Chameleonic reactivity of vicinal diazonium salt of acetylenyl-9,10- anthraquinones: Synthetic application toward two heterocyclic targets

Article abstract of DOI:10.1021/jo2014214

The nature of products in the diazotization of 1-amino-2-acetylenyl-9,10- anthraquinones strongly depends on the nature of substituents at both the alkyne and at the anthraquinone core. Donor substitution (NHAr, OH) at the fourth position stabilizes the d

Full text of DOI:10.1021/jo2014214

ARTICLE
pubs.acs.org/joc
Chameleonic Reactivity of Vicinal Diazonium Salt of
Acetylenyl-9,10-anthraquinones: Synthetic Application
toward Two Heterocyclic Targets
A. A. Stepanov,† L. M. Gornostaev,‡ S. F. Vasilevsky,*,† E. V. Arnold,‡ V. I. Mamatyuk,§ D. S. Fadeev,§
B. Gold,^ and I. V. Alabugin*,^
†Institute of Chemical Kinetics and Combustion and §N. N. Vorozhtsov Novosibirsk Institute of Organic Chemistry,
Siberian Branch of the Russian Academy of Sciences, Novosibirsk 630090, Russian Federation
‡Department of Chemistry, Krasnoyarsk State Pedagogical University, Krasnoyarsk 660049, Russian Federation
^Department of Chemistry and Biochemistry, Florida State University, Tallahassee, Florida 32306, United States
S Supporting Information
b
ABSTRACT: The nature of products in the diazotization of
1-amino-2-acetylenyl-9,10-anthraquinones strongly depends
on the nature of substituents at both the alkyne and at the
anthraquinone core. Donor substitution (NHAr, OH) at the
fourth position stabilizes the diazonium salt at C1, decelerating
electrophilic cyclization at the arylethynyl substituent at C2.
This effect allows the replacement of the diazonium with azide
group and subsequent closure into isoxazole ring with preservation of the alkyne. In contrast, electrophilic 5-exo-dig cyclizations to
condensed pyrazoles is observed for the combination of donor substituents at the aryl alkyne moiety and an OAc substituent at C4.
The latter process provides a new synthetic route to 3-ethynyl-[1,9-cd]isoxazol-6-ones that are difficult to access otherwise. DFT
calculations suggest that donor substituents have only a minor effect on alkyne and diazonium polarization in the reactant but
provide specific transition state stabilization by stabilizing the incipient vinyl cation. This analysis provides the first computational
data on electrophilic 5-exo-dig cyclization in its parent form and the nucleophile-promoted version. This cyclization is a relatively fast
but endothermic process that is rendered thermodynamically feasible by the enol-keto tautomerization with concomitant
aromatization in the five-membered heteroaromatic ring. Computations suggest that the importance of nucleophilic assistance
in the transition state for a relatively weak nucleophile such as water is minor because the energy gain due to the Lewis base
coordination to the carbocationic center is more than compensated for by the unfavorable entropic term for the bimolecular proces.
’ INTRODUCTION
recyclization of the amine to naphtho[2,3-g]indole-6,11-diones
instead of the desired acetylenylisoxazoles (Scheme 1).
Synthetic transformations of plant metabolites constitute an
important direction of medicinal chemistry.1 Since hybrid mol-
ecules that combine two structural units of different nature lend
themselves well to rational structural design and often possess
high biological activity,2 a number of hybrids are described in
the literature such as steroidꢀantibiotic,3 steroidꢀnucleoside,4
triterpenoidꢀpeptide,5 DNA-cleaving agentꢀamino acid,6 etc.
In this work, we report a successful approach to bioconjugates
that combine acetylenic derivatives known to have anticancer
activity7 and condensed anthraquinoid cycles, capable of inter-
calating DNA duplex.8
Earlier we have described an attempt to prepare such hybrids
via cross-coupling of independently prepared 3-haloisoxazolan-
thrones 1a,b either with terminal alkynes in the presence of
Pd(PPh3)2Cl2 and CuI or with copper acetylides.9 However,
these commonly used synthetic approaches proved to be in-
applicable for this target: in the catalytic version the isoxazole ring
opened with the formation of 4-aryl-1-amino-2-(phenylethynyl)-
anthracene-9,10-diones, whereas the acetylide process led to
Considering these difficulties, we designed an alternative
approach (Scheme 2): preparation of vic-acetylenylamino-9,10-
anthraquinones 2aꢀd, amine-azide transformation via the inter-
mediate diazonium salts, and subsequent cyclizations of the peri-
azido 2-acetylenyl-9,10-anthraquinones 3aꢀd into the target
5-NHAr-3-R-ethynyl-6H-anthra[1,9-cd]isoxazol-6-ones 4aꢀd (vide
infra). This approach was based on the early precedent for the
formation of polycyclic isoxazoles from peri-azido anthraquinones10
as well as the literature report of preparation of simple aromatic
azides with vicinal ethynyl moiety.11
However, success of the above approach has not been, a priori,
guaranteed because vic-acetylenylanthranyl diazonium salts were
also known to form either the respective condensed diazines12
or annealed pyrazoles.13 We supposed that the fast diazonium f
azide exchange via quick addition of sodium azide to the
Received: July 8, 2011
Published: September 12, 2011
r
2011 American Chemical Society
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Scheme 1. Earlier Attempts To Prepare Isoxazoles via Cross-Coupling Chemistrya
a Reagents and conditions: (i) CuCtCPh, Py, 115ꢀ C; (ii) HCtCPh, C6H6, Et3N, Pd(PPh3)2Cl2, PPh3, CuI, 45-50ꢀ C; (iii) DMF, CuI, 155ꢀ C.
acetylenes of 9,10-anthraquinone family, in particular the deri-
vatives containing a hydroxyl group at the fourth position of the
ring. The requisite substrates are available in 64ꢀ76% via
Sonogashira cross-coupling of aryl acetylenes with 1-amino-2-
bromo-4-hydroxyanthracene-9,10-dione (Scheme 3).
Scheme 2. Synthesis of 3-R-Ethynyl-6H-anthra[1,9-
cd]isoxazol-6-ones 4aꢀe and Numeration of Substituent
Positions in the Anthraquinone Moiety of Diazonium Salts
Because diazotization of 4-hydroxy derivatives 5aꢀe was
accompanied by decomposition, we have protected the OH group
via acylation. Interestingly, reaction of 5aꢀe with acetic anhy-
dride in pyridine proceeded selectively at the hydroxyl group,
even in the presence of the amine functionality.15
Diazotization of acetates 6aꢀcwith nitrosylsulfuric acid (method a)
with subsequent treatment of the diazonium salt solution with
sodium azide yielded azides 7aꢀc (Scheme 4). Deazotization
was accompanied by deacetylation; the acyl group was absent in
the products. These azides underwent smooth cyclization
(20ꢀ40 min in refluxing toluene) into isoxazoles 8aꢀc without
the triple bond participation.
However, diazotization of the donor substrates 6dꢀe proceeded
in a drastically different manner. In particular, reaction of amines
6dꢀe with nitrosylsulfuric acid (method a) led to the formation of
cyclic products 9dꢀe16 via nucleophilic attack of the alkyne moiety
at the terminal nitrogen of the diazonium group. Interestingly, the
regiochemistry ofattackis different from that observed in the classic
von Richter synthesis of cinnolines.17 Use of a milder diazotizing
reagent, amyl nitrite (method b), increased the reaction time, but
for neither the acceptor- nor donor-substituted substrates did it
change the nature of the products. Partial deacylation was observed
during diazotization of 6e with the formation of a ∼1:1 mixture of
the acylated product 9e and the free phenol 11e. Basic hydrolysis of
this mixture led to its full conversion into the deacylated product
11e. We have distinguished between the alternative 5-exo-dig
an 6-endo-dig18,19 product structures (compounds 9 and 10 in
Scheme 5) on the basis of heteronuclear multiple bond coherence
(HMBC) NMR spectra. HMBC spectra clearly favor a five-
membered compound 9d rather than a six-membered heterocycle.
In particular, the C-12 carbonyl in this experiment correlates with
ortho-protons of the anisole ring but not with the H-4 proton of the
anthraqunone core. Such correlation would be impossible for the
alternative six-membered structure. A more detailed discussion of
the NMR experiments can be found in the Supporting Information.
diazonium salt would allow us to minimize the probability of
undesired competitive cyclizations and open access to the target
3-R-ethynyl-6H-anthra[1,9-cd]isoxazol-6-ones 4.
’ RESULTS
Indeed, the Sonogashira cross-coupling of respective bro-
mides and terminal alkynes provided 1-amino-2-alkynyl-9,10-
anthraquinones 2aꢀe in 75ꢀ85%. Diazotization of the amines
was carried out with amyl nitrite in glacial acetic acid at room
temperature. Addition of sodium azide to the diazonium salt
solution afforded, after 1.5ꢀ2 h, 81ꢀ93% of azides 3aꢀd.14 The
cyclizations of azides to the 3-(R-ethynyl)-6H-anthra[1,9-
cd]isoxazol-6-ones 4aꢀe was completed in 5ꢀ15 min in reflux-
ing toluene to provide 64ꢀ83% of the target product, thus
validating the new synthetic path to this class of heterocycles with
preservation of the alkynyl moiety.
’ DISCUSSION AND COMPUTATIONAL ANALYSIS
To test scope and limitations of this approach to acety-
lenylanthra[1,9-cd]isoxazoles, we investigated other vic-amino
To gain further insight into reactions described in the pre-
vious section, we performed computational studies of the key
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Scheme 3. Preparation of Acyl-Protected Starting Alkynes
Scheme 4. Divergent Pathways Observed As a Function of
Alkyne Polarizationa
Scheme 5. Heteronuclear Multiple Bond Coherence
(HMBC) Used To Distinguish between the 5-exo (9d) and
6-endo (10d) Cyclized Productsa
a The carbonyl (C12) correlates with the ortho-protons at C2 in the
anisole ring (the dashed line), but not those at C4 of the anthraquinone
core, allowing the 5-exo-dig product 9d to be identified.
reactivity (Scheme 6). First, the donor groups can assist the
cyclization by increasing electron density at the alkyne moiety.
Second, the acceptor group can facilitate hydrolysis of of the ester
moiety at C4. The latter reaction transforms the acetyl moiety
into a donor hydroxyl group, which provides additional stabiliza-
tion to the diazonium salt and prevents the cyclization.
In the second scenario, the loss of acetyl group controls the
reactivity: the more electron-deficient substrates 6aꢀc do not
undergo nucleophilic cyclization because hydrolysis of acetate
proceeds fast. In contrast, when the OAc group remains intact in
the donor substrates 6e,d, the diazonium salts do not receive
resonance stabilization from the OH group at C4 and react with
the adjacent triple bond. This scenario would also explain why
the diazonium salts prepared from compounds 2aꢀe with the
NHR group do not cyclize.
In the case of an accelerating effect of electron-releasing
substituents on the dig cyclizations, one would expect the positive
charge development at the vinyl carbon adjacent to the terminal
electron-donor substituent. This mechanistic model is consistent
with the selective formation of a five-membered ring. However,
the relatively subtle substituent effect (Ph vs Ph-OMe, Scheme 7)
on the observed selectivity was intriguing and prompted us to
investigate polarization of reactants and the nature of transition
states computationally.
Our experiments did not provide the information whether the
loss of acetyl group happens before or after the electrophilic
cyclization. On one hand, it is possible that deacylation precedes
the cyclization. On the other hand, we cannot exclude the
possibility that hydrolysis of ester proceeds after the formation
a Electron-donating groups led to unexpected 5-exo-dig products 9dꢀe,
whereas other substituents allowed preparation of the azides and their
subsequent thermal cyclization into the isoxazoles 8aꢀc.
intramolecular steps of the observed reaction cascade. All of the
reactant, product, and transition-state geometries involved in the
fragmentation reaction were optimized at the B3LYP/6-31G(d,p)
level of theory20 using the Gaussian 03 program.21
Two electronic factors are potentially important for the
observed experimental effect of aromatic substituents on the
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Scheme 6. Two Possible Contributions of Alkyne
Substituents to the Observed Trends in Reactivity
Scheme 7. Proposed Pathway for the Formation of the
5-exo-dig Cyclization and the Possible 6-endo-dig Cyclization
(Not Observed), Proceeding through a Nucleophile-Promoted
Electrophilic Cyclization
of diazonium but before the cyclization. To address the two pos-
sibilities, our computational analysis includes substrates with the
both the OH and OAc groups.
Effects of substituents at the electronic properties of the alkyne
and the diazonium moieties are summarized in Table 1. The
effects of terminal aryl groups are more pronounced in the alkyne
moiety, especially in the πout orbital directly communicating with
the terminal aryl π-system. Both the in-plane and out-of-plane
alkyne π-systems are polarized toward the anthraquinone moi-
ety, and the α-carbon, which has to serve as a nucleophile in the
5-exo-dig cyclizations, has the greatest π-density. This effect is, as
expected, the largest for the methoxy-substituted substrate.
However, even the p-nitro group does not change the overall
direction of alkyne polarization, which is dominated by the str-
ongly accepting anthraquinone core. It is also potentially im-
portant that the diazonium π*-orbital has a larger coefficient at
the terminal nitrogen, which is the point of nucleophilic attack by
the alkyne moiety.22 However, the effect of substituents in these
reactants is, at best, moderate. It has to manifest itself more
strongly at one of the subsequent reaction stages in order to
explain the observed differences in reactivity. In particular, one
can expect that the terminal aryl moiety has to rotate 90ꢀ in order
to provide stabilization to the developing positive charge at the
alkyne β-carbon along the 5-exo cyclizations potential energy
surface.
The effect of OAc f OH transformation on the electronic
properties of alkyne is minor, which is not surprising considering
the meta arrangement of the two groups. On the other hand,
polarization of the diazonium group is moderately affected by the
increased donor ability of the OH group. Interestingly, polariza-
tion of the two orthogonal π-bonds of the diazonium moiety
changes in the opposite direction upon the ester hydrolysis. As
the polarization of the out-of-plane π-system decreases, the
polarization of the in-plane π-bond changes in the opposite
direction. As the result, the overall positive charge on the dia-
zonium nitrogens remain unchanged. The π*in coefficient at the
terminal nitrogen increases, suggesting that orbital overalp
leading to the bond forming πin(alkyne) f π*in(N2 ) interac-
tion is, somewhat cointerintuitively, enhanced by the OAc f OH
+
transformation.
We have also analyzed the electronic interaction of alkyne
substituents with the acetate moiety (Scheme 8). Due to the meta
arrangement of the two groups, variations at the arylethynyl
group has little effect at the electronic density at the carbonyl,
suggesting that the rate of acetate hydrolysis should be similar for
alkynes 12a,b,d.
We have investigated the 5-exo/6-endo competition within
two alternative mechanistic scenarios (vide infra) using calcula-
tions at B3LYP/6-31G(d,p) level of theory. The most straight-
forward mechanism includes the direct nucleophilic attack of the
alkyne at the β-nitrogen of the polarized diazonium moiety,
which leads to the formation of a vinyl cation.23,24 In this
mechanism, the 6-endo cyclization would be highly unfavorable
due to the energy penalty for the inclusion of a sp-hybridized
vinyl cation center in the six-membered ring. Formation of an
exocyclic cation avoids the ring strain and would be more
favorable, especially in the presence of cation-stabilizing substit-
uents at the terminal carbon (Scheme 9).
Scheme 9 compares the effect of OAc versus OH substituent at
C4 on the cyclization of a p-OMe-substituted alkyne. The 5-exo-
dig cyclization of the acetate is predicted to have ∼1.5 kcal/mol
lower barrier. Acetate hydrolysis disfavors the cyclization both
kinetically and thermodynamically. The 6-endo-dig product for
the OH-substituted substrate opens to the reactant barrierlessly
in silico.
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Table 1. Natural Bond Orbital (NBO) Analysis of Substituent Effects on Polarization of the Alkyne and Diazonium Moieties in
Acetyl- and Arylamino-Substituted Reactants at B3LYP-6-31G(d,p)a
R = OAc/OH
p-OMe-Ph, 12d
Ph, 12a
p-NO2-Ph, 12b
Acetylene
πin polarization, % at α-carbon
πout polarization, % at α-carbon
natural charge Cβ, e
52.13/52.20
55.70/55.74
52.50/52.55
55.37/55.36
ꢀ0.084/ꢀ0.088
0.161/0.159
52.35/52.40
54.43/54.42
ꢀ0.068/ꢀ0.071
0.148/0.146
ꢀ0.085/ꢀ0.091
0.153/0.151
natural charge Ca, e
Diazonium
π*in polarization, % at β-nitrogen
π*out polarization, % at β-nitrogen
natural charge Nα, e
59.29/59.71
56.25/55.80
0.108/0.107
0.237/0.238
59.23/59.70
56.53/56.01
0.111/0.110
0.250/0.250
59.16/59.70
56.68/56.18
0.114/0.111
0.256/0.258
natural charge Nβ, e
a Polarization of the alkyne π-orbital (the nucleophilic cyclization component) and diazonium π*-orbital (the electrophilic cyclizations component) are
shown in the table graphic (orbital lobe sizes are not to scale).
Scheme 8. Substituent Effects on Natural (NBO) Charges for
the Acyl Moiety
Scheme 9. Free Energy (ΔG) Diagram of the Electrophilic
5-exo and 6-endo-dig Cyclizations of the π-Methoxy
Substituted Substrate (kcal/mol) Calculated at the B3LYP/
6-31G(d,p) Level with CPCM (Water) Correctiona
The effects of aryl substitution on the cyclization of OAc-
substituted reactants are illustrated in Table 2. For R = p-OMe,
the computations clearly predicted that the 5-exo-dig closure
should be preferred both kinetically and thermodynamically.
Although both 5-exo and 6-endo cationic cyclizations are endo-
thermic, the energy cost for the formation of the 5-endo product
is significantly lower and the cyclic cation resides in a deeper
potential energy minimum where it can be trapped by a nucle-
ophile with a higher probability. Interestingly, in the phenyl- and
p-nitrophenyl-substituted cases, where 5-exo-dig cyclizations
were not observed experimentally, the exocyclic products open
back upon geometry optimization to give the acyclic starting
materials. No energy minima corresponding to such products
could be located computationally for both X = OAc and OH.
Although these computational results generally agree with
experimental observations, we have investigated the possibility of
an alternative mechanism, where the two bond formation steps
(CꢀN (a) and CꢀNu(b)) are coordinated. To account for the
a Energy values for the PES are relative to the reactant (the diazonium
salt).
experimental observations, this process has to be asynchronous
with the CꢀN bond formation proceeding ahead of the CꢀNu
bond formation. Interception of the incipient vinyl cation in
this mechanism avoids the formation of this high energy
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Table 2. Activation Energies, Activation Free Energies,
Reaction Energies, and Reaction Free Energies for
the Electrophilic Cyclizations (kcal/mol) Calculated at the
B3LYP/6-31G(d,p) Level
Scheme 10. Comparison of 5-exo Cyclization Reported in
the Present Work with Nucleophile-Promoted Electrophilic
Cyclization (NPEC) Reported by Overman
5-exo 13a,b,d
6-endo 14a,b,d
X
ΔEq (ΔGq) ΔErxn (ΔGrxn
)
ΔEq (ΔGq) ΔErxn (ΔGrxn
)
MeO, 12d 12.0 (12.1)a
3.0 (5.6)a
opens to SM
opens to SM
22.3 (23.2)a
23.3 (24.5)
24.3 (25.5)
21.9 (23.1)a
22.3 (24.5)
23.4 (25.6)
H, 12a
NO2, 12b
a CPCM (water) (radii = UA0) solvation corrections.
intermediate. This mechanistic scenario is analogous to nucleo-
phile-promoted electrophilic cyclizations (NPEC) of alkynes and
iminium ions suggested by Overman (Scheme 10).25 In those
systems, NPECs proceed only in the presence of a nucleophilic
agent that intercepts the incipient vinyl carbocation, suggesting
that this step is crucial for the cyclizations success.
Despite the significant electronic differences between our sys-
tems and the classic NPECs (e.g., different hybridization of
the electrophilic part, relatively weak nucleophile (water) in our
case), and much milder conditions for cyclizations described in this
work than the above NPECs (∼120ꢀ150 ꢀC), we expected this
mechanism to be relevant in our systems as well because in the
NPEC the nucleophile intercepts the incipient vinyl cation, thus
avoiding formation of this unstable intermediate
In the NPEC version, both 5-exo- and 6-endo-dig products
correspond to shallow local energy minima. The large differences
between energy and free energy barriers of activation are
noteworthy. Overall, a small decrease in the ΔEq due to
coordination of water to the carbocationic center is minor in
comparison to the unfavorable entropic contribution for this
bimolecular process. At this level of theory, the NPEC pathway in
the presence of a relatively weak nucleophile such as water does
not offer a kinetic advantage relative to the unimolecular
cyclization path. Interestingly, the energy minima corresponding
to all 5-exo-dig products could be located in the NPEC calcula-
tions in contrast to the results reported in Table 2. Nevertheless,
the 5-exo cyclization of a p-OMe-substituted substrate is still
predicted to proceed much faster than the cyclizations of the two
substrates lacking assistance from the donor group (Scheme 11).
Another interesting feature of the calculated energy landscape
is that the 5-exo products reside in a deeper energy well where
they can be trapped by the subsequent highly thermodynamically
favorable enol-keto tautomerization. For these systems, tauto-
merization also leads to aromatization that provides the very
large thermodynamic driving force for the overall transfor-
mation.26 Although tautomerization of the 6-endo product would
produce a stable aromatic product as well, the observed absence
of 6-endo products with our experimental conditions suggests that
this path remains disfavored even when the 5-exo path is switched
off by the electronic effect of substituents.
several comments are warranted regarding the nature of transi-
tion states in this process. The 5-exo transitions states for the two
possible mechanistic scenarios are given in Scheme 12. The
classic electrophilic cyclization proceeds via a much earlier trans-
ition state (TS) with the incipient C N distance of 2.1 Å. On
3 3 3
the other hand, in the TS for the much more endothermic NPEC
process, the C N distance is much shorter in a full agreement
3 3 3
with the HammondꢀLeffler postulate. Another interesting fea-
ture of the NPEC TS is that the formation of CꢀN bond is more
pronounced than the formation of CꢀO bond, suggesting that
significant carbocationic character should develop at the vinyl
carbon during the cyclizations process. Rotation of the terminal
aryl ring is an important motion because it aligns the aromatic
π-system with the developing vinyl cation in both of the transition
states. This effect, which does not manifest itself in the reactant,
leads to selective TS stabilization and explains why electronic
structures of reactants (Table 1) could not provide a satisfactory
explanation to the observed trends in reactivity.
In summary, we have found that the nature of products in
the diazotization of 1-amino-2-acetylenyl-9,10-anthraquinones
strongly depends on the nature of substituents at both the
alkyne and at the anthraquinone core. Donor substitution
(NHAr, OH) at the fourth position stabilizes the diazonium
salt and prevents electrophilic cyclization on an arylethynyl
substituent at C2. This effect allows the replacement of the
diazonium with azide group and subsequent closure into an
isoxazole ring with preservation of the alkyne. In contrast,
5-exo-dig cyclization to condensed pyrazoles is observed for
the combination of donor substituents at the aryl alkyne moiety
and OAc substituent at C4. The latter process provides a new
synthetic route to 3-ethynyl-[1,9-cd]isoxazol-6-ones, which are
difficult to access otherwise. Computational analysis illustrates
the role of alkyne polarization and selective TS stabilization via
rotation of the terminal aryl group in controlling electrophilic
cyclization of alkynes. This analysis provides the first computa-
tional data on electrophilic 5-exo-dig cyclization in its parent
form and the nucleophile-promoted version. This cyclization is
a relatively fast but endothermic process that is rendered
thermodynamically feasible by enol-keto tautomerization with
concomitant aromatization in the five-membered heteroaro-
matic ring. In the present computational model, the importance
of nucleophilic assistance of in the transition state for such
relatively weak nucleophile as water is minor because the small
decrease in ΔEq is more than compensated for by the unfavor-
able ΔSq term for the bimolecular proces.
As expected, the OAc f OH change renders nucleophile-
promoted electrophilic cyclizations less favorable as well because
the electron-releasing OH group provides extra stabilization to
the starting material. The ∼2 kcal/mol increase in the activation
barriers after acetate hydrolysis suggests that 5-exo-dig cycliza-
tions should be significantly decelerated.
Because this work provides the first computational analysis
of a nucleophile-promoted electrophilic digonal cyclizations,
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Scheme 11. Energy Diagram of the Nucleophile-Promoted Electrophilic 5-exo and 6-endo-dig Cyclizations for Acetates (Top) and
Hydrolyzed Diazonium Salts (Bottom) Calculated at the B3LYP/6-31G(d,p) Levela
a Energy values for the PES are given in kcal/mol relative to the diazonium salt and water (ΔG values are given in parentheses).
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Scheme 12. Comparison of Transition State Geometries for
5-exo-dig Electrophilic (EC)a and Nucleophile-Promoted
Electrophilic (NPEC) Cyclizations Calculated at the
B3LYP-6-31G(d,p) Levelb
177ꢀ179 ꢀC (dioxane). 1H NMR (400 MHz, CDCl3) δ 2.38 (s, 3H),
7.00 (d, J = 7.5 Hz, 1H), 7.07ꢀ7.11 (m, 2H), 7.29 (t, J = 7.6 Hz, 1H),
7.36ꢀ7.39 (m, 3H), 7.52ꢀ7.54 (m, 2H), 7.69 (s, 1H), 7.69ꢀ7.71 (dd,
J = 3.3 Hz, J = 5.8 Hz, 2H), 8.29ꢀ8.32 (m, 2H), 11.93 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 21.3, 83.6, 99.1, 110.1, 111.7, 120.4, 120.7, 121.5,
124.4, 125.3, 126.1, 126.2, 126.8, 128.4, 129.2, 129.3; 131.6, 132.5, 133.9,
134.3, 139.4, 139.5, 142.0, 145.5, 183.1, 183.5; HRMS found m/z
428.1522 [M]+, C29H20N2O; calcd M = 428.1519. IR (cmꢀ1) ν 1620
(CdO), 2203 (CtC), 3064 (NH), 3449 (NH2).
4-(p-Toluidino)-1-amino-2-(3-hydroxy-3-methylbut-1-ynyl)-
anthracene-9,10-dione 2d. Time of reaction 2 h, 70 ꢀC (0.53 g,
75%), mp 245ꢀ247 ꢀC (dioxane). 1H NMR (400 MHz, CDCl3) δ 1.63
(s, 6H), 2.36 (s, 3H), 7.11ꢀ7.21 (dd, J = 8.0 Hz, J = 28.4 Hz, 4H), 7.52
(s, 1H), 7.70ꢀ7.72 (m, 2H), 8.31ꢀ8.32 (m, 2H), 11.87 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 20.9, 31.4, 65.8, 76.8, 77.2, 103.9, 110.2,
111.5, 120.0, 124.3, 126.3, 126.4, 127.0, 130.2, 132.73, 132.76, 134.1,
134.4, 134.6, 136.8, 142.6, 145.4, 183.3, 183.6; HRMS found m/z
410.1628 [M]+, C26H22N2O3; calcd M = 410.1625. IR (cmꢀ1) ν 1611
(CdO), 2215 (CtC), 3065 (NH), 3453 (NH2).
4-(m-Toluidino)-1-amino-2-(3-hydroxy-3-methylbut-1-ynyl)-
anthracene-9,10-dione 2c. Time of reaction 2 h, 75 ꢀC (0.33 g,
80%), mp 182ꢀ184 ꢀC (dioxane). 1H NMR (400 MHz, CDCl3) δ 1.62
(s, 6H), 2.38 (s, 3H), 6.96ꢀ7.04 (m, 3H), 7.25 (t, J = 8 Hz, 1H), 7.54 (s,
1H), 7.68ꢀ7.70 (m, 2H), 8.28ꢀ8.29 (m, 2H), 11.86 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 21.3, 31.2, 65.6, 76.6, 103.9, 110.1, 111.7, 119.8,
120.7, 124.5, 125.3, 126.2, 126.3, 127.0, 129.2, 132.62, 132.63, 133.9,
134.2, 139.4, 139.5, 141.9, 145.4, 183.3, 183.5; HRMS found m/z
410.1623 [M]+, C26H22N2O3; calcd M = 410.1625. IR (cmꢀ1) ν 1619
(CdO), 2217 (CtC), 3068 (NH), 3443 (NH2).
4-(p-Toluidino)-1-amino-2-((4-methoxyphenyl)ethynyl)-
anthracene-9,10-dione 2e. Time of reaction 3 h, 75 ꢀC (0.5 g,
78%), mp 187ꢀ189 ꢀC (toluene). 1H NMR (400 MHz, CDCl3) δ 2.38
(s, 3H), 3.82 (s, 3H), 6.87 (d, J = 8.7 Hz, 2H), 7.17 (d, J = 8.5 Hz, 2H),
7.23 (d, J = 8.5 Hz, 2H), 7.46 (d, J = 8.7 Hz, 2H), 7.61 (s, 1H), 7.69ꢀ7.72
(m, 2H), 8.30ꢀ8.32 (m, 2H), 11.96 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 20.8, 55.2, 82.6, 99.5, 110.0, 111.1, 113.5, 114.1, 121.0, 124.1,
126.1, 126.2, 130.0, 132.4, 132.5, 133.2, 134.0, 134.3, 134.4, 136.8, 142.6,
145.4, 160.3, 182.9, 183.4; HRMS found m/z 458.1623 [M]+,
C30H22N2O3; calcd M = 458.1625; IR (cmꢀ1) ν 1606 (CdO), 2200
(CtC), 3440 (NH2).
a CPCM (water) (radii = UA0) solvation corrections. b Key incipient
bond lengths are shown in Å.
’ EXPERIMENTAL SECTION
Materials. Column chromatography was performed on silica (0.063ꢀ
0.2 mm). UV-254 plates were used for TLC analysis. The IR spectra
were recorded in KBr pellets. All organic solvents were of analytical
quality. Mass spectra (HRMS) were measured at 70 eV. NMR spectra
were recorded at 300.13 (1H) and 75.47 MHz (13C) at 25 ꢀC, 400.13
(1H) and 100.61 MHz (13C) at 25 ꢀC, and 600 MHz in DMSO-d6
at 50 ꢀC.
Typical Procedure for the Preparation of Substituted
9,10-Anthraquinones 5aꢀe
Typical Procedure for the Preparation of Substituted
1-Amino-4-hydroxy-2-(phenylethynyl)anthracene-9,10-
dione 5a. A mixture of the 1-amino-2-bromo-4-hydroxyanthracene-
9,10-dione (1.9 g, 6 mmol), Et3N (2 mL), Pd(PPh3)2Cl2 (20 mg), CuI
(10 mg) and alkyne-1 (0.67 g, 6.6 mmol) in 15 mL of Py was stirred
under argon stream at 45 ꢀC for 11 h until bromide is disappeared (TLC
control). The reaction mixture was cooled and poured into 700 mL of
iceꢀwater. After filtration, the precipitate was washed with water and
ethanol. The crude product was recrystallized from dioxane and char-
acterized, yielding 1-amino-4-hydroxy-2-(phenylethynyl)anthracene-
9,10-dione 5a (1.47 g, 72%), mp 245ꢀ246 ꢀC (dioxane). 1H NMR (400
MHz, CDCl3) δ 7.39ꢀ7.43 (m, 4H), 7.57ꢀ7.60 (m, 2H), 7.73ꢀ7.82
(m, 2H), 8.31ꢀ8.34 (m, 2H), 13.39 (s, 1H); 13C NMR (100 MHz,
CDCl3 + DMSO-d6) δ 83.2, 100.1, 108.2, 113.3, 121.1, 121.4, 125.9,
126.4, 128.2, 129.1, 129.3, 131.6, 132.3, 132.7, 134.0, 134.3, 146.2, 155.3,
182.1, 186.6; HRMS found m/z 339.0891 [M]+, C22H13N1O3; calcd
M = 339.0890. IR (cmꢀ1) ν 1624 (CdO), 2199 (CtC), 3296 (OH),
3458 (NH2).
9,10-Anthraquinones 2aꢀe
4-(p-Toluidino)-1-amino-2-(phenylethynyl)anthracene-9,
10-dione 2b. A mixture of the 4-(p-toluidino)-1-amino-2-bromoan-
thracene-9,10-dione (4.65 g, 11.42 mmol), Et3N (5 mL), Pd(PPh3)2Cl2
(40 mg), CuI (20 mg), and ethynylbenzene (1.34 g, 13 mmol) in 50 mL
of Py was stirred under argon stream at 55 ꢀC for 4 h until bromide was
consumed (TLC control). The reaction mixture was cooled and poured
into 700 mL of water. The precipitate was filtered and washed with water
and ethanole. The crude product was recrystallized from dioxane to
afford 4-(p-toluidino)-1-amino-2-(phenylethynyl)anthracene-9,10-dione
1
2b (4.14 g, 85%), mp 208ꢀ209 ꢀC (dioxane). H NMR (400 MHz,
CDCl3) δ 2.38 (s, 3H), 7.17ꢀ7.26 (dd, J = 8.3 Hz, J = 17.2 Hz, 4H),
7.35ꢀ7.40 (m, 3H), 7.52ꢀ7.55 (m, 2H), 7.65 (s, 1H), 7.70ꢀ7.72 (dd,
J = 3.3 Hz, J = 5.8 Hz, 2H), 8.30ꢀ8.33 (m, 2H), 11.94 (s, 1H); 13C NMR
(100 MHz, CDCl3) δ 20.8, 83.6, 99.1, 110.1, 111.3, 120.4, 121.5, 124.1,
126.1, 126.2, 126.6, 128.4, 129.3; 130.0, 131.6, 132.52, 132.56, 133.9,
134.3, 134.4, 136.7, 142.5, 145.4, 183.0, 183.5; HRMS found m/z
428.1522 [M]+, C29H20N2O; calcd M = 428.1519. IR (cmꢀ1) ν 1614
(CdO), 2203 (CtC), 3063 (NH), 3456 (NH2).
1-Amino-4-hydroxy-2-[(4-nitrophenyl)ethynyl]anthracene-
9,10-dione 5b. Time of reaction 3 h, 70 ꢀC (1.18 g, 64%), mp
276ꢀ277 ꢀC (dioxane). 1H NMR (400 MHz, CDCl3) δ 7.44 (s, 1H),
7.74 (d, J = 8.9 Hz, 2H), 7.77 (dt, 1H, J = 7.5 Hz, J = 1.5 Hz), 7.82 (dt,
1H, J = 7.5 Hz, J = 1.5 Hz), 8.28 (d, J = 8.8, 2H), 8.32ꢀ8.37 (m, 2H),
4-(m-Toluidino)-1-amino-2-(phenylethynyl)anthracene-
9,10-dione 2a. Time of reaction 1 h, 65 ꢀC (0.29 g, 81%), mp
8744
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ARTICLE
13.29 (s, 1H); 13C NMR (100 MHz, DMSO-d6) δ 88.6, 98.2, 108.7,
113.9, 124.2, 126.4, 127.0, 128.5, 129.3, 129.4, 131.0, 132.6, 133.7, 134.0,
134.8, 135.4, 147.3, 154.9, 182.6, 187.4; HRMS found m/z 384.0735
[M]+, C22H12N2O5; calcd M = 384.0741. IR (cmꢀ1) ν 1624 (CdO),
2203 (CtC), 3291 (OH), 3450 (NH2).
1-Amino-2-[(4-bromophenyl)ethynyl]-4-hydroxyanthracene-
9,10-dione 5c. Time of reaction 4 h, 70 ꢀC (0.61 g, 72%), mp 195ꢀ
197 ꢀC (dioxane). 1H NMR (400 MHz, CDCl3 + DMSO-d6) δ 7.37 (s,
1H), 7.55ꢀ7.63 (m, 4H), 7.76ꢀ7.87 (m, 2H), 8.22ꢀ8.28 (m, 2H),
13.31 (s, 1H); 13C NMR (100 MHz, CDCl3 + DMSO-d6) δ 84.7, 98.8,
108.0, 113.5, 120.4, 121.1, 123.3, 125.9, 126.4, 129.4, 131.5, 132.2, 132.9,
133.5, 134.3, 134.4, 146.5, 155.0, 181.9, 186.6; HRMS found m/z
416.9987 [M]+, C22H13N1O3; calcd M = 416.9995. IR (cmꢀ1) ν 1623
(CdO), 2204 (CtC), 3272 (OH), 3439 (NH2).
1-Amino-4-hydroxy-2-[(4-methoxyphenyl)ethynyl]anthr-
acene-9,10-dione 5d. Time of reaction 6 h, 75 ꢀC (0.56 g, 76%), mp
214ꢀ216 ꢀC (dioxane). 1H NMR (400 MHz, DMSO-d6) δ 3.82ꢀ3.83
(s, 1H), 7.06 (d, 2H, J = 8.8 Hz), 7.49 (d, 1H, J = 1.5 Hz), 7.73 (d, 2H, J =
8.8 Hz), 8.25ꢀ8.31 (m, 2H), 8.87ꢀ8.99 (m, 2H), 13.42ꢀ13.43 (m,
1H); 13C NMR (100 MHz, DMSO-d6) δ 55.4, 82.9, 83.8, 93.4, 101.1,
113.0, 114.4, 122.1, 126.1, 126.6, 129.1, 132.2, 133.4, 133.9, 134.4, 134.8,
146.6, 155.2, 160.5, 182.0, 186.5; HRMS found m/z 369.0988 [M]+,
C23H15N1O4; calcd M = 369.0996. IR (cmꢀ1) ν 1637, 1620 (CdO),
2200 (CtC), 3288 (OH), 3454 (NH2).
1-Amino-2-[(1,5-dimethyl-1H-pyrazol-4-yl)ethynyl]-4-hy-
droxyanthracene-9,10-dione 5e. Time of reaction 8 h, 75 ꢀC (0.5
g, 70%), mp 260ꢀ262 ꢀC (dioxane). 1H NMR (400 MHz, CDCl3) δ
2.25 (s, 3H), 3.65 (s, 3H), 7.13 (s, 1H), 7.44 (s, 1H), 7.56ꢀ7.65 (m,
2H), 8.14 (dd, 2H, J = 7.6 Hz, J = 1.2 Hz), 13.28 (s, 1H); 13C NMR (100
MHz, DMSO-d6) δ 36.9, 72.8, 94.7, 100.4, 108.0, 114.5, 123.0, 126.4,
126.9, 128.7, 132.6, 133.7, 134.7, 135.1, 140.8, 143.4, 146.5, 155.7, 159.4,
182.3, 186.7; HRMS found m/z 357.1105 [M]+, C21H15N3O3; calcd
M = 357.1108. IR (cmꢀ1) ν 1635, 1623 (CdO), 2209 (CtC), 3299
(OH), 3454 (NH2).
MHz, CDCl3) δ 2.46 (s, 3H), 7.38 (s, 1H), 7.41 (d, J = 8.4 Hz, 2H), 7.54
(d, J = 8.4 Hz, 2H), 7.70ꢀ7.78 (m, 2H), 8.16 (d, J = 7.6 Hz, 1H), 8.26 (d,
J = 7.2 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 21.0, 77.0, 84.2, 98.9,
112.8, 116.7, 120.5, 123.8, 124.3, 126.5, 126.6, 131.8, 132.9, 133.3, 133.4,
133.6, 133.7, 140.1, 149.6, 170.0, 181.9, 184.8; HRMS found m/z
459.0100 [M]+, C24H14N1O4Br1; calcd M = 459.0101. IR (cmꢀ1) ν
1633, 1660, and 1764 (CdO), 2201 (CtC), 3470 (NH2).
4-Amino-3-[(4-methoxyphenyl)ethynyl]-9,10-dioxo-9,10-
dihydroanthracen-1-yl Acetate 6d. Time of reaction 1 h, 80 ꢀC
(0.09 g, 87%), mp 228ꢀ230 ꢀC (dioxane). 1H NMR (400 MHz, CDCl3)
δ 2.44 (s, 3H), 3.83 (s, 3H), 6.90 (d, 2H, J = 8.9 Hz); 7.33 (s, 1H), 7.47
(d, J = 8.9 Hz, 2H), 7.66ꢀ7.76 (m, 2H), 8.13ꢀ8.25 (m, 2H); 13C NMR
(100 MHz, CDCl3) δ 21.0, 55.3, 77.1, 82.1, 100.7, 112.6, 113.6, 114.2,
117.8, 123.7, 126.5, 126.6, 133.24, 133.27, 133.5, 133.6, 133.7 140.3,
149.6, 160.4, 170.0, 181.9, 184.9; HRMS found m/z 411.1103 [M]+,
C25H17N1O5; calcd M = 411.1101. IR (cmꢀ1) ν 1633, 1657, and 1761
(CdO), 2194 (CtC), 3468 (NH2).
4-Amino-3-[(1,5-dimethyl-1H-pyrazol-4-yl)ethynyl]-9,10-
dioxo-9,10-dihydroanthracen-1-yl Acetate 6e. Time of reac-
tion 1.5 h, 80 ꢀC (0.2 g, 77%), mp 239ꢀ241 ꢀC(toluene). 1H NMR (400
MHz, CDCl3) δ 2.39 (s, 3H), 2.45 (s, 3H), 3.81 (s, 3H), 7.31 (s, 1H),
7.59 (s, 1H), 7.68ꢀ7.75 (m, 2H), 8.16 (d, J = 7.5 Hz, 1H), 8.25 (d, J = 7.5
Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 10.2, 21.0, 36.6, 77.1, 85.4,
92.9, 101.1, 112.6, 118.0, 123.5, 126.4, 126.6, 132.9, 133.2, 133.5, 133.6,
133.7, 134.0, 140.5, 149.4, 170.0, 181.9, 184.8; HRMS found m/z
399.1210 [M]+, C23H17N3O4; calcd M = 399.1214. IR (cmꢀ1) ν
1633, 1656, and 1760 (CdO), 2197 (CtC), 3458 (NH2).
Typical Procedure for the Preparation of Substituted
Azides 3aꢀd
4-(p-Toluidino)-1-azido-2-(phenylethynyl)anthracene-9,10-
dione 3b. To 4-(p-toluidino)-1-amino-2-(phenylethynyl)anthracene-
9,10-dione 2b (4.1 g, 9.58 mmol) in 70 mL of CH3COOH at room tem-
perature was added amyl nitrite (0.93 g, 10 mmol) during 5 min.
The reaction mixture was stirred at room temperature for 45 min. The
solution was poured into 250 mL of iceꢀwater. To the stirred mixture
was added a solution of sodium azide (1.5 g, 23 mmol) in 20 mL water,
and the mixture was stirred at room temperature for 2.5 h. The
precipitate was washed with water and dried by heating to 30 ꢀC within
48 h. Yield 3b 93%. IR (cmꢀ1) ν 1618 and 1675 (CdO), 2125 (N3),
2198 (CtC).
Typical Procedure for the Acylation of Substituted 9,10-
Anthraquinones 6aꢀe
1-Amino-9,10-dioxo-3-(phenylethynyl)-9,10-dihydroan-
thracen-1-yl Acetate 6a. To 1-amino-4-hydroxy-2-(phenylethynyl)-
anthracene-9,10-dione 5a (0.68 g, 2 mmol) in 5 mL of Py at room tem-
perature was added acetic anhydride (1 mL, 10 mmol). After stirring for
6.5 h at 80 ꢀC, the solution was poured into ice and filtered. The precipitate
was washed with water and ethanole. The crude product was recrystallized
from toluene to afford 1-amino-9,10-dioxo-3-(phenylethynyl)-9,10-dihy-
droanthracen-1-yl acetate 6a (0.67g, 88%), mp244ꢀ245 ꢀC (toluene). 1H
NMR (400 MHz, CDCl3 + DMSO-d6) δ 2.34 (s, 3H), 7.35ꢀ7.39 (m,
4H), 7.58ꢀ7.62 (m, 2H), 7.69ꢀ7.80 (m, 2H), 8.06 (dd, J = 7.0 Hz, J =
1.8 Hz, 1H), 8.19 (dd, J = 7.3 Hz, J = 1.5 Hz, 1H); 13C NMR (100 MHz,
CDCl3 + DMSO-d6) δ 21.1, 76.5, 78.7, 83.5, 100.1, 117.1, 121.7, 126.3,
126.5, 128.6, 129.5, 131.9, 133.3, 133.5, 133.6, 133.8, 134.0, 139.8, 150.0,
169.5, 184.3, 191.0; HRMS found m/z 381.0993 [M]+, C22H13N1O3;
calcd M = 381.0996. IR (cmꢀ1) ν 1634, 1661, and 1752 (CdO), 2207
(CtC), 34043 (NH2).
4-(m-Toluidino)-1-azido-2-(phenylethynyl)anthracene-9,10-
dione 3a. Time of diazotization 0.5 h, time of reaction with sodium
azide 1.5 h (0.32 g, 81%). IR (cmꢀ1) ν 1626 and 1662 (CdO), 2124
(N3), 2210 (CtC).
4-(p-Toluidino)-1-azido-2-(3-hydroxy-3-methylbut-1-ynyl)-
anthracene-9,10-dione 3d. Time of diazotization 0.5 h, time of re-
action with sodium azide 2 h (0.94 g, 88%). %). IR (cmꢀ1) ν 1620 and
1672 (CdO), 2127 (N3), 2207 (CtC).
4-(m-Toluidino)-1-azido-2-(3-hydroxy-3-methylbut-1-ynyl)-
anthracene-9,10-dione 3c. Time of diazotization 0.5 h, time of re-
action with sodium azide 2 h (0.74 g, 87%). %). IR (cmꢀ1) ν 1625 and
1668 (CdO), 2128 (N3), 2201 (CtC).
4-(p-Toluidino)-1-azido-2-((4-methoxyphenyl)ethynyl)-
anthracene-9,10-dione 3e. To 4-(p-toluidino)-1-amino-2-((4-
methoxyphenyl)ethynyl)anthracene-9,10-dione 2e (0.155 g, 0.34 mmol)
in 5 mL of CH3COOH at room temperature was added isopropyl nitrite
(0.06 g, 0.67mmol) during5min. Thereactionmixturewasstirredatroom
temperature for 20 min. The solution waspoured into 10 mL of iceꢀwater.
The precipitate was filtered and washed with water. Solution sodium azide
(0.05 g, 0.77 mmol) in 2 mL water was added to filtrate and stirred at room
temperature for 2.5 h. The precipitate was washed with water and dried by
heating to 30 ꢀC within 48 h. Yield 3e 0.076 g, 47%. IR (cmꢀ1) ν 1626 and
1656 (CdO), 2119 (N3), 2206 (CtC).
1-Amino-3-[(4-nitrophenyl)ethynyl]-9,10-dioxo-9,10-di-
hydroanthracen-1-yl Acetate 6b. Time of reaction 1 h, 80 ꢀC
(0.19 g, 78%), mp 235ꢀ237 ꢀC (toluene). 1H NMR (400 MHz, CDCl3)
δ 2.46 (s, 3H), 7.42 (s, 1H), 7.69ꢀ7.76 (m, 4H), 8.16 (dd, J = 1.6 Hz, J =
7.3 Hz, 1H), 8.25ꢀ8.27 (m, 3H); 13C NMR (100 MHz, CDCl3) δ 21.1,
77.2, 87.9, 97.5, 113.3, 115.6, 123.8, 125.2, 126.6, 126.7, 128.4, 133.5,
133.62, 133.68, 133.9, 134.3, 140.2, 147.7, 149.8, 170.1, 182.0, 185.0;
HRMS found m/z 426.0850 [M]+, C24H14N2O6; calcd M = 426.0846.
IR (cmꢀ1) ν 1635, 1662, and 1760 (CdO), 2197 (CtC), 3456 (NH2).
1-Amino-3-[(4-bromophenyl)ethynyl]-9,10-dioxo-9,10-di-
hydroanthracen-1-yl Acetate 6c. Time of reaction 1 h, 80 ꢀC
1
(0.14 g, 73%), mp 234ꢀ236 ꢀC (toluene + hexane). H NMR (400
8745
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ARTICLE
Typical Procedure for the Preparation of Substituted
Azides 7aꢀc
3-(4-Methoxybenzoyl)-6,11-dioxo-6,11-dihydro-1H-naph-
tho[2,3-g]indazol-5-yl Acetate 9d (Method b). To 4-amino-
3-[(4-methoxyphenyl)ethynyl]-9,10-dioxo-9,10-dihydroanthracen-1-yl
acetate 6d (0.082 g, 0.2 mmol) in 4 mL of CH3COOH at room
temperature was added amyl nitrite (0.035 g, 0.3 mmol) during 5 min.
The reaction mixture was stirred at room temperature for 32 h (TLC
control). The solution was poured into 5 mL of iceꢀwater. The
precipitate was filtered and washed with water, and water was removed
by heating to 70 ꢀC within 2 h; 0.062 g (70%) of 9d was isolated, mp
323ꢀ324 ꢀC (DMF).
1-Azido-4-hydroxy-2-(phenylethynyl)anthracene-9,10-
dione 7a. Solution of NaNO2 (0.07 g, 1 mmol) in 1 mL H2SO4 was
added within 5 min to solution of 1-amino-9,10-dioxo-3-(phenylethynyl)-
9,10-dihydroanthracen-1-yl acetate 6a (0.25 g, 0.65 mmol) in 5 mL of
CH3COOH at room temperature. The reaction mixture was stirred at
room temperature for 30 min and poured into 1 mL of iceꢀwater. A sol-
ution of 1 mmol of sodium azide in 1 mL of water was added with
stirring. The reaction mixture was stirred at room temperature for 2.5 h.
The precipitate was washed with water. Water was removed by by
heating to 30 C within 48 h. Yield 7a 0.22 g, 82%. IR (cmꢀ1) ν 1635 and
1672 (CdO), 2130 (N3), 2211 (CtC).
Typical Procedure for the Preparation of Substituted
Isoxazoles 4aꢀd and 8aꢀc
5-(p-Toluidino)-3-(phenylethynyl)-6H-anthra[1,9-cd]iso-
xazol-6-one 4b. Azide 3b was boiled in 15 mL of toluene 15 min. The
reaction mixture was cooled. The precipitate was filtered. The crude
product was recrystallized from benzene to afford 5-(p-toluidino)-
3-(phenylethynyl)-6H-anthra[1,9-cd]isoxazol-6-one 4b (3.13 g, 82%),
1-Azido-4-hydroxy-2-[(4-nitrophenyl)ethynyl]anthracene-
9,10-dione 7b. Time of diazotization 0.5 h, time of reaction with
sodium azide 2 h. (0.19 g, 84%). IR (cmꢀ1) ν 1636 and 1670 (CdO),
2129 (N3), 2208 (CtC).
1-Azido-2-[(4-bromophenyl)ethynyl]-4-hydroxyanthracene-
9,10-dione 7c. Time of diazotization 0.5 h, time of reaction with
sodium azide 2 h. (0.39 g, 88%). IR (cmꢀ1) ν 1633 and 1668 (CdO),
2128 (N3), 2205 (CtC).
1
mp 229ꢀ231 ꢀC (benzene). H NMR (400 MHz, CDCl3) δ 2.45 (s,
3H), 7.28ꢀ7.36 (m, 4H), 7.37ꢀ7.42 (m, 3H), 7.61ꢀ7.68 (m, 4H), 7.79
(t, J = 7.4 Hz, 1H), 8.16 (d, J = 7.5 Hz), 8.16 (d, J = 7.5 Hz), 11.43 (s,
1H); 13C NMR (100 MHz, CDCl3) δ 20.9, 84.1, 100.0, 101.5, 117.0,
120.7, 121.6, 122.2, 124.4, 125.3, 126.9, 128.2, 128.3, 128.5, 129.5, 130.3,
132.0, 132.1, 132.4, 134.5, 136.7, 149.2, 151.2, 156.3, 180.1; HRMS
found m/z 426,1359 [M]+, C29H20N2O; calcd M = 426,1362. IR
(cmꢀ1) ν 1674 (CdO), 2203 (CtC), 3054 (NH).
Typical Procedure for the Preparation of Substituted
Indazoles 9dꢀe
Method a. Solution of NaNO2 (0.1 g, 1.5 mmol) in 1 mL H2SO4
was added to solution of 4-amino-3-[(4-methoxyphenyl)ethynyl]-9,10-
dioxo-9,10-dihydroanthracen-1-yl acetate 6d (0.41 g, 1 mmol) in 20 mL
of CH3COOH at room temperature within 5 min. The reaction mixture
was stirred at room temperature for 2 h (TLC control). The solution
was poured into 50 mL of iceꢀwater. The precipitate was filtered and
washed with water. Water was removed by heating to 70 ꢀC within 2 h,
yielding 3-(4-methoxybenzoyl)-6,11-dioxo-6,11-dihydro-1H-naphtho-
[2,3-g]indazol-5-yl acetate 9d (0.39 g. 89%), mp 323ꢀ324 ꢀC (DMF).
1H NMR (600 MHz, DMSO-d6) δ 2.46 (s, 3H), 3.90 (s, 3H), 7.14ꢀ7.16
(m, 2H, J = 8.79, 2.48, 0.09 Hz), 7.96 (m, 1H, J = 7.35, 7.34, 1.57 Hz),
7.97 (m, 1H, J = 7.43, 7.34, 1.68 Hz), 8.18 (m, 1H, J = 7.35, 1.68, 0.54
Hz), 8.24 (m, 1H, J = 7.43, 1.57, 0.54 Hz), 8.39 (m, 2H, J = 8.79, 2.35,
0.09), 8.40 (s, 1H); 13C NMR (150.96 MHz, DMSO-d6, 50 ꢀC) δ 20.80
(C-16), 55.47 (C-14), 113.68 (C-30), 119.23, 123.23 (C-4), 123.68,
125.91 (C-7), 126.75 (C-10), 127.12, 129.33 (C-13), 131.91, 132.49 (C-
20), 133.21, 134.35 (C-9), 134.70 (C-8), 134.90 (C-11b), 142.57 (C-3),
144.46 (C-5), 163.24 (C-40), 169.56 (C-15), 181.70 (C-6), 182.85 (C-
11), 185.48 (C-12); HRMS found m/z 440.0997 [M]+, C25H16N2O6;
calcd M = 440.1003; IR (cmꢀ1) ν 1632, 1672, and 1768 (CdO). Anal.
Calcd for C25H16N2O6: C, 68.18; H, 3.66; N, 6.36. Found: C, 68.19; H,
3.57; N, 6.63.
5-(m-Toluidino)-3-(phenylethynyl)-6H-anthra[1,9-cd]isoxazol-
6-one 4a. Time of reaction 5 min (0.32 g, 81%), mp 223ꢀ225 ꢀC
(benzene). 1H NMR (400 MHz, CDCl3) δ 2.44 (s, 3H), 7.15ꢀ7.23 (m,
3H), 7.35ꢀ7.41 (m, 4H), 7.59ꢀ7.63 (m, 4H), 7.75 (t, J = 7.2 Hz, 1H),
8.10 (d, J = 7.6 Hz, 1H), 8.50 (d, J = 7.8 Hz, 1H), 11.39 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 21.3, 84.2, 100.0, 101.6, 117.0, 120.7, 121.5,
121.6, 122.1, 125.0, 125.2, 126.9, 127.4, 128.2, 128.3, 128.5, 129.5, 129.6,
132.0, 132.1, 132.4, 137.1, 139.9, 148.9, 151.1, 156.4, 180.1; HRMS
found m/z 426.1353 [M]+, C29H20N2O; calcd M = 426.1363. IR
(cmꢀ1) ν 1675 (CdO), 2198 (CtC), 3059 (NH).
5-(p-Toluidino)-3-(3-hydroxy-3-methylbut-1-ynyl)-6H-anthra-
[1,9-cd]isoxazol-6-one 4d. Time of reaction 5 min (0.72 g, 81%),
1
mp 246ꢀ248 ꢀC (benzene). H NMR (400 MHz, CDCl3) δ 1.69 (s,
6H); 2.43 (s, 3H), 7.23ꢀ7.31 (m, 4H), 7.46 (s, 1H), 7.65 (t, J = 6.9 Hz,
1H), 7.77 (t, J = 6.9 Hz,1H), 8.10 (d, J = 8 Hz, 1H), 8.53 (d, J = 8 Hz,
1H), 11.37 (s, 1H); 13C NMR (100 MHz, CDCl3) δ 20.9, 30.9, 65.5,
76.7, 101.4, 104.7, 116.8, 120.1, 122.1, 124.4, 125.2, 127.1, 128.2, 128.6,
130.3, 132.0, 132.4, 134.4, 136.8, 149.0, 151.0, 156.3, 180.1; HRMS
found m/z 408.1459 [M]+, C26H20N2O3; calcd M = 408.1473. IR
(cmꢀ1) ν 1675 (CdO), 2220 (CtC), 3050 (NH).
5-(m-Toluidino)-3-(3-hydroxy-3-methylbut-1-ynyl)-6H-
anthra[1,9-cd]isoxazol-6-one 4c. Time of reaction 5 min (0.61 g,
83%), mp 235ꢀ237 ꢀC (benzene). 1H NMR (400 MHz, CDCl3) δ 1.69
(s, 6H), 2.45 (s, 3H), 7.17ꢀ7.19 (m, 3H), 7.37ꢀ7.42 (m, 1H), 7.51 (s,
1H), 7.66 (t, J = 7.3 Hz, 1H), 7.78 (t, J = 8 Hz, 1H), 8.13 (d, J = 7.9 Hz,
1H), 8.55 (d, J = 7.9 Hz, 1H), 11.40 (s, 1H); 13C NMR (100 MHz,
CDCl3) δ 21.3, 30.9, 65.4, 76.7, 101.4, 104.9, 116.7, 120.1, 121.3, 122.0,
124.9, 125.0, 126.9, 127.4, 128.1, 128.5, 129.4, 132.0, 132.3, 137.0,
139.9, 148.7, 150.9, 156.2, 180.0; HRMS found m/z 408.1451 [M]+,
C26H20N2O3; calcd M = 408.1473. IR (cmꢀ1) ν 1675 (CdO), 2209
(CtC), 3048 (NH).
3-(1,5-Dimethyl-1H-pyrazole-4-carbonyl)-5-hydroxy-1H-
naphtho[2,3-g]indazole-6,11-dione 11e (Method a). Time of
reaction 5 min. In this case a mixture of 9e and 11e (∼1/1) was
obtained (0.32 g. 74%), of which 0.06 g underwent full hydrolysis by
KOH in EtOH within 50 min. The solution was poured into 10 mL of
water, and the mixture was neutralized by conc HCl. The precipitate
was filtered and washed with water. Water was removed by heating
to 70 ꢀC within 2 h. The crude product was recrystallized from DMF
to afford 3-(1,5-dimethyl-1H-pyrazole-4-carbonyl)-5-hydroxy-1H-
naphtho[2,3-g]indazole-6,11-dione 11e (0.039 g, 72%), mp >370 ꢀC
(DMF). 1H NMR (400 MHz, DMSO-d6) δ 2.64 (s, 3H), 3.83 (s, 3H),
7.98ꢀ8.03 (m, 2H), 8.16ꢀ8.17 (m, 1H), 8.25ꢀ8.30 (m, 2H), 8.53 (s,
1H), 12.02 (s, 1H), 14.45 (s, 1H); 13C NMR spectrum is absent due to
the very low solubility of this compound (0.15 mg in 0.4 mL of DMSO
at 50 ꢀC). HRMS found m/z 428.1106 [M]+, C23H16N4O5; calcd M =
428.1115. IR (cmꢀ1) ν 1635, 1668, and 1768 (CdO). Anal. Calcd for
C23H16N4O5: C, 64.48; H, 3.76; N, 13.08. Found: C, 64.55; H, 3.79;
N, 13.57.
5-(p-Toluidino)-3-((4-methoxyphenyl)ethynyl)-6H-anthra-
[1,9-cd]isoxazol-6-one 4e. Time of reaction 3 min (0.047 g, 64%),
1
mp 236ꢀ238 ꢀC (benzene). H NMR (400 MHz, CDCl3) δ 2.44 (s,
3H), 3.85 (s, 3H), 6.9 (d, J = 8.5 Hz, 2H), 7.29ꢀ7.33 (m, 4H), 7.55 (s,
1H), 7.58 (d, J = 8.5 Hz, 2H), 7.66 (t, J = 7.5 Hz, 1H), 7.78 (t, J = 7.8 Hz,
1H), 8.16 (d, J = 7.9 Hz, 1H), 8.57 (d, J = 7.9 Hz, 1H), 11.44 (s, 1H); 13C
NMR (100 MHz, CDCl3) δ 20.9, 55.2, 83.5, 100.8, 101.4, 113.6, 114.0,
117.1, 121.3, 122.2, 124.5, 125.3, 126.1, 128.2, 128.5, 130.3, 132.0, 132.5,
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133.9, 134.6, 136.7, 149.5, 151.3, 156.3, 160.7, 180.1; HRMS found m/z
456.1465 [M]+, C30H20N2O3; calcd M = 456.1468. IR (cmꢀ1) ν 1674
(CdO), 2193 (CtC), 3055 (NH).
(4) Kortylewicz, Z. P.; Nearman, J.; Baranowska-Kortylewicz, J.
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modifications of triterpenoids, see also:Vasilevsky, S. F.; Govdi, A. I.;
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Mamatuyk, V. I.; Alabugin, I. V. Bioorg. Med. Chem. Lett. 2011, 21,
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Tolstikov, G. A.; Alabugin, I. V. Bioorg. Med. Chem. 2009, 17, 5164–
5169.
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Kovalenko, S. V.; Alabugin, I. V. Chem. Commun. 2005, 1444–1446.
(d) Yang, W.-Y.; Breiner, B.; Kovalenko, S. V.; Ben, C.; Singh, M.;
LeGrand, S. N.; Sang, Q.-X.; Strouse, G. F.; Copland, J. A.; Alabugin, I. V.
J. Am. Chem. Soc. 2009, 131, 11458–11470. (e) Yang, W.-Y.; Marrone,
S. A.; Minors, N.; Zorio, D. A. R.; Alabugin, I. V. Beilstein J. Org. Chem.
2011, 7, 813–823.
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1, 405–429. Nicolaou, K. C.; Smith, A. L.; Yue, E. W. Proc. Natl. Acad. Sci.
U.S.A. 1993, 90, 5881. Liu, W.; Christenson, S. D.; Standage, S.; Shen, B.
Science 2002, 297, 1170. For further use of acetylenes in the design of
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127, 4270–4285. Kauffman, J. F.; Turner, J. M.; Alabugin, I. V.; Breiner,
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5-Hydroxy-3-(phenylethynyl)-6H-anthra[1,9-cd]isoxazol-
6-one 8a. Time of reaction 40 min (0.15 g, 70%), mp 221ꢀ223 ꢀC
(toluene). 1H NMR (400 MHz, CDCl3) δ 7.16 (s, 1H), 7.39ꢀ7.45 (m,
3H), 7.67ꢀ7.69 (m, 2H), 7.75 (t, J = 7.7 Hz, 1H), 7.89 (t, J = 7.6 Hz,
1H), 8.32 (d, J = 8 Hz, 1H), 8.57 (d, J = 8.2 Hz, 1H); 13C NMR (100
MHz, CDCl3) δ 72.2, 83.4, 102.5, 104.6, 116.1, 121.4, 122.7, 124.6,
125.0, 127.1, 128.0, 128.5, 128.7, 130.1, 132.4, 135.4, 151.6, 155.7, 166.6,
178.8; HRMS found m/z 337.0745 [M]+, C22H11N1O3; calcd M =
337.0733. IR (cmꢀ1) ν 1678 (CdO), 2200 (CtC), 3430 (OH).
3-[(4-Nitrophenyl)ethynyl]-5-hydroxy-6H-anthra[1,9-cd]iso-
xazol-6-one 8b. Time of reaction 40 min (0.09 g, 55%), mp 248ꢀ
250 ꢀC (benzene). 1H NMR (400 MHz, CDCl3+DMSO-d6) δ 6.81 (s,
1H), 7.30 (t, J = 7.4 Hz, 1H), 7.40 (d, J = 8.8 Hz, 2H), 7.45 (t, J = 7.4 Hz,
1H), 8.80ꢀ7.84 (m, 3H), 8.08 (d, J = 8.2 Hz, 1H); 13C NMR (100 MHz,
CDCl3) δ 77.9, 87.0, 97.9, 104.7, 115.9, 122.2, 123.44, 123.49, 124.2,
127.1, 128.7, 132.5, 132.8, 133.2, 136.3, 147.6, 150.7, 155.7, 167.8, 174.9;
HRMS found m/z 382.0583 [M]+, C22H10N2O5; calcd M = 382.0584.
IR (cmꢀ1) ν 1681 (CdO), 2206 (CtC), 3422 (OH).
3-[(4-Bromophenyl)ethynyl]-5-hydroxy-6H-anthra[1,9-cd]iso-
xazol-6-one 8c. Time of reaction 20 min (0.28 g, 84%), mp 200ꢀ
202 ꢀC (benzene). 1H NMR (400 MHz, CDCl3) δ 7.13 (s, 1H), 7.49ꢀ
7.56 (m, 4H), 7.72 (t, J = 7.4 Hz, 1H), 7.86 (t, J = 7.5 Hz, 1H), 8.27 (d, J =
7.9 Hz, 1H), 8.52 (d, J = 8.1 Hz, 1H); 13C NMR (100 MHz,
CDCl3+DMSO-d6) δ 84.0, 100.3, 104.3, 115.7, 119.9, 122.2, 123.6,
124.0, 124.3, 126.8, 127.8, 128.6, 131.6, 132.3, 133.4, 135.3, 150.9, 155.4,
166.6, 177.0; HRMS found m/z 414.9831 [M]+, C22H10N1O3; calcd
M = 414.9838. IR (cmꢀ1) ν 1682 (CdO), 2203 (CtC), 3442 (OH).
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’ ASSOCIATED CONTENT
Supporting Information. 1H and 13C NMR spectra;
S
b
total energy and Cartesian coordinates for each optimized stat-
ionary point at the reaction hypersurfaces. This material is
available free of charge via the Internet at http://pubs.acs.org.
’ AUTHOR INFORMATION
(13) Shvartsberg, M. S.; Ivanchikova, I. D.; Fedenok, L. G. Tet. Lett.
1994, 6749–6752.
Corresponding Author
*E-mail: vasilev@kinetics.nsc.ru; alabugin@chem.fsu.edu.
(14) Diazotization of 2e by amyl nitrite proceeded sluggishly and
with the formation of byproduct. An improvement was achieved when
isopropyl nitrite was used instead (reaction is complete within 50 min
and 47% of 3e was isolated after the addition of sodium azide).
(15) Sokolova, M. S.; Beresnev, V. A.; Kargina, O. I.; Gornostaev,
L. M. Russ. J. Org. Chem. 2008, 44, 1631–1635.
(16) (a) See refs 12 and 13. (b) Vasilevsky, S. F.; Tretyakov, E. V.
Synth. Commun. 1994, 24, 1733–1736. (c) Zolnikova, N. A.; Fedenok,
L. G.; Polyakov, N. E. Org. Prep. Proced. Int. 2006, 38, 476–480. (d)
Goeminne, A.; Scammells, P. J.; Devine, S. M.; Flynn, B. L. Tetrahedron
Lett. 2010, 51, 6882–6885.
’ ACKNOWLEDGMENT
This work was supported by the Interdisciplinary Grant No.93
of SB of the Russian Academy of Sciences (2009-2011), Grant
RFBR No. 10-03-00257-a (2010-2012), Grant 5.9.3. of the
Russian Academy of Sciences (2009ꢀ2011), and the Chemical
Service Centre of SB RAS. Work at FSU has been supported by
National Science Foundation (CHE-0848686).
(17) von Richter, V. Ber. Dtsch. Chem. Ges. 1883, 16, 677–683.
(18) Baldwin, J. E. J. Chem. Soc., Chem. Commun. 1976, 734–736.
(19) Topologicaly similar nucleophilic cyclizations: Vasilevsky, S. F.;
Mikhailovskaya, T. F.; Mamatyuk, V. I.; Bogdanchikov, G. A.; Manohar-
an, M.; Alabugin, I. V. J. Org. Chem. 2009, 74, 8106–8117. See also:
Vasilevsky, S. F.; Baranov, D. S.; Mamatyuk, V. I.; Gatilov, Y. V.;
Alabugin, I. V. J. Org. Chem. 2009, 74, 6143–6150.
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