz, TMS)
d
13.9, 22.6, 43.8, 63.2, 104.9, 110.4,
n
114.3,116.4,124.0,127.3,127.9, 128.8, 130.0, 134.9, 144.5, 146.1,147.8,
161.7, 164.9; IR (CH2Cl2): 2962, 2920, 2840, 2218, 1717, 1608, 1584,
1716, 1609, 1583, 1468, 1380, 1275, 1108, 855, 764, 600, 515 cmꢁ1
;
n
MS (MALDI/DHB) m/z (%): 455.1 [MþNa]þ (100); MS (MALDI/DHB)
calcd for C28H20N2NaO3 [MþNa]þ requires 455.1366, found:
455.1361.
1558, 1540, 1472, 1372, 1338, 1269, 1186, 1160, 1096, 1013, 735,
542 cmꢁ1; MS (%) (EI) m/z 346 (Mþ, 24.8), 317 (8.7), 272 (17.0), 244
(7.3), 92 (7.7), 91 (100), 71 (6.5), 65 (9.8). HRMS (EI) calcd for
C21H18N2O3 requires 346.1317, found: 346.1321.
4.1.1.12. (E)-tert-Butyl 3-(1-cyano-2-ethoxy-2-oxoethylidene)-2-
oxoindoline-1-carboxylate (3l). Mp 130e131 ꢀC; 1H NMR (CDCl3,
4.1.1.7. (E)-Ethyl 2-(1-benzyl-5,7-dimethyl-2-oxoindolin-3-
400 MHz, TMS)
d
1.41 (t, 3H, J¼7.2 Hz, CH3),1.63 (s, 9H, CH3), 4.46 (q,
ylidene)-2-cyanoacetate (3g). Mp 145e148 ꢀC; 1H NMR (CDCl3,
2H, J¼7.2 Hz, CH2), 7.27 (d, 1H, J¼5.6 Hz, ArH), 7.54 (t, 1H, J¼7.2 Hz,
400 MHz, TMS)
d
1.45 (t, 3H, J¼7.2 Hz, CH3), 2.21 (s, 3H, CH3), 2.25 (s,
ArH), 7.91 (d, 1H, J¼8.0 Hz, ArH), 8.20 (d, 1H, J¼8.0 Hz, ArH); 13C
3H, CH3), 4.46 (q, 2H, J¼7.2 Hz, CH2), 5.19 (s, 2H, CH2), 6.94 (s, 1H,
ArH), 7.14 (d, 2H, J¼8.0 Hz, ArH), 7.25e7.33 (m, 3H, ArH), 7.92 (s, 1H,
NMR (CDCl3, 100 MHz, TMS) d 13.9, 27.9, 63.7, 85.5, 106.8, 113.9,
115.7, 118.6, 124.7, 125.1, 134.9, 138.2, 142.1, 148.1, 160.4, 162.0; IR
ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d
13.9, 18.7, 20.7, 45.3, 63.4,
(CH2Cl2): n 2962, 2925, 1717, 1577, 1368, 1091, 1010, 855, 746,
105.8, 114.3, 119.6, 120.2, 123.7, 125.6, 127.4, 128.9, 132.6, 136.7,
678 cmꢁ1; MS (%) (EI) m/z 342 (Mþ, 3.6), 242 (72.4), 196 (29.1), 168
(28.2), 57 (100), 41 (18.3). HRMS (EI) calcd for C18H18N2O5 requires
342.1216, found: 342.1217.
140.5, 141.5,143.8,161.7,165.6; IR (CH2Cl2): n 2957, 2925, 2212,1718,
1618, 1560, 1379, 1253, 1195, 1124, 1011, 820, 734, 698 cmꢁ1; MS (%)
(EI) m/z 360 (Mþ, 18.6), 331 (4.4), 272 (17.0), 286 (69), 92 (7.6), 91
(100), 65 (7.3). HRMS (EI) calcd for C22H20N2O3 requires 360.1474,
found: 360.1473.
4.1.1.13. (E)-Ethyl 2-cyano-2-(1-(methoxymethyl)-2-oxoindolin-
3-ylidene)acetate (3m). Mp 137e140 ꢀC; 1H NMR (CDCl3, 400 MHz,
TMS)
d
1.45 (t, 3H, J¼7.2 Hz, CH3), 3.37 (s, 3H, CH3), 4.46 (q, 2H,
4.1.1.8. (E)-Ethyl 2-(1-benzyl-5-methoxy-2-oxoindolin-3-
J¼7.2 Hz, CH2), 5.17 (s, 2H, CH2), 7.03e7.14 (m, 1H, ArH), 7.47e7.49
ylidene)-2-cyanoacetate (3h). Mp 150e152 ꢀC; 1H NMR (CDCl3,
(m, 1H, ArH), 7.63e7.67 (m, 1H, ArH), 8.34 (d, 1H, J¼8.1 Hz, ArH); 13C
300 MHz, TMS)
d
1.44 (t, 3H, J¼7.2 Hz, CH3), 3.77 (s, 3H, CH3), 4.45
NMR (CDCl3, 100 MHz, TMS) d 13.9, 56.7, 63.5, 71.5, 110.3, 111.6,
(q, 2H, J¼7.2 Hz, CH2), 4.89 (s, 2H, CH2), 6.60 (d, 1H, J¼8.1 Hz, ArH),
6.90 (t, 1H, J¼8.1 Hz, ArH), 7.27e7.31 (m, 5H, ArH), 7.98 (s, 1H, ArH);
123.7, 125.4, 129.9, 135.9, 138.6, 144.2, 144.9, 161.4, 164.8; IR
(CH2Cl2):
n 2973, 2941, 2212, 1720, 1620, 1380, 1171, 1124, 820,
13C NMR (CDCl3, 100 MHz, TMS)
d
13.9, 43.9, 55.8, 63.4, 106.7, 110.2,
735 cmꢁ1; MS (%) (EI) m/z 286 (Mþ, 1.33), 191 (24.0), 146 (100), 132
(24.6), 90 (21.9), 77 (16.6), 45 (22.1). HRMS (EI) calcd for C15H14N2O4
requires 286.0954, found: 286.0950.
114.1, 115.3, 119.3, 120.4, 121.6, 127.4, 128.9, 134.8, 139.6, 145.1, 155.6,
161.4, 164.3; IR (CH2Cl2): n 3032, 2927, 2861, 2213, 1716, 1584, 1455,
1124, 937, 699 cmꢁ1; MS (%) (EI) m/z 362 (Mþ, 27.5), 288 (4.4), 260
(3.4), 199 (2.9), 91 (100), 65 (7.7). HRMS (EI) calcd for C21H18N2O4
requires 362.1267, found: 362.1266.
4.1.2. Typical reaction procedure for the preparation of 4. Under an
argon atmosphere, N-protected isatin derived electron-deficient
alkene 3a (0.1 mmol), but-3-yn-2-one
2 (0.3 mmol), PPh3
4.1.1.9. (E)-Ethyl
2-cyano-2-(1-methyl-2-oxoindolin-3-ylidene)
1.44
(0.02 mmol), and THF (1.0 mL) were added into a Schlenk tube. The
reaction mixture was stirred at room temperature for 5 h and the
reaction proceeding was monitored by TLC. Then, the solvent was
removed under reduced pressure and the residue was purified by
a flash column chromatography (silica gel PE/EtOAc¼2:1) to afford
compound 4a as a white solid in 93% yield.
acetate (3i). Mp 121e125 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
d
(t, 3H, J¼6.8 Hz, CH3), 3.25 (s, 3H, CH3), 4.45 (q, 2H, J¼6.8 Hz, CH2),
6.81 (d, 1H, J¼8.0 Hz, ArH), 7.02e7.07 (m, 1H, ArH), 7.45e7.49 (m,
1H, ArH), 8.30 (d, 1H, J¼8.0 Hz, ArH); 13C NMR (CDCl3, 100 MHz,
TMS)
d 13.9, 26.3, 63.3, 106.3, 108.8, 114.0, 118.6, 123.1, 129.9, 135.7,
144.7,146.5,161.4, 164.2; IR (CH2Cl2): n 3031, 2981, 2920, 2207, 1719,
1654, 1585, 1496, 1355, 1184, 1004, 749, 699 cmꢁ1; MS (%) (EI) m/z
256 (Mþ, 100), 211 (30.0), 184 (68.0), 155 (60.3), 128 (25.8). HRMS
(EI) calcd for C14H12N2O3 requires 256.0848, found: 256.0845.
4.1.2.1. Ethyl 3-acetyl-9-benzyl-4-cyano-4,9-dihydropyrano[2,3-
b]indole-4-carboxylate (4a). Yield 37 mg, 93%. Mp 219e221 ꢀC; 1H
NMR (CDCl3, 300 MHz, TMS)
3H, CH3), 4.21e4.34 (m, 2H, CH2), 4.29 (s, 2H, CH2), 7.14 (d, 2H,
J¼6.9 Hz, ArH), 7.23e7.32 (m, 6H, ArH), 7.83e7.85 (m, 1H, ArH), 7.89
d
1.36 (t, 3H, J¼6.9 Hz, CH3), 2.44 (s,
4.1.1.10. (E)-Ethyl 2-(1-allyl-2-oxoindolin-3-ylidene)-2-
cyanoacetate (3j). Mp 132e133 ꢀC; 1H NMR (CDCl3, 400 MHz,
(s, 1H, ArH); 13C NMR (CDCl3, 75 MHz, TMS)
d 14.1, 25.3, 42.1, 45.8,
TMS)
d
1.44 (t, 3H, J¼6.8 Hz, CH3), 4.37 (d, 2H, J¼5.6 Hz, ]CH2), 4.46
63.6, 83.7, 109.8, 116.5, 119.3, 121.7, 122.3, 122.4, 122.7, 126.6, 128.0,
(q, 2H, J¼6.8 Hz, CH2), 5.28 (d, 2H, J¼7.6 Hz, CH2), 5.79e5.86 (m, 1H,
]CH), 6.81 (d, 1H, J¼8.0 Hz, ArH), 7.04 (t, 1H, J¼8.0 Hz, ArH), 7.43 (t,
1H, J¼8.0 Hz, ArH), 8.31 (d, 1H, J¼8.0 Hz, ArH); 13C NMR (CDCl3,
129.0, 132.3, 135.8, 142.5, 152.2, 166.5, 193.3. IR (CH2Cl2): n 3031,
2957, 2930, 2101, 1747, 1651, 1282, 1249, 1153, 1030, 772 cmꢁ1; MS
(MALDI/DHB) m/z (%): 423.2 [MþNa]þ (100); MS (MALDI/DHB)
calcd for C24H21N2O4 [MþH]þ requires 401.1496, found: 401.1494.
100 MHz, TMS)
d 13.9, 42.5, 63.4, 106.4, 109.6, 114.0, 118.4, 118.7,
123.1, 129.9, 130.4, 135.6, 144.5, 145.8, 161.5, 164.0; IR (CH2Cl2):
n
2984, 2925, 2207, 1718, 1610, 1380, 1299, 1194, 1124, 1003, 855,
699 cmꢁ1; MS (%) (EI) m/z 282 (Mþ, 100), 303 (9.7), 208 (66.8), 180
(38.1), 154 (20.4), 41 (47.4). HRMS (EI) calcd for C16H14N2O3 requires
282.1004, found: 282.0999.
4.1.2.2. Ethyl 3-acetyl-9-benzyl-4-cyano-6-fluoro-4,9-dihydro
pyrano[2,3-b]indole-4-carboxylate (4b). Yield 38 mg, 91%. Mp
227e230 ꢀC; 1H NMR (CDCl3, 300 MHz, TMS)
d
1.37 (t, 3H, J¼7.2 Hz,
CH3), 2.44 (s, 3H, CH3), 4.28e4.39 (m, 2H, CH2), 5.29 (s, 2H, CH2),
6.93 (dt, 1H, J1¼2.4 Hz, J2¼9.0 Hz, ArH), 7.12e7.17 (m, 3H, ArH),
7.31e7.36 (m, 3H, ArH), 7.50 (dd,1H, J1¼2.4 Hz, J2¼9.0 Hz, ArH), 7.90
4.1.1.11. (E)-Ethyl 2-(1-(anthracen-10-ylmethyl)-2-oxoindolin-3-
ylidene)-2-cyanoacetate (3k). Mp 142e145 ꢀC; 1H NMR (CDCl3,
(s, 1H, ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d 14.0, 25.2, 41.9, 46.0,
400 MHz, TMS)
d
1.43 (t, 3H, J¼7.2 Hz, CH3), 4.44 (q, 2H, J¼7.2 Hz,
63.7, 84.0, 105.1 (d, J¼25.9 Hz), 110.8 (d, J¼14.2 Hz), 111.0 (d,
CH2), 5.95 (s, 2H, CH2), 6.23 (d, 1H, J¼8.0 Hz, ArH), 6.77 (t, 1H,
J¼12.1 Hz), 116.3 (d, J¼3.6 Hz), 122.9 (d, J¼10.4 Hz), 126.6, 127.5,

Z. Lian et al. / Tetrahedron 68 (2012) 2401e2408
2407
128.1, 128.6, 128.9 (d, J¼8.7 Hz), 135.4, 143.3, 152.1, 158.0 (d,
J¼236.4 Hz), 166.2, 193.2. 19F NMR (CDCl3, 282 MHz, CFCl3)
n
2961, 2925, 1746, 1672, 1581, 1355, 1237, 1039, 799, 736 cmꢁ1; MS
(MALDI/DHB) m/z (%): 451.2 [MþNa]þ (100); MS (MALDI/DHB)
d
ꢁ118.3; IR (CH2Cl2):
n 2952, 2924, 2856, 1746, 1671, 1491, 1238,
calcd for C26H25N2O4 [MþH]þ requires 429.1809, found: 429.1818.
1089, 772 cmꢁ1; MS (MALDI/DHB) m/z (%): 419.1 [MþH]þ (100); MS
(MALDI/DHB) calcd for C24H20N2O4F [MþH]þ requires 419.1402,
found: 419.1409.
4.1.2.8. Ethyl 3-acetyl-9-benzyl-4-cyano-6-methoxy-4,9-dihydro-
pyrano[2,3-b]indole-4-carboxylate (4h). Yield 38 mg, 88%. Mp
224e225 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
CH3), 2.41 (s, 3H, CH3), 3.85 (s, 3H, CH3), 4.25e4.37 (m, 2H, CH2),
5.25 (s, 2H, CH2), 6.82 (dd, 1H, J1¼2.8 Hz, J2¼8.8 Hz, ArH), 7.10e7.13
(m, 3H, ArH), 7.27e7.30 (m, 4H, ArH), 7.87 (s, 1H, ArH); 13C NMR
d
1.35 (t, 3H, J¼7.2 Hz,
4.1.2.3. Ethyl 3-acetyl-9-benzyl-4-cyano-6-methyl-4,9-dihydro-
pyrano[2,3-b]indole-4-carboxylate (4c). Yield 37 mg, 89%. Mp
220e223 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
CH3), 2.43 (s, 3H, CH3), 2.45 (s, 3H, CH3), 4.28e4.38 (m, 2H, CH2),
5.30 (s, 2H, CH2), 7.03 (d, 1H, J¼8.4 Hz, ArH), 7.11e7.15 (m, 3H, ArH),
7.26e7.33 (m, 3H, ArH), 7.63 (s, 1H, ArH), 7.88 (s, 1H, ArH); 13C NMR
d
1.37 (t, 3H, J¼7.2 Hz,
(CDCl3, 100 MHz, TMS)
d 14.1, 25.2, 42.1, 45.8, 55.7, 63.4, 83.5, 101.5,
110.7, 112.3, 116.3, 116.4, 123.0, 126.5, 126.9, 127.9, 128.9, 135.8,
142.5, 152.2, 155.4, 166.3, 193.3. IR (CH2Cl2): n 2961, 2851, 1747, 1673,
(CDCl3, 100 MHz, TMS)
d
14.0, 18.9, 25.1, 42.2, 46.8, 63.4, 83.3, 116.4,
1582, 1353, 1241, 1089, 1030, 799 cmꢁ1; MS (MALDI/DHB) m/z (%):
431.2 [MþH]þ (100); MS (MALDI/DHB) calcd for C25H23N2O5
[MþH]þ requires 431.1602, found: 431.1603.
116.6,116.9,120.9,123.4, 125.0, 127.4,127.5,129.0, 129.2, 131.2, 137.7,
142.7,152.2,166.4,193.4. IR (CH2Cl2): n 2968, 2924, 2861,1746,1650,
1582,1495, 1378, 1291,1090,1039, 734, 701 cmꢁ1; MS (MALDI/DHB)
m/z (%): 415.2 [MþH]þ (100); MS (MALDI/DHB) calcd for
C25H23N2O4 [MþH]þ requires 415.1652, found: 415.1653.
4.1.2.9. Ethyl 3-acetyl-4-cyano-9-methyl-4,9-dihydropyrano[2,3-
b]indole-4-carboxylate (4i). Yield 23 mg, 71%. Mp 190e192 ꢀC; 1H
NMR (CDCl3, 400 MHz, TMS)
d
1.34 (t, 3H, J¼6.8 Hz, CH3), 2.44 (s,
4.1.2.4. Ethyl 3-acetyl-9-benzyl-6-bromo-4-cyano-4,9-dihydro-
pyrano[2,3-b]indole-4-carboxylate (4d). Yield 38 mg, 81%. Mp
3H, CH3), 3.68 (s, 3H, CH3), 4.25e4.35 (m, 2H, CH2), 7.23e7.28 (m,
3H, ArH), 7.79e7.81 (m, 1H, ArH), 7.92 (s, 1H, ArH); 13C NMR (CDCl3,
235e238 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
d
1.31 (t, 3H, J¼7.2 Hz,
100 MHz, TMS)
d 14.0, 25.2, 28.1, 42.1, 63.5, 83.2, 109.2, 116.4, 116.6,
CH3), 2.36 (s, 3H, CH3), 4.21e4.33 (m, 2H, CH2), 5.20 (s, 2H, CH2),
7.01e7.05 (m, 3H, ArH), 7.18e7.27 (m, 4H, ArH), 7.82 (s,1H, ArH), 7.89
119.1, 121.4, 122.2, 122.4, 132.6, 142.5, 152.2, 166.5, 193.4; IR
(CH2Cl2):
n 3061, 2960, 2925, 1746, 1673, 1582, 1354, 1291, 1235,
(s, 1H, ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d
14.0, 25.3, 41.9, 45.9,
63.8, 83.4, 111.4, 114.9, 116.3, 116.4, 121.8, 123.9, 125.7, 126.5, 128.2,
129.0, 135.2, 130.9, 143.0, 152.0, 166.0, 193.1; IR (CH2Cl2): 2952,
1185, 1090, 1039, 964, 799, 701 cmꢁ1; MS (MALDI/DHB) m/z (%):
325.1 [MþH]þ (100); MS (MALDI/DHB) calcd for C18H17N2O4
[MþH]þ requires 325.1183, found: 325.1180.
n
2924, 2851,1745,1649,1488,1352,1290,1234,1091,1038, 799 cmꢁ1
;
MS (MALDI/DHB) m/z (%): 479.1 [MþH]þ (100); MS (MALDI/DHB)
4.1.2.10. Ethyl 3-acetyl-9-allyl-4-cyano-4,9-dihydropyrano[2,3-b]
calcd for C24H20N2O4Br [MþH]þ requires 479.0601, found: 479.0619.
indole-4-carboxylate (4j). Yield 27 mg, 77%. Mp 198e203 ꢀC; 1H
NMR (CDCl3, 400 MHz, TMS)
d
1.30 (t, 3H, J¼7.2 Hz, CH3), 2.39 (s, 3H,
4.1.2.5. Ethyl 3-acetyl-9-benzyl-7-bromo-4-cyano-4,9-dihydro-
CH3), 4.22e4.31 (m, 2H, CH2), 4.66e4.68 (m, 1H, CH2), 4.66e4.68
(m, 1H, ]CH), 5.03 (dd, 1H, J1¼0.8 Hz, J2¼16.8 Hz, ]CH), 5.17 (dd,
1H, J1¼0.8 Hz, J2¼10.4 Hz, ]CH), 5.85 (m, 1H, CH2), 7.17e7.24 (m,
3H, ArH), 7.76e7.79 (m, 1H, ArH), 7.87 (s, 1H, ArH); 13C NMR (CDCl3,
pyrano[2,3-b]indole-4-carboxylate (4e). Yield 36 mg, 75%. Mp
231e235 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
d
1.32 (t, 3H, J¼7.2 Hz,
CH3), 2.42 (s, 3H, CH3), 4.27e4.34 (m, 2H, CH2), 5.23 (s, 2H, CH2),
7.11e7.13 (m, 2H, ArH), 7.25e7.40 (m, 5H, ArH), 7.70 (d, 1H, J¼8.4 Hz,
100 MHz, TMS)
d 14.0, 25.2, 42.1, 44.4, 63.4, 83.4, 109.7, 116.3, 116.5,
ArH), 7.89 (s, 1H, ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d 14.0, 25.2,
117.7,119.2,121.5, 122.3, 122.5, 131.6, 132.0, 142.2, 152.2, 166.4,193.4.
41.9, 45.8, 63.6, 83.9, 112.8, 116.0, 116.3, 120.5, 121.2, 124.9, 126.5,
128.0,128.1,129.0,132.9, 135.2,142.6,152.1,166.1,193.2. IR (CH2Cl2):
IR (CH2Cl2): n 3031, 2961, 2854, 1746, 1673, 1489, 1455, 1291, 1234,
1090,1039, 800, 701 cmꢁ1; MS (MALDI/DHB) m/z (%): 351.2 [MþH]þ
(100); MS (MALDI/DHB) calcd for C20H19N2O4 [MþH]þ requires
351.1339, found: 351.1344.
n
2952, 2924, 1747, 1652, 1575, 1290, 1091, 770 cmꢁ1; MS (MALDI/
DHB) m/z (%): 478.1 [M]þ (100); MS (MALDI/DHB) calcd for
C24H20N2O4Br [MþH]þ requires 479.0601, found: 479.0596.
4.1.2.11. Ethyl 3-acetyl-9-(anthracen-10-ylmethyl)-4-cyano-4,9-
4.1.2.6. Ethyl 3-acetyl-9-benzyl-4-cyano-7-methyl-4,9-dihydro-
dihydropyrano[2,3-b]indole-4-carboxylate (4k). Yield 47 mg, 90%.
pyrano[2,3-b]indole-4-carboxylate (4f). Yield 31 mg, 73%. Mp
Mp 215e220 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
d 1.30 (t, 3H,
227e230 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
CH3), 2.43 (s, 3H, CH3), 2.45 (s, 3H, CH3), 4.27e4.39 (m, 2H, CH2),
5.28 (s, 2H, CH2), 7.03 (d, 1H, J¼8.4 Hz, ArH), 7.11e7.14 (m, 3H, ArH),
7.26e7.33 (m, 3H, ArH), 7.63 (s, 1H, ArH), 7.88 (s, 1H, ArH); 13C NMR
d
1.37 (t, 3H, J¼7.2 Hz,
J¼7.2 Hz, CH3), 2.31 (s, 3H, CH3), 4.22e4.30 (m, 2H, CH2), 6.08 (s, 2H,
CH2), 6.98e7.00 (m, 2H, ArH), 7.12e7.15 (m, 1H, ArH), 7.45e7.52 (m,
4H, ArH), 7.58 (s, 1H, ArH), 7.78 (d, 1H, J¼8.0 Hz, ArH), 8.04 (d, 2H,
J¼8.0 Hz, ArH), 8.19 (d, 2H, J¼8.0 Hz, ArH), 8.53 (s,1H, ArH); 13C NMR
(CDCl3, 100 MHz, TMS)
d
14.0, 21.2, 25.2, 42.2, 46.8, 63.4, 83.3, 116.4,
(CDCl3,100 MHz, TMS) d 14.0, 25.1, 40.4, 63.4, 83.8,110.3,116.0,116.4,
116.6, 116.9, 120.9, 123.4, 125.1, 127.4, 127.6, 129.0, 129.2, 131.2, 137.7,
119.2,121.4,122.5, 122.6, 122.7, 123.2, 124.7, 125.1,127.1, 129.3, 129.5,
142.7,152.2,166.4,193.4. IR (CH2Cl2):
n
2968, 2924, 2861,1746,1650,
130.9,131.2,132.5,143.0,152.1,166.3,193.3. IR (CH2Cl2): n 2962, 2923,
1582,1495, 1378, 1291,1090,1039, 734, 701 cmꢁ1; MS (MALDI/DHB)
m/z (%): 415.2 [MþH]þ (100); MS (MALDI/DHB) calcd for
C25H23N2O4 [MþH]þ requires 415.1652, found: 415.1653.
2851, 1970, 1718, 1290, 1245, 1024, 799 cmꢁ1; MS (MALDI/DHB) m/z
(%): 523.2 [MþNa]þ (100); MS (MALDI/DHB) calcd for C32H24N2O4Na
[MþNa]þ requires 523.1628, found: 523.1617.
4.1.2.7. Ethyl 3-acetyl-9-benzyl-4-cyano-6,8-dimethyl-4,9-
4.1.2.12. 9-tert-Butyl 4-ethyl 3-acetyl-4-cyanopyrano[2,3-b]in-
dihydropyrano[2,3-b]indole-4-carboxylate (4g). Yield 35 mg, 81%.
dole-4,9(4H)-dicarboxylate (4l). Yield 33 mg, 76%. Mp 187e191 ꢀC;
Mp 220e222 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
d
1.28 (t, 3H,
1H NMR (CDCl3, 400 MHz, TMS)
d
1.33 (t, 3H, J¼7.2 Hz, CH3), 1.70 (s,
J¼7.2 Hz, CH3), 2.32 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.35 (s, 3H, CH3),
4.18e4.30 (m, 2H, CH2), 5.44 (s, 2H, CH2), 6.70 (s, 1H, ArH), 6.84 (d,
2H, J¼7.6 Hz, ArH), 7.17e7.23 (m, 3H, ArH), 7.24 (s, 1H, ArH), 7.75 (s,
9H, CH3), 2.45 (s, 3H, CH3), 4.25e4.28 (m, 2H, CH2), 7.33e7.36 (m,
2H, ArH), 7.80e7.83 (m, 1H, ArH), 7.92 (s, 1H, ArH), 8.09e8.12 (m,
1H, ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d
14.0, 25.2, 28.1, 41.7,
63.8, 85.7, 89.8, 115.2, 115.7, 115.8, 119.1, 122.9, 124.2, 125.0, 131.6,
142.1, 147.9, 152.1, 166.0, 193.2. IR (CH2Cl2): 2968, 2898, 1748, 1652,
1558, 1275, 1260, 750 cmꢁ1; MS (MALDI/DHB) m/z (%): 449.1
1H, ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d 14.0, 18.9, 21.2, 25.2,
42.2, 46.8, 63.4, 83.3, 116.4, 116.6, 116.9, 120.9, 123.4, 125.1, 127.4,
127.6,129.0, 129.2, 131.2, 137.7,142.7, 152.2, 166.4,193.4. IR (CH2Cl2):
n

2408
Z. Lian et al. / Tetrahedron 68 (2012) 2401e2408
[MþK]þ (100); MS (MALDI/DHB) calcd for C22H22N2O6Na [MþNa]þ
pp 313e376; (i) Sundberg, R. J. Best Synthetic Methods, Indoles; Academic: New
York, NY, 1996, pp 7e11; (j) Joule, J. A. In Indole and Its Derivatives in Science of
Synthesis: Houben Weyl Methods of Molecular Transformations; Thomas, E. J., Ed.;
George Thieme: Stuttgart, Germany, 2000; p 10, Category 2, Chapter 10.13; (k)
Brown, R. K. In Indoles in Houlihan; Wiley Interscience: New York, NY, 1972.
2. (a) Nicolaou, K. C.; Pfefferkorn, J. A.; Roecker, A. J.; Cao, G. Q.; Barluenga, S. H.;
Mitchell, J. J. Am. Chem. Soc. 2000, 122, 9939e9953; (b) Nicolaou, K. C.; Pfef-
ferkorn, J. A.; Barluenga, S.; Mitchell, H. J.; Roecker, A. J.; Cao, G. Q. J. Am. Chem.
Soc. 2000, 122, 9968e9976; (c) Nicolaou, K. C.; Pfefferkorn, J. A.; Mitchell, H. J.;
Roecker, A. J.; Barluenga, S.; Cao, G. Q.; Affleck, R. L.; Lillig, J. E. J. Am. Chem. Soc.
2000, 122, 9954e9967.
3. (a) Cingolani, G.; Gualtieri, F.; Pigini, M. J. Med. Chem. 1969, 12, 531e532; (b)
Kaczka, E. A.; Wolf, F. J.; Rathe, F. P.; Folkers, K. J. J. Am. Chem. Soc. 1955, 77,
6404e6405; (c) Mukund, J.; Stephanie, G.; Chou, T. Y. Tetrahedron Lett. 2011,
4337e4341; (d) Manian, R. S.; Raghunathan, R. Synlett 2007, 874e880.
4. (a) Boger, D. L.; Weinreb, S. M. Hetero DielseAlder Methodology in Organic
Synthesis; Academic: New York, NY, 1987; (b) Buomora, P.; Olsen, J. C. Tetra-
hedron 2001, 57, 6099e6103; (c) Carruthers, W. Cycloaddition Reactions in Or-
ganic Synthesis; Pergamon: New York, NY, 1990.
5. (a) Daly, J. W.; Spande, T. F. In Alkaloids: Chemical and Biological Perspectives;
Pelletier, S. W., Ed.; Wiley: New York, NY, 1986; Vol. 4, pp 1e274; (b) Foder, G.
B.; Colasanti, B. In Alkaloids: Chemical and Biological Perspectives; Pelletier, S. W.,
Ed.; Wiley: New York, NY, 1985; Vol. 3, pp 1e90.
6. (a) Boger, D. L. In Combining CeC p-Bonds; Paquette, L. A., Ed.; Comprehensive
Organic Chemistry; Pergamon: Oxford, 1991; Vol. 5, pp 451e512; (b) Ho, T.-L.
Tandem Organic Reactions; Wiley: New York, NY, 1992.
7. Tietze, L. F.; Beifuss, U. Angew. Chem. 1993, 105, 137e140; Angew. Chem., Int. Ed.
Engl. 1993, 32, 131e134.
8. Ziegler, F. E. In Combining CeC p-Bonds; Paquette, L. A., Ed.; Comprehensive
requires 433.1370, found: 433.1371.
4.1.2.13. Ethyl 3-acetyl-4-cyano-9-(methoxymethyl)-4,9-
dihydropyrano[2,3-b]indole-4-carboxylate (4m). Yield 30 mg, 79%.
Mp 195e200 ꢀC; 1H NMR (CDCl3, 400 MHz, TMS)
d 1.28 (t, 3H,
J¼7.2 Hz, CH3), 2.38 (s, 3H, CH3), 3.25 (s, 3H, CH3), 4.18e4.30 (m, 2H,
CH2), 5.39 (s, 2H, CH2), 7.19e7.23 (m, 2H, ArH), 7.37e7.39 (m, 1H,
ArH), 7.74e7.76 (m, 1H, ArH), 7.85 (s, 1H, ArH); 13C NMR (CDCl3,
100 MHz, TMS)
d 14.0, 25.3, 42.0, 56.5, 63.6, 73.0, 84.6, 110.0, 116.3,
116.5, 119.3, 122.3, 122.5, 123.2, 132.4, 142.4, 152.0, 166.3, 193.3. IR
(CH2Cl2):
n 2961, 2925, 1746, 1672, 1581, 1355, 1237, 1039, 799,
736 cmꢁ1; MS (MALDI/DHB) m/z (%): 377.3 [MþNa]þ (100); MS
(MALDI/DHB) calcd for C19H18N2O5Na [MþNa]þ requires 377.1108,
found: 377.1103.
Compound 7. Yield 47 mg, 91%. Mp 262e265 ꢀC; 1H NMR (CDCl3,
400 MHz, TMS)
d
2.29 (s, 3H, CH3), 4.95 (d, 1H, J¼15.6 Hz, CH2), 5.21
(d, 1H, J¼15.6 Hz, CH2), 5.29 (s, 2H, CH2), 6.53 (s, 1H, ArH), 6.77 (d,
1H, J¼7.6 Hz, ArH), 6.92 (s, 1H, ArH), 6.98e7.07 (m, 1H, ArH),
7.12e7.17 (m, 1H, ArH), 7.24e7.29 (m, 3H, ArH), 7.30e7.35 (m, 4H,
ArH), 7.41 (t, 2H, J¼7.2 Hz, ArH), 7.54 (d, 2H, J¼7.2 Hz, ArH), 7.98 (s,
1H, ArH); 13C NMR (CDCl3, 100 MHz, TMS)
d25.7, 45.1, 45.8, 48.6,
88.3, 110.0, 110.7, 117.8, 120.0, 122.2, 123.6, 123.9, 126.5, 126.6, 127.7,
127.8, 128.0, 128.2, 128.5, 129.0, 129.1, 130.7, 134.9, 135.5, 135.9,
Organic Synthesis; Pergamon: Oxford, 1991; Vol. 5, Chapter 7.3.
9. (a) Jayagobi, M.; Raghunathan, R. Tetrahedron Lett. 2009, 50, 6886e6890; (b)
Jayagobi, M.; Raghunathan, R. Tetrahedron: Asymmetry 2010, 21, 2726e2732; (c)
Kathiravan, S.; Raghunathan, R. Synlett 2010, 1927e1930; (d) Maiti, S.; Panja, S.
K.; Bandyopadhyay, C. Tetrahedron 2010, 66, 7625e7632.
10. (a) Tietze, L. F.; Rackelmann, N. Pure Appl. Chem. 2004, 76, 1967e1983; (b)
Tietze, L. F.; Rackelmann, N. In Multicomponent Reactions; Zhu, J., Bie, H., Eds.;
Wiley-VCH: Weinheim, Germany, 2005; pp 121e168.
11. (a) Zhang, X.-C.; Cao, S.-H.; Wei, Y.; Shi, M. Chem. Commun. 2011, 1548e1550; (b)
Zhang, X.-C.; Cao, S.-H.; Wei, Y.; Shi, M. Org. Lett. 2011, 13, 1142e1145.
12. Lian, Z.; Shi, M. Eur. J. Org. Chem. 2012, 581e586.
141.5,144.2,153.2, 176.9,194.1. IR (CH2Cl2): n 2968, 2924, 2861, 1746,
1650, 1582, 1495, 1378, 1291, 1090, 1039, 734, 701 cmꢁ1; MS
(MALDI/DHB) m/z (%): 579.1 [MþH]þ (100); MS (MALDI/DHB) calcd
for C34H25N2O3Cl2 [MþH]þ requires 519.1237, found: 519.1218.
Acknowledgements
13. The crystal data of 3a have been deposited in CCDC with number 805743. Em-
pirical formula: C20H16N2O3; Formula weight: 332.35; crystal color, habit: color-
less; crystal dimensions: 0.405ꢂ0.285ꢂ0.067 mm; crystal system: orthorhombic;
We thank the Shanghai Municipal Committee of Science and
Technology (08dj1400100-2), National Basic Research Program of
China (973)-2009CB825300, and the National Natural Science
Foundation of China for financial support (21072206, 20472096,
20872162, 20672127, 20821002, and 20732008) and Mr. Jie Sun for
performing X-ray diffraction.
¼90ꢀ,
b
¼90ꢀ,
ꢀ
ꢀ
ꢀ
lattice parameters: a¼15.187(3) A, b¼24.995(5) A, c¼4.4581(9) A,
a
3
g
¼90ꢀ, V¼1692.3(6) A ; space group: Pna2(1); Z¼4; Dcalcd¼1.304 g/cm3;
ꢀ
F000¼696; diffractometer: Rigaku AFC7R; residuals: R; Rw: 0.0500, 0.1219.
14. The crystal data of 4j have been deposited in CCDC with number 824482. Em-
pirical formula: C20H18N2O4; formula weight: 350.36; Crystal color, habit: col-
orless; crystal dimensions: 0.35ꢂ0.28ꢂ0.18 mm; crystal system: triclinic; lattice
ꢀ
ꢀ
ꢀ
parameters: a¼12.220(2) A, b¼12.549(2) A, c¼19.013(3) A,
a
¼78.526(3)ꢀ,
¼82.
b
Supplementary data
3
ꢀꢀ
ꢀ
058(3)ꢀ,
g
¼66.143(3) , V¼1784.8(6) A ; Space group: Pꢁ1; Z¼4;Dcalcd¼1.304 g/
cm3; F000¼736; final R indices [I>2
(I)] R1¼0.0559, wR2¼0.1575.
s
The 1H and 13C NMR spectroscopic data and charts of the
compounds shown in Tables 1 and 2 and X-ray crystal data of
products 3a, 4j, and 7 are included in the Supplementary data.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.036.
15. (a) Hudson, H. R. In The Chemistry of Organophosphorus Compounds: Primary
Secondary and Tertiary Phosphines and Heterocyclic Organophosphorus(III)
Compounds. Hantely, F. R. Ed.; Wiley: New York, NY, 1990; pp 386e472; (b)
Engel, R. Synthesis of CarbonePhosphorus Bonds; CRC: Boca Raton, FL, 1998; (c)
Cadogan, J. I. G. Organophosphorus Reagents in Organic Synthesis; Academic:
New York, NY, 1979; (d) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89,
863e927; (e) Kolodiazhynyi, O. I. Russ. Chem. Rev. 1997, 66, 225e254; (f) Yavari,
I.; Alizadeh, A. Tetrahedron Lett. 2003, 2877e2879; (g) Angle, S. R.; Qian, X. L.;
Pletnev, A. A.; Chinn, J. J. Org. Chem. 2007, 72, 2015e2020; (h) Grossman, R. B.;
Pendharkar, D. S.; Patrick, B. O. J. Org. Chem. 1999, 64, 7178e7183; (i) Kuehne,
M. E.; Brook, C. S.; Frasier, D. A.; Xu, F. J. Org. Chem. 1995, 60, 1864e1867; (j)
Wender, P. A.; Christy, J. P. J. Am. Chem. Soc. 2006, 128, 5354e5355.
References and notes
1. (a) Husson, H.-P. In The Alkaloids; Brossi, A., Ed.; Academic: London, 1985; Vol.
26, Chapter 1; (b) Lounasmaa, M.; Hankinen, P.; Westersund, M. In The Alka-
loids; Cordell, G. A., Ed.; Academic: London, 1999; Vol. 52, Chapter 2; (c)
Szantay, C. In The Alkaloids; Cordell, G. A., Ed.; Academic: London, 1998; Vol. 50,
Chapter 10; (d) Lounasmaa, M.; Somersalo, P. In Progress in the Chemistry of
Organic Natural Products; Herz, W., Grisebach, H., Kirby, G. W., Eds.; Springer:
Wien, 1979; Vol. 38, pp 1e45; (e) Franck, R. W. In Progress in the Chemistry of
Organic Natural Products; Herz, W., Griesbach, H., Kirby, G. W., Tamm, C., Eds.;
Springer: Wien, 1986; Vol. 50, pp 27e56; (f) Remers, W. A.; Dorr, R. T. In Al-
kaloids: Chemical and Biological Perspectives; Pelletier, S. W., Ed.; Wiley: New
York, NY, 1988; Vol. 6, Chapter 1; (g) Sundberg, R. J. The Chemistry of Indoles;
Academic: New York, NY, 1970; (h) Sundberg, R. J. In Pyrroles and Their Ben-
zoderivatives: Synthesis and Applications in Comprehensive Heterocyclic Chemis-
try; Katritzky, A. R., Rees, C. W., Eds.; Pergamon: Oxford, UK, 1984; Vol. 4,
16. (a) Evans, C. A.; Miller, S. J. J. Am. Chem. Soc. 2003, 125, 12394e12395; (b) Meng,
L.-G.; Cai, P.; Guo, Q.-X.; Xue, S. J. Org. Chem. 2008, 73, 8491e8496.
17. (a) Overman, L. E.; Larrow, J. F.; Stearns, B. A.; Vance, J. M. Angew. Chem. 2000,
112, 219e221; Angew. Chem., Int. Ed. 2000, 39, 213e215; (b) Link, J. T.; Overman,
L. E. J. Am. Chem. Soc. 1996, 118, 8166e8167.
18. The crystal data of 7 have been deposited in CCDC with number 821911. Em-
pirical formula: C35H25Cl5N2O3; formula weight: 698.82; crystal color, habit:
colorless; crystal dimensions: 0.38ꢂ0.30ꢂ0.10 mm; crystal system: triclinic;
ꢀ
ꢀ
3
ꢀ
lattice type: primitive; lattice parameters: a¼9.5528(19) A, b¼10.166(2) A,
ꢀ
c¼17.258(3) A,
a
¼85.184(3)ꢀ,
b
¼84.545(3)ꢀ,
g
¼70.455(3)ꢀ, V¼1569.9(5) A ;
Space group: Pꢁ1; Z¼2; Dcalcd¼1.478 g/cm3; F000¼716; final R indices [I>2
s(I)]
R1¼0.0485, wR2¼0.1352.