Multicomponent reactions of phosphines, enynedioates and cinnamaldimines give γ-lactams with a 1,3,5-hexatriene moiety for facile 6π electrocyclization: Access to oxindoles, isatins and isoxazolinones

Article abstract of DOI:10.1002/adsc.201401134

Multicomponent reactions of phosphines, enynedioates and cinnamaldimines generated 3-phosphorus ylide γ-lactams having a 1,3,5-hexatriene moiety with low activation energy barrier for 6π electrocyclization, through initial formation of 1,3-dipoles from th

Full text of DOI:10.1002/adsc.201401134

FULL PAPERS
DOI: 10.1002/adsc.201401134
Multicomponent Reactions of Phosphines, Enynedioates and
Cinnamaldimines Give g-Lactams with a 1,3,5-Hexatriene Moiety
for Facile 6p Electrocyclization: Access to Oxindoles, Isatins and
Isoxazolinones
a
a
a
a,
Jie-Cheng Deng, Wu-Yin Chen, Chaoyuan Zhu, and Shih-Ching Chuang *
a
Department of Applied Chemistry, National Chiao Tung University, Hsinchu 30010, Taiwan, R. O. C
Fax : (+886)-3572-3764; Tel: (+886)-3573-1858; e-mail: jscchuang@faculty.nctu.edu.tw
Received: December 4, 2014; Revised: February 3, 2015; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201401134.
Abstract: Multicomponent reactions of phosphines, ylide oxindoles as platform molecules toward isatins
enynedioates and cinnamaldimines generated 3- and isoxazolinones. The key step, 6p electrocycliza-
phosphorus ylide g-lactams having a 1,3,5-hexatriene tion, was further examined by a kinetic and a compu-
moiety with low activation energy barrier for 6p tational study.
electrocyclization, through initial formation of 1,3-di-
poles from the a(d’)-Michael addition of phosphines
to enynedioates. The reactive 1,3-dipoles underwent Keywords: electrocyclic reactions; Michael addition;
addition to cinnamaldimines, lactamization, 6p elec- multicomponent reactions; phosphorus; transition
trocyclization and oxidation to give 3-phosphorus states
Introduction
can be divided into four bond formation pathways a–
d for generating the g-lactam moiety from substituted
Oxindoles, structurally indispensable heterocyclics in benzenes. For bond formation through a, isatins can
pharmaceutical applications, possess numerous bioac- be obtained by cyclization of isonitrosoacetanilide in
[
1]
[5]
tive properties, and are important precursors for the the presence of sulfuric acid; in addition, 3-alkyli-
[7]
[
6]
synthesis of potential drugs, such as physostigmine for
A
H
U
G
R
N
U
G
and 3,3-disubstituted oxindoles
[
2]
[
3]
tenidap for treatment of inflammation and arthritis,
cyclization of N-arylpropiolamides, N-arylacrylamides
as well as a new class of spiro-oxindoles such as non- and diazo-b-ketoanilide. For bond formation through
peptide MDM2 inhibitors for inhibiting tumor cell b, 3-alkylideneoxindoles can be achieved by palladi-
[4]
growth. Methodology towards the preparation of um-catalyzed cyclization of 2-(alkynyl)aryl isocya-
structurally-diverse oxindoles such as 1H-indole-2,3- nates, intramolecular cyanoamidation of alkynyl and
diones (isatins, X’=O), 3-alkylideneoxindoles (X’= alkenyl cyanoformamides, and cyclization of carbamo-
1
2
CR R ), and 3,3-disubstituted oxindoles has therefore yl chlorides with a proximate alkenyl or alkynyl
[
8]
[9]
become a significant synthetic topic (Scheme 1). The moiety or by taking advantage of rhodium or iron
[
10]
developed synthetic methodology toward oxindoles 5 catalysis
with the above substrates. Further ap-
Scheme 1. Traditional and our proposed synthetic strategy toward oxindoles 5.
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proaches to oxindoles through amidic bond formation
via c generally involve insertion of carbon monoxide tuted hexatrienes at room temperature were rare
Examples of facile 6p electrocyclization of disubsti-
[20]
under metal catalysis; for example, carbonylative cy- and those with higher substituted hexatrienes were
cloaddition of 2-alkynylanilines or 2-alkenylanilines even scarcely available for practical study. We noted
to give 3-alkylideneoxindoles by Co, Pd or Rh cataly- that 3,4-thienyl-fused 1,3,4,5-tetrasubstituted hexa-
[
11]
sis. In this bond formation pathway, isatins can also trienes A required 6 h for electrocyclization at
[
21]
be synthesized by amination of the CÀH bond from 2008C and 3,4-indolo-fused B furnished electrocy-
-aminoaryl methyl ketone under an oxygen atmos- clization products only at reflux in xylenes (138–
phere by Cu(I) catalysis. Lastly, the highly efficient 1408C) for 24 h [Supporting Information, Scheme S1
2
ACHTUNGTRENNUNG
[
12]
[
22]
N-arylation methodology provided oxindoles from 2- (b)].
In another context, photochromic materials
arylpropanamides by Cu, Pd or Ag catalysis through have been developed for practical applications
[
13]
formation of bond d. The common feature of previ- through light-controlled isomerization involving 6p
[23]
ous versatile synthetic methods to oxindoles was the electrocyclization of diarylethene photoswitches.
use of substituted benzenes as their starting substrates Hampered by synthetic availability, our knowledge on
and no synthetic reports ever concerned approaches 6p electrocyclization of 3,4-aromatic ring-fused
via the initial set-up of a g-lactam moiety followed by 1,3,4,6-tetrasubstituted hexatrienes was relatively lim-
construction of the fused benzene moiety. We have ited. Our synthetically available g-lactams through
developed three-component reactions (3CRs) of orga- one-pot 3CRs prompted us to explore the 6p electro-
[
14]
nophosphines with alkynoates,
acetylenedicarboxylate (DMAD),
ynedioic acid dimethyl ester,
such as dimethyl cyclization of 3,4-g-lactam-fused hexatrienes and un-
[
14b]
(E)-hex-2-en-4- derstand the corresponding changes of activation
[
15]
[16]
and oligoynoates,
energy. The cyclization led to useful 3-phosphorus
generating zwitterions, followed by addition to elec- ylide oxindoles as platform molecules toward isatins
trophiles, such as aldehydes and imines, to give highly and isoxazolinones. Herein, we report the syntheses
substituted g-lactones or lactams. In principle, the de- of 3-phosphorus ylide oxindoles through facile 6p
veloped methodology could be employed to prepare electrocyclization of 3,4-g-lactam-fused 1,3,4,6-tetra-
oxindole derivatives, provided that both b- and g-car- substituted hexatrienes. The 3,4-g-lactam-fused hexa-
bons of g-lactams were equipped with an alkenyl trienes were prepared through three-component reac-
moiety for subsequent 6p electrocyclization and oxi- tions of phosphines, enynedioates and cinnamaldi-
dation (Scheme 1). This approach would be syntheti- mines and were found to undergo slow 6p electrocy-
cally challenging since placement of an alkenyl func-
tionality on both b- and g-carbons on lactams to give The key step, 6p electrocyclization, was also observed
is non-trivial by conventional methods. Further- to be accelerated by light, thermal conditions and
ACHTUNGTRENNUcGN lization at room temperature in the absence of light.
4
more, to the best of our knowledge, 6p electrocycliza- acid additives, and was corroborated with kinetic and
tion of hexatrienes was relatively disfavored to give computational transition state studies. Furthermore,
1
,3-cyclohexadiene with a free energy of activation 3-phosphorus ylide oxindoles were used as platform
°
À1
DG of 30.7 kcal·mol at 298 K [see Supporting In- molecules toward biologically important isatins and
formation, Scheme S1(a)] and could proceed under isoxazolinones upon oxidation.
thermodynamic and photochemical conditions for ap-
[
17]
plication in natural products synthesis. A study to-
wards understanding the thermodynamics and kinetics Results and Discussion
of the 6p electrocyclization of 1-dimethylamino-1,3,5-
hexatriene relevant to substitution effects by hybrid To commence this study, lactams 4 were prepared
density functional calculations revealed a decreased through three-component reactions of enynedioates 1,
À1
activation barrier of 17–25 kcal·mol by placement of phosphines 2 and cinnamaldimines 3, via a(d’)-Mi-
[
18]
an electron-withdrawing group (EWG) at C-2. Sig- chael addition of phosphines to 1 followed by addi-
[
15c]
nificant findings through the two-layer ONIOM tion to cinnamaldimines.
Dark purple colored lac-
method by Fu and Liu suggested approaches to pro- tams 4 can be prepared in 28–68% yields in one pot,
mote the sluggish electrocyclization of 1,3,5-hexa- but cannot be isolated in pure form since they under-
[
19]
trienes by specific captodative substitution. In this went 6p electrocyclization spontaneously and subse-
context, monosubstitution of hexatriene at C- quent oxidation gradually to give less polar yellowish
1
showed minute effects on the activation energy and compounds 5 (2–16%) under ambient conditions.
that at C-2 or C-3 may reduce the activation energy Thus, retrieving pure 4 for spectroscopic characteriza-
À1
À1
by up to 6 kcal·mol (24.8–31.9 kcal·mol ). Further- tion was implausible. Furthermore, N-substituted a,b-
more, a particular captodative disubstitution of hexa- conjugated imines 3 with an aliphatic chain (X=
trienes may cause a decrease of the activation energy alkyl) were not suitable for the synthesis of 4 due to
À1
[24]
by up to 10 kcal·mol .
their labile property upon isolation (Scheme 1).
Upon silica gel chromatography in aerobic conditions,
2
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Multicomponent Reactions of Phosphines, Enynedioates and Cinnamaldimines
[a]
Table 1. Optimization of the reaction conditions.
benzene (o-DCB) and chlorobenzene, gave promising
outcomes (entries 4–8; 70%, 62%, 45%, 57% and
52%, respectively); but that in the non-chlorinated ar-
omatic solvent, toluene, did not. Furthermore, the re-
action rate of the 6p electrocyclization can be acceler-
ated under photochemical conditions with halogen
lamp irradiation, providing good yields of 5a (en-
tries 10 and 11). Doubly reducing or increasing the so-
lution concentration also gave comparable yields
under photochemical conditions (entries 12 and 13).
To our delight, the reaction rate of 6p electrocycliza-
tion was accelerated evidently by the addition of
acetic acid (entries 14 and 15). We obtained 92%
yield with 3 equiv. of acetic acid as an additive under
photochemical conditions for 1 h. A control experi-
ment displayed that the use of bases as additives such
as Cs CO impeded the performance of the 6p elec-
Entry Solvent Temp.
Time
[h]
Conc.
[mM]
Yield
[%]
o
[b]
[
C]
1
2
3
4
5
6
7
8
9
1
1
1
1
1
1
1
EA
EA
r.t.
77
83
84
24
24
24
24
24
24
24
24
24
24
3
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.25
0.13
0.50
0.50
0.50
0.50
14
26
46
70
62
45
57
52
21
41
79
79
75
63
92
3
ACN
DCE
CHCl3 62
DCM 40
o-DCB 84
2
3
trocyclization, resulting in
a
poor yield (3%,
entry 16). In contrast to the oxidation of cyclohexa-
dienyl to the benzene moiety with a catalytic amount
[25]
of Pd/C as reported by Srinivasan and co-workers,
PhCl
toluene 111
84
we found that cyclohexadienyl fused g-lactam inter-
mediate 4a’ can be readily oxidized to 5a in air with-
out additional Pd/C. In short, this 6p cyclization was
accelerated by thermal and photochemical condi-
[
[
[
[
[
[
[
c]
0
1
2
3
4
5
6
DCE
DCE
DCE
DCE
DCE
DCE
DCE
84
84
84
84
84
84
84
c]
c]
3
3
3
1
c]
[26]
tions as well as by the use of acid additives.
c,d]
c,d]
e]
After optimizing the reaction conditions for the 6p
electrocyclization, we next scaled up the reaction and
examined the reaction scope (Table 2). We found that
increasing the reaction scale by 3-fold did not require
extension of the reaction time for the 6p electrocycli-
zation to achieve comparable yields (Table 2, entry 1,
24
[
a]
Reactions were carried out with 4a (0.010 mmol) in de-
noted solvents under aerobic conditions unless otherwise
noted.
[
[
b]
1
Yields were determined by H NMR spectroscopy with 1 h, 88% versus Table 1, entry 15, 1 h, 92%). Changes
mesitylene as an internal standard.
Irradiated by a 500W halogen lamp at a distance of
of the substitution on lactams 4 resulted in different
reactivities in the 6p electrocyclization step. Lactams
c]
2
3
3
5 cm.
4
equipped with electron-releasing phosphines were
[
[
d]
e]
equiv. of acetic acid were added as an additive.
equiv. of Cs CO were added as an additive and the
found to be more reactive – electrocyclization of in-
termediates 4b and 4c equipped with electron-releas-
ing phosphines resulted in good yields (entries 2 and
2
3
mixture was bubbled with O2.
3
; 85 and 80%) under the same irradiation time as
we observed that 4 also slowly underwent 6p electro- compared to that with unsubstituted triphenylphos-
cyclization to give oxindoles 5. We investigated the phine 4a, and lactam 4d required even less halogen
optimal conditions for their transformation to 5 lamp irradiation time for comparable yields (entry 4,
through 6p electrocyclization in a freshly prepared so- 85%). However, intermediates 4e and 4f with elec-
lution containing both 4 and 2–16% of 5 (Table 1). tron-withdrawing phosphines demanded for more ir-
Lactam 4a (0.25 mM in solvents) was chosen as the radiation time to give comparably good yields
model substrate for optimization of the conditions of (entry 5, 88%; entry 6, 85%). Furthermore, a minor
the 6p electrocyclization under aerobic and thermal influence on the reactivity of 4 was observed with dif-
conditions. Although lactam 4a was easily converted fering N-substitution. When the tosyl (Ts) substitution
to 5a during column chromatography, we found that on the lactam nitrogen was altered to benzenesulfonyl
its transformation to 5a was sluggish in ethyl acetate (Bs), the intermediates 4 became slightly less reactive
(
14% and 26% yields, entries 1 and 2) and moderate toward cyclization (entry 7, 87%; entry 8, 80%;
in acetonitrile (46%, entry 3) – this finding indicated entry 9, 84%). When 4 were equipped with ethyl
that such a cyclization may be promoted by slightly esters, their reactivity also became lower – an extend-
acidic silica gel. We further noted that reactions in ed reaction time was required to achieve good yields
chlorinated solvents, such as 1,2-dichloroethane (entries 10–15, 81–89%). Lastly, the 4-cyanocinnam-
(
DCE), CHCl , dichloromethane (DCM), o-dichloro-
ACHTUNGTRENNUaGN ldimine derived lactam 4p accelerated its 6p electro-
3
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[a]
Table 2. Scope of the reaction.
[a]
Reactions were carried out with 4 in DCE (0.030 mmol; conc.=0.50 mM) and
3
equiv. of acetic acid as an additive, and irradiated by a 500W halogen lamp at a dis-
[b]
tance of 25 cm.
Isolated yields (%).
4
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Multicomponent Reactions of Phosphines, Enynedioates and Cinnamaldimines
Figure 2. UV-vis absorption spectra of 4a in DCE under hal-
ogen lamp irradiation at 258C, measured every 15 min.
Figure 1. X-ray single crystal structure of compound 5a.
200 equiv. of acetic acid in the absence of light (Sup-
cyclization but with relatively lower yield (entry 16, porting Information, Figure S58). Furthermore, the
À4 À1
7
0%). Overall, the more electron-rich the lactams 4, reaction rate was measured to be 1.48Æ0.03ꢃ10
the higher is the reactivity that 4 exhibited.
We characterized the isolated 3-phosphorus ylide porting Information, Figure S59).
s
under halogen lamp irradiation (Figure 2 and Sup-
1
13
31
oxindoles 5a–p by H, C, P NMR spectroscopy, IR,
Furthermore, we calculated the activation energy
ESI-MS, and X-ray crystallography. Taking compound for the 6p electrocyclization of 4a to 4a’ at the B3LYP
5
a as an example, we found two singlet signals at d= 6-31G(d) level of theory and found two possible tran-
2.45 and 3.43 ppm corresponding to the methyl sition state structures, TS1 and TS2 (Figure 3), for for-
moiety on the tosyl and methoxy groups, respectively, mation of electrocyclization intermediates 4a ’ and
1
1
in the H NMR spectrum. The two protons on C-8 4a ’ through a suprafacial fashion, respectively. Transi-
2
and C-40 (Figure 1) appeared1 at d=5.97 and tion structure TS2 with 4-nitrophenyl and methyl
3
7
.91 ppm, respectively. In the C NMR spectrum, ester groups syn to the 4-methylphenyl moiety of the
a doublet centered at d=54.8 ppm represented the tosyl group possessed an unusually low activation
1
À1
phosphorus ylidic carbon C-5 with J =132.1 Hz and energy (E ) of 12.6 kcal·mol , while the other transi-
P, C
a
the two carbonyl groups, from the lactam moiety and
2
the carboxylic ester, appeared at d=166.8 ( J
=
P, C
1
7.1 Hz) and 168.1 ppm, respectively. We observed
31
a typical singlet at d=12.2 ppm in the P NMR spec-
trum. The carbonyl stretching bands of the lactam
À1
and ester appeared at 1660 and 1723 cm in the IR
spectrum, respectively. Furthermore, a single crystal
of 5a was grown from a chloroform solution for X-ray
[
27]
diffraction analysis (Figure 1). The b and g carbons
of the lactam moiety were covalently bonded to the
benzene moiety, proving the core structure of the ox-
indole. The oxindole skeleton was close to planar, as
evidenced by the torsional angles of C-6ÀC-7ÀC-8ÀC-
9
and N-1ÀC-7ÀC-8ÀC-9, À0.1(4)8 and 178.6(3)8, re-
spectively. Due to negative charge delocalization from
the ylidic carbon C-5 to the carbonyl group (C-20ÀO-
2
), the C-5ÀC-20 bond was shorter, 1.424(4) ꢂ, than
a typical carbon-carbon single bond.
We further investigated the reaction rate of the 6p
electrocyclization with 4a under thermal and photo-
1
chemical conditions by H NMR and UV-vis spectros-
copy, respectively. As reflected from the descending
absorption at 529 nm and slight ascending absorption
at 392 nm, the purple coloured solution faded and
À1
Figure 3. Relative energies (kcal·mol ) of the thermal 6p
electrocyclization pathways computed at the B3LYP 6-
1G(d) level of theory; values in parentheses were the rela-
3
became a yellowish solution of 5a. The reaction rate tive energies of this electrocyclization through transition
À6 À1
was found to be 6.02Æ0.14ꢃ10
s
at 258C with state TS1.
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Scheme 2. Proposed mechanism for the formation of 3-phosphorus ylide oxindoles 5.
tion structure TS1 with 4-nitrophenyl and methyl
We accounted for this overall studied reaction with
ester groups anti to the 4-methylphenyl moiety of the the following mechanism. First, PAr underwent nu-
3
À1
tosyl group showed E of 13.5 kcal·mol . These com- cleophilic attack to the a(d’)-carbon of enynedioates
a
puted activation energies (E ) for 6p electrocycliza- 1 (Scheme 2), generating zwitterions Ia with a negative
a
tion were close to the results of our kinetic study with charge on the b(g’)-carbon. Addition of Ia to the
À1
1
E =13.6Æ0.4 kcal·mol by H NMR spectroscopy carbon-nitrogen double bond of cinnamaldimines 3,
a
tracing (Supporting Information, Figures S60 and followed by intramolecular cyclization of Ib, gave in-
S61). The measured thermal 6p electrocyclization termediates Ic. After alkoxides had been released, de-
À4 À1
rates were found to be 1.06Æ0.05ꢃ10 s , 1.83Æ protonation of Id took place to form labile intermedi-
À4 À1
À4 À1
0
1
.07ꢃ10 s , 3.20Æ0.09ꢃ10 s , and 5.77Æ0.16ꢃ ates Ie. Oxindoles 5 were then formed after 6p elec-
À4 À1
0
s
at 60, 70, 80 and 908C, respectively.
trocyclization and air oxidation from Ie through cy-
clohexadiene intermediates If.
Scheme 3. a) Synthesis of isatins 6a, b from oxindoles 5a and 5g. b) Synthesis of isoxazolinones 7a–c from oxindoles 5a, 5g
and 5j. c) Deprotection of the Ts group of 5a, 6a and 7a by treatment with concentrated sulfuric acid to give oxindole 8a,
isatin 6a’ and isoxazolinone 7a’, respectively.
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Multicomponent Reactions of Phosphines, Enynedioates and Cinnamaldimines
Scheme 4. Synthesis of g-lactone 9a and benzofuranone 10a.
Figure 4. X-ray single crystal structure of isoxazolinone 7a.
3
-Phosphorus oxindoles 5 were reactive toward and isoxazolinone 7a’ can also be obtained by treat-
both oxidizing and reducing agents. To convert com- ment of 37]concentrated H SO , respectively
pound 5a to functional substituted isatins, we attempt- (Scheme 3c).
ed to oxidize its ylidic C=P bond to a carbonyl The reactivity of 4-nitrocinnamaldehyde was lower
2
4
[
[
28]
moiety. As our first choice, we used NaIO4 as oxi- than those of 4-nitro- and 4-cyanocinnamaldimines in
dant in ethanol/H O as co-solvents, but no expected the three-component reaction with phosphines and
2
reaction occurred under reflux for overnight. Another enynedioates. A thermally stable g-lactone 9a was iso-
attempted oxidation of 5a by O in dichloromethane lated in 38% yield. The 6p electrocyclization was also
2
under photochemical conditions for 24 h was also in- found to be slower under standard conditions, giving
[29]
[38]
effective.
b was observed on using mCPBA
Scheme 3a). Oxidative cleavage of the C=P bond re- not yield the corresponding lactone and lactam due to
quired more than two equivalents of mCPBA their poor reactivity.
2.4 equiv.) for providing oxygen to by-product phos-
To our delight, formation of isatins 6a, benzofuranone 10a in 62% yield (Scheme 4). Reac-
[30]
as an oxidant tions with cinnamaldehyde and cinnamaldimine did
(
(
phine oxides and isatins. Oxindole 5a was not con-
sumed completely with an insufficient amount of Conclusions
mCPBA (1.2 equiv.) at À258C, evidenced by two sets
of aromatic signals corresponding to 5a and isatin 6a In conclusion, we have successfully developed distin-
1
in the H NMR spectra of the crude mixture. To guished approaches to 3-phosphorus oxindoles, isatins
obtain pure isatins 6a, b, the reaction mixtures were and isoxazolinones from three-component reactions
quenched and extracted with saturated sodium bicar- of phosphines, enynedioates and cinnamaldimines –
bonate first for removal of unreacted mCPBA. Pure via a(d’)-Michael addition of phosphines to enyne-
orange solid isatins 6a, b were isolated in ca. 85% dioates followed by addition to cinnamaldimines, and
yield by precipitation of 6a, b with n-hexane. The further 6p electrocyclization and oxidation. The over-
isatin derivatives are biologically active compounds all reaction involves a facile 6p electrocyclization of
that could exhibit antitumor and antibacterial activi- 3,4-g-lactam-fused 1,3,4,6-tetrasubstituted 1,3,5-hexa-
[31]
ties.
trienes with an unusually low activation barrier ac-
Furthermore, overoxidation of oxindoles 5a, 5g, cording to computational and kinetic studies. The C=
and 5j with excess mCPBA (10 equiv.) at À258C gave P bond of 3-phosphorus ylide oxindoles can be oxi-
isoxazolinones 7a–c as the major products (50–64%), dized to a carbonyl group to give isatins with appro-
respectively (Scheme 3b). Compound 7a was unam- priate amounts of mCPBA and to provide isoxazoli-
biguously characterized by its single crystal structure nones with excess mCPBA by overoxidation. This
[32]
(
Figure 4). Isoxazolinones, normally synthesized by methodology provides a distinguished protocol to the
reduction of methyl ortho-nitrobenzoate with zinc 3-phosphorus oxindole derivatives, isatins and isoxa-
[
33]
and NH Cl
or photolysis of ortho-azidobenzoic zolinones through a(d’)-Michael addition and 6p elec-
4
[
34]
acid, possess anticonvulsant, antimicrobial and anti- trocyclization as key steps.
leukemic activities. Last, the tosyl group (Ts) of ox-
[
35]
indole 5a can be removed with sodium naphthale-
[36]
nide to give only 10% yield of 8a. However, 8a was
formed in 91% yield under treatment with neat
H SO at room temperature; deprotected isatin 6a’
2
4
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Experimental Section
subjected to flash chromatography with EA/MeOH or EA/
hexanes as eluents to give white solid 6a’ and yellow solids
7
a’ and 8a.
General Procedure for the Synthesis of Oxindole
Derivatives 5a–p
General Procedure for the Synthesis of 9a
A benzene solution containing enynedioate 1 (0.45 mmol)
and cinnamaldimine 3 (0.15 mmol) was distilled to remove
moisture residues for three time (anhydrous benzene,
A benzene solution containing enynedioate 1a (0.90 mmol)
and 4-nitrocinnamaldehyde (0.30 mmol) was distilled to
remove moisture residues for three time (benzene, 10 mLꢃ
1
0 mLꢃ3) with a Dean–Stark apparatus. Then, 22.5 mL of
anhydrous dichloromethane (DCM) were added to the re-
sulting mixture followed by addition of phosphine
0.45 mmol). The mixture was stirred under 08C for 2 h, and
3
) with a Dean–Stark apparatus. Then, 7.5 mL of DCM
were added to the resulting mixture followed by addition of
triphenylphosphine (0.90 mmol). The mixture was stirred
under 408C for 2 h. Upon completion of the reaction, the
mixture was then subjected to flash chromatography after
removal of DCM under vacuum. Elution with EA/hexanes
2
(
then at room temperature for 22 h. Upon completion of the
reaction, DCM was removed under vacuum and the residue
then subjected to flash chromatography. Elution with EA/
hexanes (3/1) gave purple lactam intermediates 4a–d, 4g–o
and orange lactam intermediates 4p; with EA/hexanes (1/1)
(
2/1) gave purple product 9a.
gave purple lactam intermediates 4e, f, respectively. The General Procedure for the Synthesis of 10a
1
amount of 4a–p was determined by H NMR spectroscopy
with mesitylene as an internal standard. Appropriate
To 60 mL of DCE solution containing 9a (0.017 g,
0
.030 mmol, 0.50 mM) was added acetic acid (3 equiv.,
amounts of intermediates 4 (0.030 mmol) was dissolved in
0 mL of anhydrous 1,2-dichloroethane (DCE, 0.50 mm) and
5
.15 mL). The mixture was irradiated by a halogen lamp at
6
reflux (ca. 848C) for 3 h and the solution colour changed
from purple to orange during this period. Upon completion
of the reaction, DCE was removed under vacuum and the
resulting mixture was subjected to flash chromatography.
Elution with EA/hexanes (2/1) gave yellow oxindole deriva-
tive 10a.
then acetic acid (5.1 mL, 0.090 mmol) was added to the solu-
tion. The mixture was irradiated by a halogen lamp at reflux
(
ca. 848C) for 1 to 2 h and the solution colour changed from
purple to orange during this period. Upon completion of the
reaction, DCE was removed under vacuum and the resulting
mixture was subjected to flash chromatography. Elution
with EA/hexanes (1/1) gave yellow oxindole derivatives 5a–
p.
Acknowledgements
General Procedure for the Synthesis of Isatins 6a, b
We thank the Ministry of Science and Technology of Taiwan
for supporting this research financially (MOST103-2113M-
To 20 mL of anhydrous DCM solution containing oxindole
5
a or 5g (0.014 mmol) was added 10 mL of DCM containing
0
09-017).
mCPBA (0.034 mmol) through syringe slowly in 30 min at
room temperature. The mixture was then stirred for another
3
0 min. Upon completion of the reaction, the solution was
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asc.wiley-vch.de
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crystallographic data for compound 5a: yellow bricks;
3
crystal
size:
0.10ꢃ0.06ꢃ0.03 mm ;
formula:
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
9
ÞÞ
These are not the final page numbers!

Jie-Cheng Deng et al.
FULL PAPERS
À13
3
C H N O PS; crystal system: triclinic; space group: P
À1;
d=1.540 mgm
,
V=1010.12(11) ꢂ ;
a=
41
31
2
7
À13
3
À1;
d=1.420 mgm
0.1828(4) ꢂ.; b=10.7540(4) ꢂ; c=16.2764(7) ꢂ; a=
,
V=1699.24(12) ꢂ ;
a=
7.9485(5) ꢂ; b=11.7009(7) ꢂ; c=12.1735(7) ꢂ; a=
115.4820(10)8; b=91.0210(10)8; g=97.4060(10)8; R =
1
8
1
1.419(2)8; b =74.852(2)8; g=85.151(2)8; R =0.0454;
0.0316; R =0.0841.
1
w
R =0.1255.
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[
1
1
S. A. Fuhrman, T. F. Hendrickson, D. A. Matthews,
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Centre via www.ccdc.cam.ac.uk/data_request/cif. X-ray
crystallographic data for compound 10a: yellow bricks;
3
crystal
size:
0.30ꢃ0.10ꢃ0.07 mm ;
formula:
C H NO P; crystal system: monoclinic; space group:
3
4
24
6
À13
3
crystallographic data for compound 7a: white bricks;
P 1 21/c 1; d=1.445 mgm , V=3185.9(6) ꢂ ; a=
18.186(2) ꢂ; b=10.1882(11) ꢂ; c=18.380(2) ꢂ; a=908;
b=110.688(3)8; g=908; R =0.0730; R =0.2122.
3
crystal
size:
0.30ꢃ0.22ꢃ0.12 mm ;
formula:
C H N O S; crystal system: triclinic; space group: P
22
16
2
8
1
w
10
asc.wiley-vch.de
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Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
These are not the final page numbers!

FULL PAPERS
Multicomponent Reactions of Phosphines, Enynedioates
and Cinnamaldimines Give g-Lactams with a 1,3,5-
Hexatriene Moiety for Facile 6p Electrocyclization: Access
to Oxindoles, Isatins and Isoxazolinones
11
Adv. Synth. Catal. 2015, 357, 1 – 11
Jie-Cheng Deng, Wu-Yin Chen, Chaoyuan Zhu,
Shih-Ching Chuang*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢁ 2015 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
11
ÞÞ
These are not the final page numbers!