A combined experimental and density functional theory study on the Pd-mediated cycloisomerization of o-alkynylnitrobenzenes - Synthesis of isatogens and their evaluation as modulators of ROS-mediated cell death

Article abstract of DOI:10.1002/ejoc.201000769

Highly selective cycloisomerization of o-alkynylnitrobenzenes, leading to isatogens, has been achieved by employment of a Pd^II complex. This reaction is very general and functional-group-tolerant. The possible mechanism of this reaction was inv

Full text of DOI:10.1002/ejoc.201000769

FULL PAPER
DOI: 10.1002/ejoc.201000769
A Combined Experimental and Density Functional Theory Study on the
Pd-Mediated Cycloisomerization of o-Alkynylnitrobenzenes – Synthesis of
Isatogens and Their Evaluation as Modulators of ROS-Mediated Cell Death
Chepuri V. Ramana,*[a] Pitambar Patel,[a] Kumar Vanka,*[a] Benchun Miao,[b] and
Alexei Degterev*[b]
Keywords: Nitro–alkyne cycloisomerization / Cyclization / Palladium / Isatogens / Anthranil / Density functional calcula-
tions
Highly selective cycloisomerization of o-alkynylnitrobenz-
enes, leading to isatogens, has been achieved by employ-
ment of a PdII complex. This reaction is very general and
functional-group-tolerant. The possible mechanism of this re-
action was investigated with the help of DFT calculations.
Three possible pathways – namely, the addition of the nitro
group either in (i) 5-exo-dig or (ii) 6-endo-dig mode and
(iii) halopalladation – and subsequent intramolecular events
have been considered and studied in detail. These investi-
gations revealed that pathway (i) is the favored route to isa-
togen formation. A preliminary screening of the available is-
atogens reveals the 2-alkylisatogens to be novel ROS scaven-
gers capable of inhibiting cellular necroptosis.
Our attention was drawn to the synthesis of isatogens as
part of a program directed towards the development of po-
Introduction
Bayer’s 1881 inaugural report on the cycloisomerization tent and well-tolerated ROS (reactive oxygen species) scav-
of o-nitrophenylpropiolates documented the first synthesis engers. This is because the generation of ROS is a key
of isatogens, which are unnatural.[1] To solve the problem downstream execution event in necroptotic cell death.[9] The
of the initially employed harsh reaction conditions, several isatogen nucleus was identified on consideration of its abil-
approaches to facilitate the nitro–alkyne cycloisomerization ity to trap hydroxy and superoxide radicals.[10] Because of
have been put forward.[2–8] Amongst these, the base-medi- their proximity to the reactive center, the electronic and ste-
ated cycloisomerization of o-alkynylnitrobenzene deriva- ric influence of the substituents at the C(2)-position are crit-
tives (trivially known as o-nitrotolans) under thermal or ical for the modulation of the reactivity of the N-oxides.[4b]
photochemical conditions has conventionally been em- However, the functional units at the C(2)-positions of
ployed for isatogen synthesis.[4] It has been reported re- reported isatogens are limited mainly to aryl groups,
cently that the nitro–alkyne cycloisomerization can also be with even reports dealing with C(2)-alkyl groups being
effected under mild conditions in the presence of gold(III) scarce.[3d,4b] Because the available catalytic transition metal
bromide or an iridium hydride complex. The outcome of protocols have limitations for 2-alkyl substituents, the de-
the cyclization, however, is dictated by the nature of the velopment of a versatile catalyst that promotes the nitro–
alkyne substituent:[6] o-(arylalkynyl)nitrobenzenes, for in- alkyne cycloisomerization to isatogens is warranted. Here
stance, were seen to give mixtures of isatogens 1 and anthra- we report a palladium(II)-mediated nitro–alkyne cyclo-
nils 2 (Figure 1) in the presence of catalytic amounts of gold isomerization process[5] that complements the gold- and
bromide,[6] whereas anthranils were formed exclusively from iridium-mediated cyclizations and provides an efficient and
o-(alkylalkynyl)nitrobenzenes in the presence either of gold general synthesis of isatogens.
bromide[6] or of an iridium hydride[7] complex.
Results and Discussion
Our working hypothesis [Equations (3) and (4),
Scheme 1] was based on Crabtree’s[7] mechanism [Equa-
[a] National Chemical Laboratory
Dr. Homi Bhabha Road, Pune 411008, India
tion (2), Scheme 1] given for anthranil formation and the
Fax: +91-20-25902629
mechanism given by Huisgen[11] [Equation (1), Scheme 1]
E-mail: vr.chepuri@ncl.res.in
for pyridine-mediated nitro–alkyne cycloisomerization[4b]
k.vanka@ncl.res.in
[b] Department of Biochemistry, Tufts University,
leading exclusively to isatogens. The given mechanism for
anthranil formation involves the initial nucleophilic attack
136 Harrison Ave, Stearns 703, Boston, MA 02111, USA
E-mail: alexei.degterev@tufts.ed
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Figure 1. General methods for nitro–alkyne cycloisomerizations leading to isatogens.
of one of the oxygen atoms of the –NO2 group on the
metal-coordinated triple bond in a 6-endo fashion, which
subsequently leads to a (carbene)metal intermediate IV. We
envisaged that a reactivity umpolung at the nitro group,
leading to the isomeric (carbene)metal VI [Equation (4)],
similarly to the case of pyridine, might provide substituent-
independent isatogen synthesis. We postulated the halopal-
ladation of the alkyne unit for such a reactivity umpolung
with the chloride being the transient nucleophile-cum-leav-
ing group,[12] albeit not ruling out such a possibility
through the addition of nitro oxygen in a 5-exo-dig fashion
[Equation (3)]. However, earlier investigations from our
own group and others had revealed that the NO2 group
remains as a spectator group when another internal nucleo-
phile is present and facilitates the addition of the nucleo-
phile on the β-carbon atom of the alkyne.[13]
With 1-nitro-2-(hept-1-ynyl)benzene (3aa)[14] as a model
substrate, the feasibility of the nitro–alkyne cycloisomeriza-
tion was examined with various PdII complexes as catalysts.
The cyclization was facile with PdCl2 and PdBr2 and with
their acetonitrile and benzonitrile complexes. Of these com-
plexes, Pd(CH3CN)2Cl2 gave better yields of the 2-pentylis-
atogen 1aa. The reactions were clean in acetonitrile,
whereas use of protic solvents resulted in several other by-
products. Pd(OAc)2 or Pd(PPh3)2Cl2 were found to be inef-
ficient for this nitro–alkyne cycloisomerization. As a con-
trol, when 3aa was exposed to AuBr3 under similar condi-
Scheme 1. Huisgen mechanism for isatogen formation [Equa-
tion (1)] and mechanism for the formation of anthranils [Equa-
tion (2)], together with the proposal for general isatogen synthesis
either through 5-exo addition [Equation (3)] or through halopallad-
ation [Equation (4)].
tions, the anthranil 2aa was obtained as the main product ethers, and also accommodated substituent functionality in-
(Scheme 2).[6]
cluding free alcohols, β-lactams, heterocycles, and olefins.
Next, various o-alkynylnitrobenzenes were prepared
The detailed mechanism of the above reaction was
through Sonogashira couplings[15] of the selected aryl io- studied with the aid of density functional theory (DFT).
dides 4 and alkynes 5[16] in order to examine the scope of The ab initio calculations were carried out with the software
the palladium-mediated nitro–alkyne cycloisomerization re- Turbomole 5.10[17] with use of the TZVP[18] basis set and
actions. These cyclizations showed excellent selectivities in- the BP-86[19] functional. The mechanism by halopalladation
dependent of alkyne substituents (Table 1). The conditions that we propose is outlined in Figures 2 and 3. The values
employed were tolerant towards commonly employed pro- provided here are the ∆E values, calculated after the incor-
tecting groups such as TBS, isopropylidene, and benzyl poration of solvent effects, with acetonitrile (ε = 37.5) taken
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Pd-Mediated Cycloisomerization of o-Alkynylnitrobenzenes to Isatogens
Scheme 2. PdII-catalyzed general synthesis of isatogens.
Table 1. Palladium-catalyzed cycloisomerization of o-alkynylnitrobenzenes.
as the solvent. To begin with, the substrate 3aa reacts with step is therefore the slowest step – the rate-determining
one molecule each of Pd(CH3CN)2Cl2 and PdCl2 to pro- step – in the reaction cycle.[22] The next step in the reaction
duce the alkene-coordinated complex A and releases one cycle is the conversion of the oxirane C into D, in which
molecule of CH3CN. This reaction is exothermic by the palladium atom has shifted its bond from the α- to the
36.7 kcalmol–1 (see Figure 2). Subsequent to this step, the β-carbon atom of the alkyl chain. The barrier for this step
system goes through a transition state TS1, in which a leav- is 19.7 kcalmol–1. This conversion is exothermic by
ing palladium species donates a chlorine atom to the β- 10.5 kcalmol–1.
carbon atom of the alkyl chain and extracts a chlorine atom
Figure 3 shows the continuation of the reaction cycle,
from the palladium atom that remains coordinated to the from species D to F. For this conversion, there is need of
original substrate complex. The barrier for the reaction is an extra molecular species, Pd(CH3CN)2Cl2, which essen-
14.9 kcalmol–1. The subsequent dissociation reaction to tially acts as a catalyst to transfer a chlorine atom from the
yield PdCl2(CH3CN) and the cis-chloropalladated species B β-carbon atom of the alkyl chain to the palladium atom.
(see Figure 2)[20] is downhill in energy with respect to the The way it does so is by acting as a “chlorine shuttle” –
transition state TS1 by 6.4 kcalmol–1, and the overall reac- forming a five-membered transition state complex TS4 by
tion converting A into B and the PdCl2(CH3CN) complex coordinating to species E (see Figure 3) – and then proceed-
is slightly endothermic, by 8.5 kcalmol–1. The intermediate ing to extract a chlorine atom from the β-carbon atom of
B is converted into the oxirane C via the transition state the alkyl chain, while simultaneously giving its own chlorine
TS2. The earlier reports by Andrews and Chen on the epox- atom to the palladium atom, ultimately to yield intermedi-
idation of cycloalkenes in the presence of stoichiometric or ate F. As shown in Figure 3, this reaction is quite facile:
catalytic amounts of Pd(CH3CN)2NO2Cl complexes at am- the formation of E from D and Pd(CH3CN)2Cl2 is only
bient temperatures supports the intermediacy of C in our marginally uphill by 4.8 kcalmol–1, and the barrier of the
mechanistic route.[21] The conversion taking place here is conversion of TS4 to E is only 12.6 kcalmol–1 (see Fig-
the transfer of an oxygen atom from the nitro group to the ure 3). It is interesting to note that an acetonitrile solvent
α-carbon atom of the alkyl chain connected at the ortho molecule, originally coordinated to the chlorine-shuttling
position of the phenyl ring. The transition state for this has Pd(CH3CN)2Cl2 species, is dissociated from the palladium
the oxygen atom coordinating to the palladium atom and center in the intermediate species E. This is the bond that
also beginning to form a bond with the α-carbon atom. the palladium sacrifices in order to coordinate to the species
The barrier for this reaction is 30.5 kcalmol–1, which is the D. However, in the transition state TS4, this acetonitrile
highest barrier in the entire catalytic cycle described. This molecule recoordinates to the palladium center. This is be-
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Figure 2. Energy profile for the first steps of the catalysis; that is, the conversion of the substrate 3aa to B, with the aid of two palladium
chloride molecules, and the subsequent conversion of the species B to D through two transition states that shift an oxygen atom from
the nitrogen atom (in B) to the carbon atom (in D) with the help of an interacting palladium species. All the reported energies were
calculated with DFT.
Figure 3. Energy profile for the continuing steps during the catalysis; that is, the conversion of species D into G with the help of a
“chlorine-shuttling” Pd(CH3CN)2Cl2 species followed by the conversion of G into the final product 1aa, occurring through the elimination
of the PdCl2 species.
cause at the transition state, the two palladium–chlorine Recent work by Popp et al.[23] shows that labile mono-
bonds in Pd(CH3CN)2Cl2 have been weakened due to the dentate ligands can readily associate with and dissociate
exchange of chlorine atoms – one being given to the palla- from palladium centers and have a significant influence on
dium atom and one taken from the β-carbon atom of the the mechanisms of palladium-mediated catalysis reactions.
alkyl chain in the original species D. This recoordination of The labile ligand in the palladium catalyst system reported
the solvent molecule is significant, because it serves to re- by Popp et al. was pyridine; in our system[23f] the labile
duce the barrier to only 12.6 kcalmol–1, by providing sta- ligand is the acetonitrile solvent molecule. The intermediate
bility to the palladium center, in which bonding to the species
F then undergoes a marginally uphill (by
transferred chlorine atom is reduced at the transition state. 0.6 kcalmol–1) conversion into the species G, in which the
Again here, the dissociation and recoordination of the labile palladium complexes preferentially with the nitrogen atom
acetonitrile species serves the crucial purpose of reducing of NO.[24] The involvement of such stable PdII–carbene spe-
the reaction barrier, and thus once again has a significant cies and subsequent electrocyclizations is well documen-
influence on the reaction cycle in our proposed mechanism. ted.[25] The calculations revealed that the conversion of the
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Pd-Mediated Cycloisomerization of o-Alkynylnitrobenzenes to Isatogens
Figure 4. Energy profile for the Pd-mediated 5-exo-dig addition of the nitro-group oxygen atom and the subsequent steps.
species G into H goes through the transition state TS5. This
From here, the next step involves the transformation into
conversion involves the bonding of the nitrogen atom, at- the intermediate species B, which has the oxygen atom of
tached in structure G to the palladium atom, to the β- the nitro group coordinated to the α-carbon atom of the
carbon atom of the alkyl chain – leading to structure H alkyne, while the palladium atom has lost its coordination
with the palladium atom coordinated to the β-carbon atom to the α-carbon atom as well as the oxygen atom and is
and two chlorine atoms (having relinquished its bonding to now bound to the β-alkyne carbon atom. This species lies
the nitrogen atom). This reaction is exothermic by 5.6 kcalmol–1 below species I, and is therefore
17.0 kcalmol–1 and has a barrier of only 14.2 kcalmol–1, 55.5 kcalmol–1 below the original reactant species (see Fig-
suggesting that it is quite feasible. Once H has been formed, ure 4). The transition state that connects the two species I
5
it can dissociate to give the desired product 1aa and the and J – TS1 – lies 24.8 kcalmol–1 above I, and features a
PdCl2 catalyst. On the potential energy surface, this reac- lengthening of the N–O bond as well as of the Pd–α-carbon
tion is endothermic by 23.1 kcalmol–1, but because the re- bond, while the palladium atom is seen to come closer to
action is favorable entropically, yielding two species (1aa the β-carbon atom of the alkyne. Subsequent to the forma-
and PdCl2) from one (H), such a dissociation is likely to tion of species J, the system undergoes further transforma-
occur at room temperature.
tion into species K, in which the palladium atom is bound
The mechanism discussed above relates to the PdCl2-cat- to the nitrogen atom as well as to the β-carbon atom of the
5
alyzed halopalladation route to form isatogen. Although alkyne. This occurs via the transition state TS2, in which
halopalladation had been envisaged by us in deciding the the oxygen atom has lost its coordination to the nitrogen
use of palladium as the catalyst for isatogen synthesis, a atom and is now bound in an epoxy fashion to the two
perusal of the mechanism makes it clear that it suffers from alkyne carbon atoms, while the palladium atom, approach-
several problems: (i) it is very circuitous and complicated, ing the nitrogen atom, is bound to both of the alkyne car-
(ii) it is likely to be entropically disfavored because two bon atoms (see Figure 4). This transition state lies
PdCl2 and one CH3CN solvent molecule have to be invoked 17.1 kcalmol–1 above species J, whereas the formed inter-
in order to catalyze the reaction, and (iii) the barrier for the mediate K is more stable than J, and lies 65.1 kcalmol–1
rate-determining step – 30.5 kcalmol–1 – is on the higher below the reactants on the potential energy surface. From
side for a reaction taking place at room temperature. These this point, intermediate K is converted into species L, which
considerations prompted us to consider the possibility that has the nitrogen atom bound to the β-alkyne carbon atom,
the transformation might be taking place through an alter- while the palladium atom has bonds to both of the atoms.
native pathway – the 5-exo-dig route discussed earlier in the This structure is formed via the transition state 5TS3, which
introduction and elucidated in Scheme 1. Calculations were features a shortening of the bond between the nitrogen and
carried out to determine the feasibility of this route, and β-alkyne carbon atoms, and has a barrier of 22.6 kcalmol–1.
the potential energy surface for the entire mechanistic route Species L is in essence the isatogen with a coordinating
is shown in Figure 4. The addition of a PdCl2 molecule to PdCl2 species, the loss of which gives the final desired prod-
the substrate 3aa leads to the formation of the complex A, uct 1aa, at an energy cost of 22.6 kcalmol–1.
which lies 45.9 kcalmol–1 below the reactant on the poten-
This 5-exo-dig route to isatogen formation has significant
tial energy surface. This complex has the PdCl2 group advantages over the halopalladation. To begin with, it is
bound to the two alkyne carbon atoms as well as to one of considerably simpler, involving three transition states as op-
the oxygen atoms of the NO2 group (sees Figure 4). The posed to five for the halopalladation, and also requiring
high exothermicity of this reaction makes it quite feasible.
only the presence of one PdCl2 molecule as the catalyst
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rather than two PdCl2 molecules and a CH3CN solvent the barrier heights for the analogous reactions when using
molecule as required for the halopalladation process. iridium and gold catalysts in place of palladium (work in
Moreover, the rate-determining step has a barrier of progress).
24.8 kcalmol–1, which is 5.7 kcalmol–1 lower than the rate-
After having established a general synthesis of isatogens
determining barrier in the halopalladation case (for the and a plausible mechanism through DFT calculations, we
oxygen transfer). Indeed, because the reaction takes place next proceeded to evaluate the efficiency of isatogens in in-
at room temperature, the necessity of the barrier for the
reaction to be less than 25.0 kcalmol–1 strongly suggests the
favorability of the 5-exo-dig route. Finally, it is interesting
to note that every successive step in the reaction pathway
for the 5-exo-dig route to isatogen formation features an
intermediate that is lower in energy than the previous inter-
mediate species (see Figure 4). This suggests that each suc-
cessive step would be thermodynamically favored in this
route, which makes this mechanism highly feasible.
It is also noted here that we have also considered the
possibility that (alkyne)palladium complex I might proceed
in a 6-endo-dig fashion to produce the regiomeric carbene
K, which was postulated by Crabtree and co-workers as a
possible intermediate when iridium was used as the catalyst.
As shown in Figure 5, this pathway is significantly disfa-
vored, with 6TS1 lying 43.6 kcalmol–1 higher in energy than
I on the potential energy surface. As also shown in Fig-
ure 5, the palladium complex I has the energetically much
more favorable choice of passing through the transition
state 5TS1 (barrier 24.8 kcalmol–1) to give the 5-exo-dig in-
termediate J, which makes the 6-endo-dig pathway unlikely
and helps explain why the isatogen is formed exclusively,
whereas the carbene M, resulting from the 6-endo-dig path-
way leading to the anthranil 2aa, is not formed. The reason
for the high barrier for this route is the steric strain in-
volved – the transition state 6TS1 has a strained nitro group
Figure 6. Inhibition of necroptosis (A) and oxidative stress (B) in
in which both oxygen atoms have bonds to two atoms,
thereby giving rise to two different rings. Therefore, when
PdCl2 is used as the catalyst, the results from the DFT cal-
culations indicate that the route to isatogen formation ex-
clusively involves the formation of the 5-exo-dig species. Fu-
L929 cells by isatogens. L929 cells were treated with mouse TNFα
(Cell Sciences, Canton, MA; 10 ngmL–1) in the presence of the
indicated concentrations of the compounds for 24 h. Cell viability
was measured by Cell Titer-Glo assay (Promega, Madison, WI).
ROS levels were determined by measuring the fluorescence of the
cells stained with Mito Sox reagent (BD Biosciences, Eugene, OR;
ture work in this regard would involve the determination of 10 µ) by FACS analysis.
Figure 5. Difference in the activation energies for the addition of the nitro-group oxygen atom in 5-exo or 6-endo-dig modes.
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Pd-Mediated Cycloisomerization of o-Alkynylnitrobenzenes to Isatogens
to designate signal multiplicity: s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet, br. = broad. The multiplicities of the
13C NMR signals were assigned with the help of DEPT spectra
and the terms s = singlet, d = doublet, t = triplet, and q = quartet
represent C (quaternary), CH, CH2, and CH3, respectively. Mass
spectroscopy was carried out with a API QStar Pulsar (Hybrid
Quadrupole-TOF LC–MS–MS) spectrometer. Elemental analysis
data were obtained with a Thermo Finnigan Flash EA 1112 Series
CHNS Analyzer.
hibiting ROS-mediated necroptotic cell death. These experi-
ments employed mouse fibrosarcoma L929 cells treated
with TNFα. As shown in Figure 6A, isatogens indeed dis-
played significant protection from necroptosis. The EC50
values of some of the active compounds are shown in
Table 2. Compound 1ad displayed the highest activity (EC50
= 188 µ). Other molecules were found to lack activity. To
confirm that inhibition of cell death was related to the sup-
pression of ROS, we directly measured the production of
mitochondrial superoxide in necroptotic L929 cells. As
shown in Figure 6B, 1ad indeed efficiently suppressed TNF
α-induced ROS, in contrast to the related inactive analogue.
The inhibition of necroptosis selectively by 2-alkylisatogens
and not by 2-arylisatogens can be explained by considering
the superior spin trapping abilities and also the longer half-
life times of the corresponding spin adducts of the former.
Overall, these data confirm that isatogens represent a new
family of ROS scavengers capable of inhibiting cellular
necroptosis.
General Procedure for the Sonogashira Coupling: Triphenylphos-
phane (TPP; 0.1 mmol) and Pd(PPh3)2Cl2 (0.1 mmol) were added
to a solution of an alkyne 5 (1 mmol) and an aryl iodide 4
(1.2 mmol) in Et3N (16 mL) and DMF (8 mL), and the mixture
was deaerated with argon for 30 min. CuI (0.1 mmol) was added,
and the mixture was deaerated with argon for 10 min and stirred
at room temp. for 6 h. The reaction mixture was partitioned be-
tween ethyl acetate and water. The organic layer was separated,
washed with brine, dried (Na2SO4), and concentrated, and the resi-
due obtained was purified by column chromatography (ethyl acet-
ate in petroleum ether) to afford a compound 3.
1
Compound 3aa:[14b] Yellow liquid, 70% yield. H NMR (400 MHz,
Table 2. EC50 values of selected compounds.
CDCl3): δ = 0.89 (t, J = 7.2 Hz, 3 H), 1.28–1.37 (m, 2 H), 1.38–
1.45 (m, 2 H), 1.56–1.63 (m, 2 H), 2.42 (t, J = 7.2 Hz, 2 H), 7.33
(br. ddd, J = 1.6, 7.3, 8.2 Hz, 1 H), 7.46 (dt, J = 1.2, 7.7 Hz, 1 H),
7.51 (dd, J = 1.6, 7.8 Hz, 1 H), 7.90 (dd, J = 8.3, 1.2 Hz, 1 H) ppm.
13C NMR (125 MHz, CDCl3): δ = 13.9 (q), 19.7 (t), 22.1 (t), 27.9
(t), 30.9 (t), 75.9 (s), 99.2 (s), 119.3 (s), 124.2 (d), 127.7 (d), 132.3
Compound:
1aa
1ah
1ab
1ad
EC50 [µ]
327.34
879.02
299.92
188.36
(d), 134.6 (d), 150.0 (s) ppm. IR (CHCl ): ν = 3022, 2958, 2922,
˜
3
2860, 2233, 1608, 1568, 1527, 1480, 1466, 1345, 1216, 851, 757,
668 cm–1. C13H15NO2 (217.27): calcd. C 71.87, H 6.96, N 6.45;
found C 71.76, H 6.91, N 6.40.
Conclusions
Cycloisomerization of o-alkynylnitroaryl systems medi-
ated by an electrophilic palladium(II) complex has been ex-
plored, and its mechanism has been proposed on the basis
of DFT calculations. We identified the 2-alkylisatogens as
new candidates for inhibiting necroptosis-mediated cell de-
ath through the efficient trapping of the reactive oxygen
species. The reaction conditions employed are catalytic in
nature and mild, accommodate both aryl and alkyl substit-
uents, and are tolerant towards commonly employed pro-
tecting groups/functional units. Given the fact that the field
of transition-metal-catalyzed cycloisomerization of nitro–
alkynes is still in its infancy, as well as the remarkable reac-
tivity differences noticed with different metal salts/com-
plexes, we believe that the results described in this paper
will provide a fresh impetus for the development of new
reactions.
1
Compound 3ab:[14a] Yellow liquid, 72% yield. H NMR (200 MHz,
CDCl3): δ = 0.05 (s, 6 H), 0.88 (s, 9 H), 1.82 (quint, J = 6.6 Hz, 2
H), 2.55 (d, J = 7.1 Hz, 2 H), 3.76 (t, J = 6.0 Hz, 2 H), 7.37 (br.
ddd, J = 2.2, 6.8, 8.2 Hz, 1 H), 7.50 (dt, J = 1.2, 7.7 Hz, 1 H), 7.55
(dd, J = 2.2, 8.2 Hz, 1 H), 7.94 (br. d, J = 8.2 Hz, 1 H) ppm. 13C
NMR (50 MHz, CDCl3): δ = –5.5 (q, 2 C), 16.1 (t), 18.2 (s), 25.8
(q, 3 C), 31.2 (t), 61.3 (t), 75.9 (s), 98.7 (s), 119.1 (s), 124.2 (d),
127.8 (d), 132.4 (d), 134.6 (d), 149.9 (s) ppm. IR (CHCl ): ν = 3032,
˜
3
2954, 2885, 1684, 1634, 1557, 1520, 1471, 1465, 1445, 1345, 1276,
1255, 1180, 1143, 1101, 1006, 980, 836, 776 cm–1. C17H25NO3Si
(319.48): calcd. C 63.91, H 7.89, N 4.38; found C 63.81, H 7.72, N
4.32.
Compound 3ac: Yellow liquid, 68% yield. 1H NMR (200 MHz,
CDCl3): δ = 1.24 (br. s, 22 H), 1.52–1.68 (m, 5 H), 2.46 (t, J =
6.8 Hz, 2 H), 3.62 (t, J = 6.6 Hz, 2 H), 7.37 (br. ddd, J = 2.1, 7.1,
8.2 Hz, 1 H), 7.51 (dt, J = 1.2, 7.7 Hz, 1 H), 7.57 (dd, J = 2.1,
8.7 Hz, 1 H), 7.96 (dd, J = 1.2, 8.2 Hz, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 19.8 (t), 25.7 (t), 28.3 (t), 28.8 (t), 29.1 (t),
29.4 (t), 29.5 (t), 29.5 (t, 3 C), 29.6 (t, 3 C), 32.7 (t), 62.9 (t), 75.9
(s), 99.4 (s), 119.3 (s), 124.3 (d), 127.8 (d), 132.5 (d), 134.7 (d),
Experimental Section
General: Air- and/or moisture-sensitive reactions were carried out
in anhydrous solvents under an argon atmosphere in oven-dried
glassware. All anhydrous solvents were distilled prior to use:
CH3CN and DMF from CaH2; Et3N from KOH. Commercial rea-
gents were used without purification. Column chromatography was
carried out by using Spectrochem silica gel (100-200 mesh). Optical
rotations were determined with a Jasco DIP-370 digital polarimeter
150.0 (s) ppm. IR (CHCl ): ν = 3367, 2922, 2852, 2400, 1608, 1528,
˜
3
1464, 1320, 1056, 755 cm–1. C23H35NO3 (373.53): calcd. C 73.96,
H 9.44, N 3.75; found C 73.88, H 9.34, N 3.71.
Compound 3ad: Yellow liquid, 62% yield. 1H NMR (200 MHz,
CDCl3): δ = 3.60–3.65 (m, 2 H), 3.67–3.76 (m, 4 H), 3.81–3.86 (m,
2 H), 4.03 (dt, J = 5.7, 1.4 Hz, 2 H), 4.50 (s, 2 H), 5.18 (ddd, J =
10.4, 3.1, 1.3 Hz, 1 H), 5.27 (ddd, J = 17.2, 3.1, 1.3 Hz, 1 H), 5.92
(ddt, J = 17.2, 10.4, 5.7 Hz, 1 H), 7.37 (br. ddd, J = 1.8, 7.1, 8.0 Hz,
1 H), 7.50 (dt, J = 1.4, 7.7 Hz, 1 H), 7.55 (dd, J = 2.0, 7.7 Hz, 1 H),
7.94 (d, J = 1.4, 8.0 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 59.0 (t), 69.2 (t), 69.3 (t), 70.4 (t), 70.6 (t), 72.1 (t), 81.5 (s), 93.4
1
at 25 °C. H and 13C NMR spectroscopy measurements were car-
ried out with a Bruker AC 200 MHz or Bruker DRX 400 MHz
spectrometer, and TMS was used as internal standard. The 1H and
13C NMR chemical shifts are reported in parts per million down-
field from tetramethylsilane. The following abbreviations are used
Eur. J. Org. Chem. 2010, 5955–5966
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5961

C. V. Ramana, P. Patel, K. Vanka, B. Miao, A. Degterev
FULL PAPER
(s), 116.9 (s), 117.9 (t), 124.5 (d), 128.8 (d), 132.7 (d), 134.7 (d),
129.70 (s), 132.82 (d), 134.91 (d), 149.55 (s), 155.29 (s) ppm. IR
134.8 (d), 149.7 (s) ppm. IR (CHCl ): ν = 2915, 2403, 1683, 1613,
(CHCl ): ν = 3372, 3019, 2953, 2400, 1656, 1616, 1587, 1531, 1487,
˜
˜
3
3
1559, 1505, 1469, 1401, 1265, 1097, 1034, 933, 765 cm–1. ESI-MS:
m/z (%) = 328.4 (100) [M + Na]+. C16H19NO5 (305.33): calcd. C
62.94, H 6.27, N 4.59; found C 62.82, H 6.21, N 4.49.
1456, 1291, 1230, 1119, 753 cm–1. C16H13NO4 (283.28): calcd. C
67.84, H 4.63, N 4.94; found C 67.79, H 4.69, N 4.83.
Compound 3aj: Gray spongy mass, 62% yield. 1H NMR (200 MHz,
CDCl3): δ = 2.83 (d, J = 6.2 Hz, 2 H), 3.19 (s, 1 H), 3.72 (s, 3 H),
3.74 (s, 6 H), 4.84 (t, J = 6.2 Hz, 1 H), 6.58 (s, 2 H), 7.27–7.36 (m,
1 H), 7.38–7.49 (m, 2 H), 7.89 (d, J = 8.1 Hz, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 30.8 (t), 55.7 (q, 2 C), 60.5 (q), 72.1 (d),
78.2 (s), 94.9 (s), 102.3 (d, 2 C), 118.3 (s), 124.3 (d), 128.1 (d), 132.6
(d), 134.5 (d), 136.7 (s), 138.4 (s), 149.4 (s), 152.8 (s, 2 C) ppm. IR
Compound 3ae: Light gray solid, 67% yield. M.p. 119 °C. [α]2D5
=
1
+42.6 (c = 1, CHCl3). H NMR (200 MHz, CDCl3): δ = 0.07 (s, 6
H), 0.87 (s, 9 H), 1.28 (d, J = 6.3 Hz, 3 H), 3.41–3.44 (m, 1 H),
4.23–4.34 (m, 1 H), 4.61 (d, J = 2.5 Hz, 1 H), 6.32 (br. s, 1 H),
7.42–7.52 (m, 1 H), 7.56–7.59 (m, 2 H), 8.04 (dd, J = 1.1, 7.7 Hz,
1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = –5.2 (q), –4.4 (q),
17.8 (s), 22.2 (q), 25.6 (q, 3 C), 39.3 (d), 64.4 (d), 67.8 (d), 79.9 (s),
95.1 (s), 117.6 (s), 124.5 (d), 128.9 (d), 132.7 (d), 134.6 (d), 149.8
(CHCl ): ν = 3352, 3010, 2939, 2400, 1694, 1593, 1505, 1463, 1328,
˜
3
1236, 1126, 1004, 754 cm–1. C19H19NO6 (357.36): calcd. C 63.86,
(s), 167.7 (s) ppm. IR (CHCl ): ν = 3414, 3019, 2956, 2930, 2885,
˜
H 5.36, N 3.92; found C 63.79, H 5.31, N 3.88.
3
2400, 1770, 1672, 1609, 1570, 1529, 1472, 1377, 1346, 1215, 1144,
1065, 959, 756 cm–1. ESI-MS: m/z (%) = 397.6 (100), [M + Na]+.
C19H26N2O4Si (374.51): calcd. C 60.93, H 7.0, N 7.48; found C
60.81, H 7.2, N 7.34.
Compound 3af: Yellow liquid, 57% yield. 1H NMR (200 MHz,
CDCl3): δ = 1.16 (s, 3 H), 1.58–1.66 (m, 1 H), 1.88–1.96 (m, 1 H),
2.04–2.16 (m, 2 H), 2.71 (t, J = 5.7 Hz, 2 H), 3.05 (br. s, 1 H), 3.31
(br. s, 1 H), 3.47–3.53 (m, 1 H), 3.62–3.71 (m, 2 H), 4.11–4.19 (m,
1 H), 7.33–7.41 (m, 1 H), 7.45–7.56 (m, 2 H), 7.93 (d, J = 7.8 Hz,
1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 23.7 (q), 26.8 (t), 30.9
(t), 32.7 (t), 63.1 (t), 76.7 (d), 77.3 (s), 78.0 (d), 85.0 (s), 95.2 (s),
118.7 (s), 124.3 (d), 128.1 (d), 132.6 (d), 134.7 (d), 149.8 (s) ppm.
Compound 3ak: Dark yellow liquid, 61% yield. 1H NMR
(200 MHz, CDCl3): δ = 2.75 (br. s, 1 H), 2.89 (d, J = 6.3 Hz, 2 H),
3.79 (s, 3 H), 4.95 (t, J = 6.0 Hz, 1 H), 6.89 (dt, J = 8.7, 2.3 Hz, 2
H), 7.34–7.45 (m, 3 H), 7.51–7.56 (m, 2 H), 8.01 (d, J = 7.7 Hz, 1
H) ppm. 13C NMR (50 MHz, CDCl3): δ = 30.8 (t), 55.1 (q), 71.8
(d), 78.3 (s), 95.2 (s), 113.7 (d, 2 C), 113.8 (s), 118.6 (s), 124.4 (d),
126.9 (d, 2 C), 128.2 (d), 128.5 (s), 132.7 (d), 134.6 (d), 149.7 (s),
159.1 (s) ppm. IR (CHCl ): ν = 3410, 3019, 2936, 2834, 2400, 2223,
˜
3
1611, 1527, 1514, 1465, 1441, 1345, 1250, 1215, 1111, 1035,
757 cm–1. C17H15NO4 (297.31): calcd. C 68.68, H 5.09, N 4.71;
found C 68.79, H 5.23, N 4.65.
Compound 3al:[14c] Orange spongy mass, 67% yield (the sample also
IR (CHCl ): ν = 3390, 2975, 2742, 2235, 1608, 1595, 1527, 1476,
˜
3
1
contains small amounts of isatogen). H NMR (200 MHz, CDCl3):
1380, 1280, 1069, 755 cm–1. C16H19NO5 (305.33): calcd. C 62.94,
δ = 7.35–7.40 (m, 3 H), 7.44–7.50 (m, 1 H), 7.56–7.62 (m, 3 H),
7.66–7.72 (m, 1 H), 8.07 (d, J = 1.2, 7.9 Hz, 1 H) ppm. 13C NMR
(100 MHz, CDCl3): δ = 84.8 (s), 97.1 (s), 113.9 (s), 122.3 (s), 124.5
(d), 128.3 (d, 2 C), 128.3 (d), 129.1 (d), 131.9 (d, 2 C), 132.6 (d),
H 6.27, N 4.59; found C 62.79, H 6.38, N 4.48.
Compound 3ag: Yellow liquid, 73% yield. [α]2D5 = +88.8 (c = 1,
1
CHCl3). H NMR (200 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.50 (s, 3
H), 4.14 (d, J = 3.0 Hz, 1 H), 4.63 (d, J = 3.8 Hz, 1 H), 4.80 (d, J
= 12.2 Hz, 1 H), 4.89 (d, J = 12.2 Hz, 1 H), 5.14 (d, J = 3.0 Hz, 1
H), 6.03 (d, J = 3.8 Hz, 1 H), 7.26–7.39 (m, 5 H), 7.52–7.61 (m, 2
H), 7.67 (dd, J = 7.6, 1.8 Hz, 1 H), 8.06 (dd, J = 7.9, 1.4 Hz, 1 H)
ppm. 13C NMR (50 MHz, CDCl3): δ = 26.1 (q), 26.8 (q), 71.5 (d),
72.8 (t), 82.7 (d), 82.9 (d), 83.0 (s), 91.0 (s), 104.7 (d), 112.1 (s),
117.7 (s), 124.5 (d), 127.7 (d, 2 C), 127.8 (d), 128.4 (d, 2 C), 129.1
134.4 (d), 149.5 (s) ppm. IR (CHCl ): ν = 3019, 2410, 1605, 1567,
˜
3
1514, 1465, 1345 cm–1. C14H9NO2 (223.23): calcd. C 75.33, H 4.06,
N 6.27; found C 75.53, H 4.16, N 6.13.
Compound 3bl: Dark orange solid, 75% yield. M.p. 45 °C. 1H
NMR (200 MHz, CDCl3): δ = 7.14 (ddd, J = 9.1, 6.4, 2.7 Hz, 1
H), 7.36–7.43 (m, 4 H), 7.57–7.63 (m, 2 H), 8.15 (dd, J = 9.2,
5.1 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 83.9 (s), 98.5
(s), 116.0 (d, JCβ,F = 24.1 Hz), 121.1 (d, JCβ,F = 24.1 Hz), 121.4 (s,
JCγ,F = 10.7 Hz), 121.7 (s), 127.4 (d, JCγ,F = 10.7 Hz), 128.4 (d, 2
C), 129.5 (d), 132.0 (d, 2 C), 145.6 (s, JCδ,F = 3.3 Hz), 164.3 (s,
(d), 132.8 (d), 135.2 (d), 137.3 (s), 149.5 (s) ppm. IR (CHCl ): ν =
˜
3
3020, 2960, 2400, 1608, 1575, 1530, 1481, 1437, 1385, 1347, 1215,
1163, 1075, 928, 758 cm–1. C22H21NO6 (395.41): calcd. C 66.83, H
5.35, N 3.54; found C 66.85, H 5.45, N 3.47.
JCα,F = 257.2 Hz) ppm. IR (CHCl ): ν = 3054, 2936, 1652, 1610,
˜
3
Compound 3ah: Yellow liquid, 75% yield. [α]2D5 = –42.2 (c = 1,
1578, 1520, 1477, 1447, 1385, 1357, 1260, 895, 780, 756, 688,
603 cm–1. C14H8FNO2 (241.22): calcd. C 69.71, H 3.34, F 7.88, N
5.8; found C 69.63, H 3.41, F 7.72, N 5.78.
1
CHCl3). H NMR (200 MHz, CDCl3): δ = 1.32 (s, 3 H), 1.48 (s, 3
H), 2.69 (br. s, 1 H), 2.85 (d, J = 5.6 Hz, 1 H), 2.89 (t, J = 2.0 Hz,
1 H), 4.14–4.29 (m, 3 H), 4.63 (d, J = 11.7 Hz, 1 H), 4.64 (d, J =
3.7 Hz, 1 H), 4.75 (d, J = 11.7 Hz, 1 H), 5.95 (d, J = 3.7 Hz, 1 H),
7.33–7.39 (m, 5 H), 7.46–7.51 (m, 1 H), 7.51–7.62 (m, 2 H), 8.03
(dd, J = 8.0, 0.9 Hz, 1 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
26.1 (t), 26.3 (q), 26.7 (q), 67.1 (d), 72.3 (t), 78.6 (s), 81.4 (d), 81.7
(d), 82.4 (d), 94.8 (s), 105.1 (d), 111.8 (s), 118.7 (s), 124.5 (d), 127.8
(d, 2 C), 128.1 (d), 128.2 (d), 128.6 (d, 2 C), 132.8 (d), 134.7 (d),
Compound 3cl: Pale brown solid, 72% yield. M.p. 101 °C. 1H NMR
(200 MHz, CDCl3): δ = 6.14 (s, 2 H), 7.04 (s, 1 H), 7.35–7.38 (m,
3 H), 7.55–7.60 (m, 3 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
5.4 (s), 96.1 (s), 103.9 (t), 105.4 (d), 112.4 (d), 114.7 (s), 122.5 (s),
128.4 (d, 2 C), 129.0 (d), 131.9 (d, 2 C), 144.4 (s), 147.8 (s), 151.5
(s) ppm. IR (CHCl ): ν = 3077, 3022, 2400, 1614, 1557, 1522, 1493,
˜
3
1443, 1341, 1297, 1210, 1073, 959, 754 cm–1. C15H9NO4 (267.24):
137.3 (s), 149.8 (s) ppm. IR (CHCl ): ν = 3678, 3020, 2950, 2934,
˜
3
calcd. C 67.42, H 3.39, N 5.24; found C 67.37, H 3.42, N 5.20.
2400, 1676, 1612, 1569, 1528, 1454, 1375, 1345, 1215, 1120, 1076,
1025, 758 cm–1. C24H25NO7 (439.46): calcd. C 65.59, H 5.73, N
3.19; found C 65.41, H 5.69, N 3.14.
Compound 3dl: Orange solid, 65% yield. M.p. 108 °C. 1H NMR
(200 MHz, CDCl3): δ = 3.97 (s, 3 H), 7.35–7.43 (m, 3 H), 7.58 (dd,
J = 0.9, 3.4 Hz, 1 H), 7.6 (br. dd, J = 2.1, 7.7 Hz, 1 H), 7.77 (d, J
= 8.1 Hz, 1 H), 8.22 (dd, J = 1.6, 8.1 Hz, 1 H), 8.70 (d, J = 1.6 Hz,
1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 52.7 (q), 84.5 (s), 100.4
Compound 3ai: Yellow liquid, 68% yield. 1H NMR (200 MHz,
CDCl3): δ = 2.42 (s, 1 H), 4.74 (s, 2 H), 5.03 (s, 2 H), 6.97–7.12
(m, 2 H), 7.26–7.36 (m, 2 H), 7.42–7.52 (m, 1 H), 7.55–7.61 (m, 2
H), 8.03 (dd, J = 7.7, 1.2 Hz, 1 H) ppm. 13C NMR (50 MHz, (s), 121.7 (s), 122.7 (s), 125.7 (d), 128.5 (d, 2 C), 129.7 (d), 130.1
CDCl3): δ = 56.65 (t), 61.46 (t), 82.40 (s), 91.58 (s), 111.97 (d),
(s), 132.1 (d, 2 C), 133.1 (d), 134.6 (d), 149.3 (s), 164.5 (s) ppm. IR
117.38 (s), 121.58 (d), 124.53 (d), 128.77 (d), 128.81 (d), 129.15 (d), (CHCl ): ν = 3022, 2924, 2400, 1728, 1617, 1557, 1532, 1437, 1345,
˜
3
5962
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© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5955–5966

Pd-Mediated Cycloisomerization of o-Alkynylnitrobenzenes to Isatogens
1286, 1115, 1026, 756 cm–1. C16H11NO4 (281.27): calcd. C 68.32,
H 3.94, N 4.98; found C 68.28, H 3.81, N 4.93.
2953, 2400, 1743, 1610, 1527, 1438, 1345, 1296, 1262, 1215, 1152,
1083, 910, 756 cm–1. C16H11NO4 (281.27): calcd. C 68.32, H 3.94,
N 4.98; found C 68.27, H 3.84, N 4.91.
Compound 3em:[14d] Brick-red spongy mass, 78% yield. M.p.
1
161 °C. H NMR (200 MHz, CDCl3): δ = 3.84 (s, 3 H), 6.89 (br.
General Procedure for the Cycloisomerization: Pd(CH3CN)2Cl2
(0.025 mmol, 5 mol-%) was added to a solution of an alkyne 3
(0.5 mmol) in CH3CN (15 mL), and the mixture was stirred under
argon at room temp. for 4 h. The reaction mixture was concen-
trated, and the residue obtained was purified by column
chromatography (ethyl acetate in petroleum ether) to afford a com-
pound 1.
dt, J = 9.1, 2.5 Hz, 2 H), 7.42 (ddd, J = 1.6, 7.3, 8.2 Hz, 1 H),
7.50–7.55 (m, 2 H), 7.59 (dd, J = 7.3, 1.5 Hz, 1 H), 7.68 (dd, J =
7.7, 1.5 Hz, 1 H), 8.07 (dd, J = 8.2, 1.2 Hz, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 55.2 (q), 83.9 (s), 97.7 (s), 114.1 (d, 2 C),
114.4 (s), 119.2 (s), 124.7 (d), 127.9 (d), 132.6 (d), 133.6 (d, 2 C),
134.3 (d), 149.4 (s), 160.4 (s) ppm. IR (CHCl ): ν = 3019, 2936,
˜
3
2400, 1720, 1611, 1600, 1567, 1523, 1464, 1439, 1342, 1288, 1251,
1080, 1029, 833, 756 cm–1. C15H11NO3 (253.26): calcd. C 71.14, H
4.38, N 5.53; found C 71.31, H 4.31, N 5.47.
Compound 1aa: Yellow syrup, 69% yield. 1H NMR (200 MHz,
CDCl3): δ = 0.89 (t, J = 7.0 Hz, 3 H), 1.31–1.40 (m, 4 H), 1.63–
1.71 (m, 2 H), 2.67 (t, J = 7.4 Hz, 2 H), 7.50–7.56 (m, 2 H), 7.60–
7.66 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 13.8 (q), 21.3
(t), 22.3 (t), 25.1 (t), 31.7 (t), 113.7 (d), 121.3 (d), 123.1 (s), 125.5
Compound 3fm: Red spongy mass, 75% yield. 1H NMR (200 MHz,
CDCl3): δ = 1.33 (s, 9 H), 7.38–7.45 (m, 3 H), 7.48–7.63 (m, 3 H),
7.72 (dd, J = 7.7, 1.6 Hz, 1 H), 8.08 (dd, J = 8.0, 1.3 Hz, 1 H) ppm.
(s), 130.9 (d), 134.3 (d), 147.4 (s), 186.8 (s) ppm. IR (CHCl ): ν =
˜
3
13C NMR (50 MHz, CDCl3): δ = 31.1 (q, 3 C), 34.8 (s), 84.2 (s), 3019, 2958, 2930, 1711, 1695, 1607, 1588, 1528, 1466, 1353, 1322,
97.4 (s), 118.9 (s), 119.3 (s), 124.6 (d), 125.4 (d, 2 C), 128.3 (d),
131.7 (d, 2 C), 132.7 (d), 134.5 (d), 141.8 (s), 152.6 (s) ppm. IR
1297, 1216, 1180, 1056, 755 cm–1. C13H15NO2 (217.27): calcd. C
71.87, H 6.96, N 6.45; found C 71.76, H 6.91, N 6.40.
(CHCl ): ν = 3020, 2960, 2400, 1603, 1568, 1526, 1476, 1346, 1293,
˜
3
Compound 2aa: AuBr3 (10 mg, 0.023 mmol, 5 mol-%) was added to
a solution of the alkyne 3aa (100 mg. 0.46 mmol) in CH3CN
(15 mL) and the mixture was stirred under argon at room temp.
1215, 1105, 1022, 837, 757 cm–1. C18H17NO2 (279.34): calcd. C
77.40, H 6.13, N 5.01; found C 77.29, H 6.24, N 4.92.
Compound 3gm:[14e] Orange spongy mass, 65% yield. 1H NMR for 4 h. The reaction mixture was concentrated, and the residue
(200 MHz, CDCl3): δ = 7.56 (ddd, J = 1.7, 7.3, 8.0 Hz, 1 H), 7.67
(dt, J = 1.5, 7.7 Hz, 1 H), 7.72–7.79 (m, 3 H), 8.15 (dd, J = 8.1,
1.3 Hz, 1 H), 8.25 (dt, J = 9.0, 2.1 Hz, 2 H) ppm. 13C NMR
obtained was purified by column chromatography (5% Ǟ 10%
ethyl acetate in petroleum ether) to afford 2aa (75 mg, 75%) as a
yellow oil. H NMR (400 MHz, CDCl3): δ = 0.93 (t, J = 6.9 Hz,
1
(50 MHz, CDCl3): δ = 89.4 (s), 94.3 (s), 117.5 (s), 123.6 (d, 2 C), 3 H), 1.36–1.45 (m, 4 H), 1.76–1.90 (m, 2 H), 3.17 (t, J = 7.4 Hz,
124.9 (d), 128.1 (s), 129.1 (s), 129.6 (d), 132.7 (d, 2 C), 133.1 (d),
2 H), 7.27 (ddd, J = 1.0, 6.4, 8.7 Hz, 1 H), 7.40 (ddd, J = 1.0, 6.4,
8.9 Hz, 1 H),7.73 (dt, J = 1.0, 8.8 Hz, 1 H), 8.05 (dt, J = 1.0,
8.8 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 13.9 (q), 22.4
(t), 23.2 (t), 31.3 (t), 40.1 (t), 115.9 (d), 119.1 (s), 121.2 (d), 128.4
134.7 (d), 147.5 (s) ppm. IR (CHCl ): ν = 2985, 2400, 1608, 1596,
˜
3
1447, 1373, 1276, 1215, 1017, 909, 759 cm–1. C14H8N2O4 (268.23):
calcd. C 62.69, H 3.01, N 10.44; found C 62.62, H 3.09, N 10.39.
(d), 131.2 (d), 157.5 (s), 159.7 (s), 190.5 (s) ppm. IR (CHCl ): ν =
˜
3
Compound 3hm: Orange spongy mass, 62% yield. 1H NMR
(200 MHz, CDCl3): δ = 7.58 (dt, J = 7.9, 1.4 Hz, 2 H), 7.69 (dd, J
= 7.3, 1.4 Hz, 1 H), 7.77 (dd, J = 7.7, 1.4 Hz, 1 H), 7.91 (dt, J =
1.2, 7.7 Hz, 1 H), 8.15 (dd, J = 1.1, 8.2 Hz, 1 H), 8.25 (ddd, J =
1.0, 2.2, 8.3 Hz, 1 H), 8.43 (t, J = 1.7 Hz, 1 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 86.9 (s), 93.9 (s), 117.6 (s), 123.8 (d), 124.2
(s), 124.9 (d), 126.6 (d), 129.4 (d), 129.5 (d), 133.1 (d), 134.7 (d),
3022, 2958, 2932, 1732, 1608, 1568, 1527, 1480, 1480, 1345, 1216,
851, 757, 668 cm–1. C13H15NO2 (217.27): calcd. C 71.87, H 6.96, N
6.45; found C 71.61, H 7.08, N 6.40.
Compound 1ab: Yellow liquid, 71% yield. 1H NMR (200 MHz,
CDCl3): δ = –0.05 (s, 6 H), 0.80 (s, 9 H), 1.81–1.94 (m, 2 H), 2.71
(t, J = 7.4 Hz, 2 H), 3.65 (t, J = 5.9 Hz, 2 H), 7.44–7.51 (m, 2 H),
7.55–7.60 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = –5.5 (q,
2 C), 18.2 (s), 18.6 (t), 25.8 (q, 3 C), 28.3 (t), 62.8 (t), 113.6 (d),
121.3 (d), 123.2 (s), 125.5 (s), 130.8 (d), 134.2 (d), 147.5 (s), 186.7
137.7 (d), 148.1 (s), 149.6 (s) ppm. IR (CHCl ): ν = 3019, 2956,
˜
3
2400, 1603, 1596, 1524, 1479, 1465, 1373, 1359, 1242, 1097, 1047,
938, 738 cm–1. C14H8N2O4 (268.23): calcd. C 62.69, H 3.01, N
10.44; found C 62.60, H 3.11, N 10.36.
(s) ppm. IR (CHCl ): ν = 2954, 2929, 2885, 1709, 1684, 1634, 1557,
˜
3
1520, 1471, 1465, 1445, 1345, 1276, 1255, 1194, 1143, 1101, 1006,
980, 836, 776 cm–1. C17H25NO3Si (319.48): calcd. C 63.91, H 7.89,
N 4.38; found C 63.81, H 7.72, N 4.32.
Compound 3im: Red solid, 55% yield. M.p. 95 °C. 1H NMR
(200 MHz, CDCl3): δ = 7.28–7.32 (m, 1 H), 7.53 (tt, J = 7.8, 1.5 Hz,
1 H), 7.62–7.66 (m, 2 H), 7.73 (tt, J = 7.7, 1.7 Hz, 1 H), 7.80–7.82
(m, 1 H), 8.12 (d, J = 8.0 Hz, 1 H), 8.66 (d, J = 4.2 Hz, 1 H) ppm. Compound 1ac: Dark brown gum, 43% yield. 1H NMR (200 MHz,
13C NMR (100 MHz, CDCl3): δ = 84.1 (s), 95.5 (s), 117.7 (s), 123.5 CDCl3): δ = 1.25–1.35 (m, 22 H), 1.50–1.69 (m, 5 H), 2.66 (t, J =
(d), 124.7 (d), 127.9 (d), 129.3 (d), 132.9 (d), 134.9 (d), 136.2 (d),
7.5 Hz, 2 H), 3.64 (t, J = 6.6 Hz, 2 H), 7.51–7.66 (m, 4 H) ppm.
13C NMR (50 MHz, CDCl3): δ = 21.4 (t), 25.4 (t), 25.7 (t), 29.2
(t), 29.4 (t, 2 C), 29.6 (t, 6 C), 29.7 (t), 32.8 (t), 63.1 (t), 113.7 (d),
142.6 (s), 149.7 (s), 150.1 (d) ppm. IR (CHCl ): ν = 3032, 2958,
˜
3
2233, 1632, 1608, 1568, 1527, 1480, 1467, 1345, 1216, 1145, 851,
757 cm–1. C13H8N2O2 (224.22): calcd. C 69.64, H 3.60, N 12.49; 121.3 (d), 123.1 (s), 125.6 (s), 130.9 (d), 134.3 (d), 147.4 (s), 186.9
found C 69.69, H 3.72, N 12.41.
(s) ppm. IR (CHCl ): ν = 3381, 2920, 2851, 1705, 1607, 1531, 1475,
˜
3
1385, 1185, 1058, 755 cm–1. C23H35NO3 (373.53): calcd. C 73.96,
Compound 3jm: Orange color solid, 85% yield. 1H NMR
(200 MHz, CDCl3): δ = 3.93 (s, 3 H), 7.45 (dt, J = 04, 7.8 Hz, 1
H), 7.47 (ddd, J = 1.6, 7.3, 8.1 Hz, 1 H), 7.61 (dt, J = 1.4, 7.7 Hz,
1 H), 7.71 (ddd, J = 0.4, 1.6, 7.3 Hz, 1 H), 7.76 (dd, J = 1.4, 7.7 Hz,
1 H), 8.09 (dd, J = 1.2, 8.1 Hz, 1 H), 8.03 (ddd, J = 1.2, 1.7, 7.8 Hz,
1 H), 8.23 (dt, J = 1.7, 0.5 Hz, 1 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 52.3 (q), 85.5 (s), 95.7 (s), 118.2 (s), 122.7 (s), 124.7
(d), 128.6 (d), 128.8 (d), 130.1 (d), 130.5 (s), 132.8 (d), 132.9 (d),
H 9.44, N 3.75; found C 73.88, H 9.34, N 3.71.
Compound 1ad: Dark brown spongy mass, 51% yield. 1H NMR
(200 MHz, CDCl3): δ = 3.54–3.60 (m, 2 H), 3.63–3.69 (m, 4 H),
3.73–3.78 (m, 2 H), 4.01 (dt, J = 5.7, 1.4 Hz, 2 H), 4.58 (s, 2 H),
5.18 (ddd, J = 10.4, 3.1, 1.3 Hz, 1 H), 5.27 (ddd, J = 17.2, 3.1,
1.3 Hz, 1 H), 5.90 (ddt, J = 17.2, 10.4, 5.7 Hz, 1 H), 7.51–7.63 (m,
2 H), 7.64–7.70 (m, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ =
58.9 (t), 69.4 (t), 70.3 (t), 70.5 (t), 71.4 (t), 72.2 (t), 112.2 (d), 117.1
134.6 (d), 136.0 (d), 149.4 (s), 166.1 (s) ppm. IR (CHCl ): ν = 3021,
˜
3
Eur. J. Org. Chem. 2010, 5955–5966
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5963

C. V. Ramana, P. Patel, K. Vanka, B. Miao, A. Degterev
FULL PAPER
(t), 119.0 (s), 123.5 (s), 123.9 (d), 125.8 (d), 134.8 (d), 138.6 (d),
1
Compound 1aj: Dark brown gum, 67% yield. H NMR (200 MHz,
149.1 (s), 182.9 (s) ppm. IR (CHCl ): ν = 3079, 2919, 2856, 1707,
CDCl3): δ = 3.08 (dd, J = 15.0, 4.0 Hz, 1 H), 3.24 (dd, J = 15.0,
8.0 Hz, 1 H), 3.84 (s, 9 H), 5.14 (dd, J = 8.0, 4.0 Hz, 1 H), 5.48 (s,
˜
3
1608, 1568, 1526, 1475, 1459, 1345, 1262, 1180, 1098, 928,
747 cm–1. C16H19NO5 (305.33): calcd. C 62.94, H 6.27, N 4.59; 1 H), 6.63 (s, 2 H), 7.50–7.65 (m, 4 H) ppm. 13C NMR (50 MHz,
found C 62.82, H 6.21, N 4.49.
CDCl3): δ = 31.8 (t), 56.1 (q, 2 C), 60.8 (q), 71.4 (d), 102.0 (d, 2
C), 114.0 (d), 121.9 (d), 122.8 (s), 131.4 (d), 134.7 (d), 136.8 (s),
137.1 (s), 138.8 (s), 147.2 (s), 153.2 (s, 2 C), 186.5 (s) ppm. IR
Compound 1ae: Yellow solid, 75% yield. M.p. 103 °C. [α]2D5 = +22.4
(c = 1, CHCl3). 1H NMR (200 MHz, CDCl3): δ = 0.11 (d, J =
1.3 Hz, 6 H), 0.89 (s, 9 H), 1.27 (d, J = 6.3 Hz, 3 H), 3.87–3.90 (m,
1 H), 4.31–4.42 (m, 1 H), 4.90 (d, J = 2.5 Hz, 1 H), 6.16 (s, 1 H),
7.57–7.69 (m, 4 H) ppm. 13C NMR (50 MHz, CDCl3): δ = –5.0
(q), –4.2 (q), 18.0 (s), 22.6 (q), 25.8 (q, 3 C), 41.8 (d), 62.8 (d), 64.5
(d), 114.1 (d), 121.9 (d), 123.1 (s), 131.9 (d), 134.6 (d), 146.8 (s),
(CHCl ): ν = 3436, 2929, 2898, 1707, 1603, 1593, 1538, 1506, 1463,
˜
3
1420, 1327, 1234, 1180, 1126, 769 cm–1. C19H19NO6 (357.36): calcd.
C 63.86, H 5.36, N 3.92; found C 63.79, H 5.31, N 3.88.
Compound 1ak: Pale gray solid, 78% yield. 1H NMR (200 MHz,
CDCl3): δ = 1.69 (s, 1 H), 3.07 (dd, J = 15.0, 4.1 Hz, 1 H), 3.21
(dd, J = 15.0, 8.1 Hz, 1 H), 3.77 (s, 3 H), 5.17 (dd, J = 8.1, 4.1 Hz,
1 H), 6.83–6.90 (m, 2 H), 7.31–7.38 (m, 2 H), 7.53–7.59 (m, 2 H),
7.62–7.67 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 31.9 (t),
55.2 (q), 70.8 (d), 113.8 (d, 2 C), 114.0 (d), 121.7 (d), 122.8 (s),
126.6 (d, 2 C), 131.2 (d), 134.6 (d), 135.3 (s), 136.8 (s), 147.2 (s),
167.7 (s), 185.2 (s) ppm. IR (CHCl ): ν = 3414, 3019, 2956, 2930,
˜
3
2885, 1770, 1712, 1672, 1609, 1570, 1529, 1472, 1377, 1346, 1215,
1180, 1144, 1065, 959, 756 cm–1. C19H26N2O4Si (374.51): calcd. C
60.93, H 7.0, N 7.48, Si 7.50; found C 60.81, H 7.2, N 7.34, Si 7.13.
Compound 1af: Orange oil. 65% yield. 1H NMR (200 MHz,
CDCl3): δ = 1.16 (s, 3 H), 1.57–1.84 (m, 3 H), 2.01–2.16 (m, 2 H),
2.69 (br. s, 1 H), 2.82 (dd, J = 5.8, 14.4 Hz, 1 H), 2.98 (dd, J = 7.3,
14.4 Hz, 1 H), 3.43–3.53 (m, 1 H), 3.60–3.69 (m, 2 H), 4.39–4.53
(m, 1 H), 7.47–7.76 (m, 4 H) ppm. 13C NMR (50 MHz, CDCl3): δ
= 24.0 (q), 29.7 (t), 32.2 (t), 32.4 (t), 63.1 (t), 76.0 (d), 76.6 (d), 85.0
(s), 113.9 (d), 121.5 (d), 123.0 (s), 127.6 (s), 132.2 (d), 134.4 (d),
159.1 (s), 186.5 (s) ppm. IR (CHCl ): ν = 3350, 3019, 2928, 1712,
˜
3
1664, 1611, 1514, 1494, 1464, 1345, 1215, 1174, 1056, 756 cm–1.
C17H15NO4 (297.31): calcd. C 68.68, H 5.09, N 4.71; found C
68.79, H 5.23, N 4.65.
Compound 1al:[4d,26a] Dark orange solid, 61% yield. M.p. 183 °C.
1H NMR (200 MHz, CDCl3): δ = 7.45–7.50 (m, 3 H), 7.53–7.57
(m, 1 H), 7.61–7.65 (m, 1 H), 7.67–7.70 (m, 2 H), 8.61–8.66 (m, 2
H) ppm. 13C NMR (125 MHz, CDCl3): δ = 114.2 (d), 121.5 (d),
122.9 (s), 125.9 (s), 127.8 (d, 2 C), 127.8 (s), 128.5 (d, 2 C), 130.7
147.3 (s), 186.6 (s) ppm. IR (CHCl ): ν = 3410, 2971, 2931, 1713,
˜
3
1608, 1559, 1527, 1463, 1376, 1217, 1174, 1089, 755 cm–1.
C16H19NO5 (305.33): calcd. C 62.99, H 6.27, N 4.59; found C
62.79, H 6.38, N 4.48.
(d), 131.1 (d), 134.7 (d), 147.9 (s), 186.7 (s) ppm. IR (CHCl ): ν =
˜
3
3054, 2986, 1702, 1601, 1569, 1527, 1512, 1496, 1422, 1374, 1265,
1178, 1046, 1029, 739, 705 cm–1. C14H9NO2 (223.23): calcd. C
75.33, H 4.06, N 6.27; found C 75.53, H 4.16, N 6.13.
Compound 1bl: Orange solid, 91% yield. M.p. 143 °C. 1H NMR
(200 MHz, CDCl3): δ = 7.29–7.35 (m, 2 H), 7.48–7.51 (m, 3 H),
7.67 (dd, J = 9.0, 3.9 Hz, 1 H), 8.57–8.62 (m, 2 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 109.66 (d, JCβ,F = 26.4 Hz), 115.92 (d, JCγ,F
= 8.6 Hz), 120.6 (d, JCβ,F = 26.4 Hz), 124.8 (s, JCγ,F = 8.6 Hz),
125.6 (s), 127.5 (d, 2 C), 128.5 (d, 2 C), 128.5 (s), 130.8 (d), 143.2
(s, JCδ,F = 2.0 Hz) 164.3 (s, J = 253.9 Hz), 185.4 (s, JCδ,F = 1.9 Hz)
Compound 1ag: Brown syrup. 83% yield. [α]2D5 = –18.5 (c = 1,
CHCl3). H NMR (400 MHz, CDCl3): δ = 1.38 (s, 3 H), 1.53 (s, 3
1
H), 4.40 (d, J = 4.5 Hz, 1 H), 4.43 (d, J = 13.1 Hz, 1 H), 4.63 (d,
J = 12.1 Hz, 1 H), 4.77 (d, J = 3.9 Hz, 1 H), 5.65 (d, J = 4.5 Hz,
1 H), 6.21 (d, J = 3.9 Hz, 1 H), 7.04–7.13 (m, 5 H), 7.54–7.58 (m,
3 H), 7.63 (dd, J = 1.5, 7.7 Hz, 1 H) ppm. 13C NMR (100 MHz,
CDCl3): δ = 26.7 (q), 27.3 (q), 72.5 (t), 74.7 (d), 83.2 (d), 83.7 (d),
105.8 (d), 112.7 (s), 113.9 (d), 121.7 (d), 123.4 (s), 127.3 (d, 2 C),
127.7 (d), 128.3 (d, 2 C), 131.5 (d), 134.1 (d), 134.3 (s), 137.0 (s),
146.6 (s), 184.2 (s) ppm. IR (CHCl ): ν = 3054, 2987, 2685, 1711,
˜
3
1606, 1575, 1502, 1421, 1265, 1165, 1061, 896, 739, 705 cm–1.
C22H21NO6 (395.41): calcd. C 66.83, H 5.35, N 3.54; found C
66.85, H 5.45, N 3.47.
ppm. IR (CHCl ): ν = 3032, 2998, 1704, 1597, 1523, 1481, 1446,
˜
3
1385, 1283, 1181, 1020, 875, 758, 685 cm–1. C14H8FNO2 (241.22):
calcd. C 69.71, H 3.34, F 7.88, N 5.81; found C 69.63, H 3.41, F
7.72, N 5.78.
Compound 1ah: Yellow oil, 87% yield. [α]2D5 = –12.8 (c = 1, CHCl3).
1H NMR (200 MHz, CDCl3): δ = 1.31 (s, 3 H), 1.45 (s, 3 H), 2.95
(dd, J = 15.3, 8.8 Hz, 1 H), 3.16 (dd, J = 15.3, 3.6 Hz, 1 H), 3.58
(br. s, 1 H), 4.08 (dd, J = 7.7, 3.2 Hz, 1 H), 4.16 (d, J = 3.2 Hz, 1
H), 4.57–4.75 (m, 3 H), 5.93 (d, J = 6.6 Hz, 1 H), 7.31–7.38 (m, 5
H), 7.51–7.66 (m, 4 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 26.3
(q), 26.7 (q), 27.7 (t), 66.9 (d), 72.2 (t), 81.6 (d), 82.3 (d), 82.5 (d),
105.1 (d), 111.8 (s), 113.9 (d), 121.7 (d), 123.0 (s), 127.9 (d, 2 C),
128.1 (d), 128.6 (d, 2 C), 131.2 (d), 134.5 (d), 137.1 (s), 137.2 (s),
Compound 1cl:[4d] Red solid, 67% yield. M.p. 176 °C. 1H NMR
(200 MHz, CDCl3): δ = 6.14 (s, 2 H), 7.02 (s, 1 H), 7.16 (s, 1 H),
7.43–7.51 (m, 3 H), 8.57–7.61 (m, 2 H) ppm. 13C NMR (50 MHz,
CDCl3): δ = 97.3 (d), 102.1 (d), 103.1 (t), 116.5 (s), 125.9 (s), 127.4
(d, 2 C), 128.4 (d, 2 C), 128.6 (s), 130.3 (d), 144.6 (s), 149.6 (s),
152.7 (s), 185.8 (s) ppm. IR (CHCl ): ν = 3100, 3090, 2917, 1702,
˜
3
1632, 1587, 1505, 1489, 1445, 1390, 1350, 1277, 1168, 1029, 919,
775 cm–1. C15H9NO4 (267.24): calcd. C 67.42, H 3.39, N 5.24;
found C 67.37, H 3.42, N 5.20.
Compound 1dl: Orange color solid, 87% yield. M.p. 150 °C. 1H
NMR (200 MHz, CDCl3): δ = 3.99 (s, 3 H), 7.48–7.51 (m, 3 H),
7.70 (d, J = 7.4 Hz, 1 H), 8.26 (dd, J = 1.3, 7.6 Hz, 1 H), 8.29 (br.
s, 1 H), 8.60–8.64 (m, 2 H) ppm. 13C NMR (50 MHz, CDCl3): δ =
52.9 (q), 114.9 (d), 121.4 (d), 125.5 (s), 125.9 (s), 127.8 (d, 2 C),
128.6 (d, 2 C), 128.6 (s), 131.0 (d), 133.0 (d), 136.2 (s), 147.6 (s),
186.5 (s) ppm. IR (CHCl ): ν = 3370, 3019, 2930, 1712, 1685, 1606,
˜
3
1555, 1535, 1454, 1438, 1216, 1174, 1076, 1012, 756 cm–1.
C24H25NO7 (439.46): calcd. C 65.59, H 5.73, N 3.19; found C
65.41, H 5.69, N 3.14.
Compound 1ai: Yellow liquid, 67% yield. 1H NMR (200 MHz,
CDCl3): δ = 1.68 (br. s, 1 H), 4.66 (s, 2 H), 5.19 (s, 2 H), 6.93–7.06
(m, 2 H), 7.24–7.28 (m, 2 H), 7.56–7.71 (m, 4 H) ppm. 13C NMR
(50 MHz, CDCl3): δ = 56.2 (t), 61.9 (t), 111.5 (d), 114.4 (d), 121.8
(d), 122.0 (d), 122.8 (s), 129.0 (d), 129.5 (d), 130.1 (s), 132.1 (d),
133.5 (s), 134.7 (d), 146.8 (s), 155.6 (s), 185.4 (s) ppm. IR (CHCl3):
164.8 (s), 185.9 (s) ppm. IR (CHCl ): ν = 3084, 3031, 2955, 1746,
˜
3
1709, 1596, 1577, 1475, 1460, 1379, 1352, 1284, 1185, 1068, 910,
807, 760 cm–1. C16H11NO4 (281.27): calcd. C 68.32, H 3.94, N 4.98;
found C 68.28, H 3.81, N 4.93.
Compound 1em:[4d,6,26e,26f] Red solid, 67% yield. M.p. 160 °C. 1H
NMR (400 MHz, CDCl3): δ = 3.86 (s, 3 H), 7.00 (dt, J = 9.5,
ν = 3431, 2923, 2852, 1705, 1655, 1608, 1588, 1530, 1487, 1458,
˜
1348, 1295, 1231, 1173, 1037, 756 cm–1. C16H13NO4 (283.28): calcd.
C 67.84, H 4.63, N 4.94; found C 67.79, H 4.69, N 4.83.
5964
www.eurjoc.org
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2010, 5955–5966

Pd-Mediated Cycloisomerization of o-Alkynylnitrobenzenes to Isatogens
2.3 Hz, 2 H), 7.46–7.51 (m, 1 H), 7.57–7.64 (m, 3 H), 8.70 (dt, J =
9.5, 2.3 Hz, 2 H) ppm. 13C NMR (400 MHz, CDCl3): δ = 55.3 (q),
113.9 (d), 114.1 (d, 2 C), 118.8 (s), 121.5 (d), 122.8 (s), 124.8 (s),
and Technology for funding through the Department of Science
and Technology under the Green Chemistry Program (No. SR/S5/
GC-20/2007). P. P. thanks the University Grants Commission
129.7 (d, 2 C), 130.7 (s), 134.8 (d), 148.0 (d), 161.3 (s), 187.3 (s) (UGC) (New Delhi) for the financial assistance in the form of a
ppm. IR (CHCl ): ν = 3054, 2958, 1709, 1615, 1540, 1520, 1496, research fellowship.
˜
3
1374, 1270, 1180, 1046, 745 cm–1. C15H11NO3 (253.26): calcd. C
71.14, H 4.38, N 5.53; found C 71.31, H 4.31, N 5.47.
[1]
[2]
a) A. Baeyer, Ber. Dtsch. Chem. Ges. 1881, 14, 1741–1746; b)
A. Baeyer, Ber. Dtsch. Chem. Ges. 1882, 15, 50–61.
Compound 1fm: Crimson-red solid, 91% yield. M.p. 130 °C. 1H
NMR (200 MHz, CDCl3): δ = 1.36 (s, 9 H), 7.50–7.57 (m, 3 H),
7.61–7.65 (m, 1 H), 7.67–7.70 (m, 2 H), 8.59 (dt, J = 8.8, 2.1 Hz,
2 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 30.9 (q, 3 C), 34.9 (s),
113.9 (d), 121.4 (d), 122.7 (s), 122.9 (s), 125.3 (s), 125.5 (d, 2 C),
127.6 (d, 2 C), 130.9 (d), 134.7 (d), 147.8 (s), 154.1 (s), 186.9 (s)
For reviews on the preparation of isatogens, see: a) S. P. Hirem-
ath, M. Hooper, Adv. Heterocycl. Chem. 1978, 22, 123–181; b)
P. N. Preston, G. Tennant, Chem. Rev. 1972, 72, 627–677.
a) P. Pfeifer, S. Braude, R. Fritsch, W. Halherstadt, G. Kirch-
huff, J. Kleber, P. Witllcop, Justus Liebigs Ann. Chem. 1916, 72,
411; b) F. Krohnke, M. Meyer-Delius, Chem. Ber. 1951, 84,
932; c) J. S. Splitter, M. Calvin, J. Org. Chem. 1955, 20, 1086–
1115; d) M. Hooper, D. G. Wibberley, J. Chem. Soc. C 1969,
1596–1600; e) C. C. Bond, M. Hooper, J. Chem. Soc. C: Org.
1969, 2453–2460; f) T. H. C. Bristow, H. E. Foster, M. Hooper,
J. Chem. Soc., Chem. Commun. 1974, 677–678; g) C. C. Bond,
M. Hooper, Synthesis 1974, 443; h) C.-S. Chien, T. Takanami,
T. Kawasaki, M. Sakamoto, Chem. Pharm. Bull. 1985, 33,
1843–1848.
a) E. K. Beak, Y. S. Chae, S. C. Shim, Bull. Kor. Chem. Soc.
1996, 17, 993–994; b) J. Boyer, V. Bernardes-Genisson, V. Far-
ines, J.-P. Souchard, F. Nepveu, Free Radical Res. 2004, 38,
459–471; c) E. Pudziuvelyte, C. Ríos-Luci, L. G. León, I. Ciko-
tiene, J. Padrón, M. Bioorg. Med. Chem. 2009, 17, 4955–4960;
d) F. Nepveu, S. Kim, J. Boyer, O. Chatriant, H. Ibrahim, K.
Reybier, M.-C. Monje, S. Chevalley, P. Perio, B. H. Lajoie, J.
Bouajila, E. Deharo, M. Sauvain, R. Tahar, L. Basco, A. Pan-
taleo, F. Turini, P. Arese, A. Valentin, E. Thompson, L. Vivas,
S. Petit, J.-P. Nallet, J. Med. Chem. 2010, 53, 699–714.
For a one-pot Sonogashira/nitro–alkyne cycloisomerization
(base-mediated under thermal conditions) limited to diaryl isa-
togens, see: a) G. M. Rosen, P. Tsai, E. D. Barth, G. D. Dorey,
P. Casara, M. Spedding, H. J. Halpern, J. Org. Chem. 2000, 65,
4460–4463. During the final stages of the preparation of this
manuscript, Pd(PPh)3Cl2- and AgNO3/NIS-mediated cycliza-
tion of o-nitroarylalkynyl halides leading to 2-haloisatogens
was documented: b) B. C. G. Söderberg, S. P. Gorugantula,
C. R. Howerton, J. L. Petersen, S. W. Dantale, Tetrahedron
2009, 65, 7357–7363; c) ref.[4d]
[3]
ppm. IR (CHCl ): ν = 3065, 2951, 1702, 1596, 1529, 1494, 1461,
˜
3
1377, 1320, 1284, 1184, 1024, 878, 839, 756 cm–1. C18H17NO2
(279.34): calcd. C 77.40, H 6.13, N 5.01; found C 77.29, H 6.24, N
4.92.
Compound 1gm:[4d,26d] Orange solid, 69% yield. M.p. 237 °C. 1H
NMR (200 MHz, CDCl3): δ = 7.58–7.69 (m, 2 H), 7.72–7.76 (m, 2
H), 8.33 (dt, J = 8.3, 2.1 Hz, 2 H), 8.89 (dt, J = 8.3, 2.1 Hz, 2 H)
ppm. 13C NMR (125 MHz, CDCl3): δ = 114.6 (d), 122.1 (d), 122.6
(s), 123.7 (d, 2 C), 123.9 (s), 128.2 (d, 2 C), 131.6 (s), 132.2 (d),
[4]
135.3 (d), 147.7 (s), 147.9 (s), 186.2 (s) ppm. IR (CHCl ): ν = 3019,
˜
3
3002, 1706, 1655, 1595, 1517, 1484, 1388, 1347, 1215, 1180, 1019,
756 cm–1. C14H8N2O4 (268.23): calcd. C 62.69, H 3.01, N 10.44;
found C 62.60, H 3.11, N 10.36.
Compound 1hm:[26d] Dark yellow solid, 56% yield. M.p. 240 °C. 1H
NMR (200 MHz, CDCl3): δ = 7.60–7.77 (m, 5 H), 8.32 (ddd, J =
0.9, 2.1, 8.3 Hz, 1 H), 9.0 (dd, J = 0.9, 1.5, 7.9 Hz, 1 H), 9.61 (t, J
= 1.9 Hz, 1 H) ppm. 13C NMR (100 MHz, CDCl3): δ = 114.6 (d),
122.1 (d), 122.3 (d), 122.6 (s), 124.8 (d), 127.3 (s), 128.0 (s), 129.6
(d), 131.9 (d), 132.9 (d), 135.2 (d), 147.6 (s), 148.3 (s), 186.1 (s)
[5]
ppm. IR (CHCl ): ν = 3020, 2927, 1711, 1619, 1595, 1529, 1469,
˜
3
1317, 1216, 1175, 1093, 754 cm–1. C14H8N2O4 (268.23): calcd. C
62.69, H 3.01, N 10.44; found C 62.60, H 3.11, N 10.36.
Compound 1im:[26b,26c] Red solid, 55% yield. M.p. 162 °C. 1H NMR
(500 MHz, CDCl3): δ = 7.35 (ddd, J = 0.4, 4.7, 7.5 Hz, 1 H), 7.61
(dt, J = 0.9, 7.3 Hz, 1 H), 7.71 (d, J = 7.1 Hz, 2 H), 7.73–7.76 (m,
1 H), 7.86 (dt, J = 7.8, 1.7 Hz, 1 H), 8.48 (d, J = 8.0 Hz, 1 H), 8.88
(d, J = 4.1 Hz, 1 H) ppm. 13C NMR (125 MHz, CDCl3): δ = 114.6
(d), 121.9 (d), 122.8 (s), 124.3 (d), 124.9 (d), 128.3 (s), 131.9 (d),
134.7 (d), 136.4 (d), 145.6 (s), 147.6 (s), 150.4 (d), 185.1 (s) ppm.
[6]
[7]
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IR (CHCl ): ν = 3084, 3031, 1708, 1596, 1519, 1485, 1459, 1376,
˜
3
1272, 1184, 1091, 871, 751 cm–1. C13H8N2O2 (224.22): calcd. C
69.64, H 3.60, N 12.49; found C 69.69, H 3.72, N 12.41.
Compound 1jm: Yellow solid, 75% yield. M.p. 183 °C. 1H NMR
(200 MHz, CDCl3): δ = 3.97 (s, 3 H), 7.55–7.61 (m, 2 H), 7.63–
7.65 (m, 1 H), 7.68–7.73 (m, 2 H), 8.14 (ddd, J = 1.1, 1.6, 7.8 Hz,
1 H), 8.82 (ddd, J = 1.1, 1.6, 8.1 Hz, 1 H), 9.30 (dt, J = 1.7, 0.5 Hz,
1 H) ppm. 13C NMR (50 MHz, CDCl3): δ = 52.3 (q), 114.3 (d),
121.7 (d), 122.6 (s), 126.0 (s), 128.7 (d, 3 C), 130.5 (s), 131.3 (s),
131.4 (d, 2 C), 131.7 (d), 134.9 (d), 147.6 (s), 166.4 (s), 186.5 (s)
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˜
3
1519, 1485, 1434, 1376, 1298, 1272, 1184, 1091, 871, 751 cm–1.
C16H11NO4 (281.27): calcd. C 68.32, H 3.94, N 4.98; found C
68.27, H 3.84, N 4.91.
Acknowledgments
We thank the Center for Excellence in Scientific Computing
(COESC, NCL, Pune), and C. V. R. thanks the Ministry of Science
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Eur. J. Org. Chem. 2010, 5955–5966
© 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
5965

C. V. Ramana, P. Patel, K. Vanka, B. Miao, A. Degterev
FULL PAPER
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Received: May 28, 2010
Published Online: August 27, 2010
5966
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Eur. J. Org. Chem. 2010, 5955–5966