Ring-expansion reaction of isatins with ethyl diazoacetate catalyzed by dirhodium(II)/DBU metal-organic system: En route to viridicatin alkaloids

Article abstract of DOI:10.1002/ejoc.201300796

We present here the NHC-dirhodium(II)/DBU-catalyzed ring expansion reaction of isatins with ethyl diazoacetate. This new one-pot protocol yields the ethyl 3-hydroxy-2(1H)-oxoquinoline-4-carboxylate core, regioselectively and in good to excellent yields. A DFT mechanistic study indicates metallocarbene formation between the 3-hydroxyindole-diazo intermediate and the dirhodium(II) complex to be the rate-limiting step of the reaction. The synthesized ethyl 3-hydroxy-2(1H)-oxoquinoline-4-carboxylate core could be readily converted to viridicatin alkaloids, in yields up to 80 % by a microwave-assisted Suzuki-Miyaura cross coupling of the 3-hydroxy-4-bromoquinolin-2(1H)-one with arylboronic acid. Copyright

Full text of DOI:10.1002/ejoc.201300796

FULL PAPER
DOI: 10.1002/ejoc.201300796
Ring-Expansion Reaction of Isatins with Ethyl Diazoacetate Catalyzed by
Dirhodium(II)/DBU Metal-Organic System: En Route to Viridicatin Alkaloids
Roberta Paterna,[a] Vânia André,[b] M. Teresa Duarte,[b] Luis F. Veiros,[b]
Nuno R. Candeias,*[c] and Pedro M. P. Gois*[a]
Keywords: Synthetic methods / Alkaloids / Ring-expansion / Rhodium / Diazo compounds
We present here the NHC-dirhodium(II)/DBU-catalyzed ring
expansion reaction of isatins with ethyl diazoacetate. This
new one-pot protocol yields the ethyl 3-hydroxy-2(1H)-oxo-
quinoline-4-carboxylate core, regioselectively and in good to
excellent yields. A DFT mechanistic study indicates metallo-
carbene formation between the 3-hydroxyindole-diazo inter-
mediate and the dirhodium(II) complex to be the rate-limit-
ing step of the reaction. The synthesized ethyl 3-hydroxy-
2(1H)-oxoquinoline-4-carboxylate core could be readily con-
verted to viridicatin alkaloids, in yields up to 80% by a micro-
wave-assisted Suzuki–Miyaura cross coupling of the 3-hy-
droxy-4-bromoquinolin-2(1H)-one with arylboronic acid.
induced by tumour necrosis (3),[12] or as promising lead
compounds for the development of new anti-inflammatory
agents.[13]
Introduction
Heterocyclic compounds have paved the way for excep-
tional achievements in the fight against many life threaten-
ing diseases.[1] Therefore, it is with no surprise that the de-
velopment of new methodologies to synthesize biologically
active heterocyclic compounds persists as a very important
goal in organic chemistry.[2,3] Consistent with this, the 4-
Arylquinolin-2(1H)-ones[4] constitute an invaluable class of
heterocyclic compounds that displays a broad range of bio-
logical activities. Members of the class have been reported
to be maxi-K channel openers for the treatment of male
erectile dysfunction,[5] neuroprotectants[6] and to have no-
table antitumor properties such as those reported for Zane-
straTM during the course of phase II clinical trials treating
patients with Neurofibromatosis Type I,[7] amongst
others.[8] An important sub-group of this heterocycle family
is represented by the 3-hydroxy-4-arylquinolin-2(1H)-ones;
included in this sub-group are several natural products like
viridicatin[9] 1, viridicatol[10] 2 and 3-O-methyl viridicatin[11]
3, which are very promising compounds capable of in-
hibiting replication of the human immunodeficiency virus
Rather surprisingly, the synthesis of 3-hydroxy-4-arylqui-
nolin-2(1H)-ones has been a relatively overlooked topic in
the literature. Early methods described the synthesis of this
family of compounds using the addition of aryldiazome-
thanes to isatins,[14,15] treatment of cyclopenin with hydro-
chloric acid,[16] ring contraction of benzodiazepinoox-
azoles[17] or through the use of Friedländer-type condensa-
tions.[5b,7,8,18] In most cases, these approaches displayed a
poor breadth of substrate compatibility and consequently
were found not practical for preparation of 3-hydroxy-4-
arylquinolin-2(1H)-ones derivative libraries for biological
evaluation. Aware of these limitations, Kobayashi and
Harayama recently disclosed the synthesis of viridicatin al-
kaloids (isolated in 64–73% yield) that uses a one-pot
Knoevenagel condensation/epoxidation of cyanoacetanil-
ines followed by decyanative epoxide-arene cyclization.[19]
(Scheme 1) .
This methodology allows for a more versatile synthesis
of 3-hydroxy-4-arylquinolin-2(1H)-ones, though it still re-
lies on the synthesis of cyanoacetanilides as starting materi-
als. Based on this, we anticipated that 3-hydroxy-4-aryl-
quinolin-2(1H)-ones could be more efficiently accessed by
Suzuki–Miyaura coupling of arylboronic acids with 3-hy-
droxy-4-bromoquinolin-2(1H)-ones prepared from ethyl 3-
[a] Research Institute for Medicines and Pharmaceutical Sciences
(iMed.UL), Faculty of Pharmacy, University of Lisbon,
Av. Prof. Gama Pinto, 1649-003 Lisbon, Portugal
E-mail: pedrogois@ff.ul.pt
[b] CQE, Complexo I, Departamento de Engenharia Química,
Instituto Superior Técnico, Universidade Técnica de Lisboa,
Av. RoviscoPais 1, 1049-001 Lisboa, Portugal
hydroxy-2(1H)-oxoquinoline-4-carboxylates.
Although
rather straightforward, this synthetic route relies on the im-
plementation of an efficient regioselective ring expansion
reaction of isatins with ethyl diazoacetate (EDA)
(Scheme 2). In the early sixties, Eistert et al. reported this
transformation using stoichiometric amounts of dieth-
ylamine to promote the addition of EDA to isatin and hy-
[c] Department of Chemistry and Bioengineering, Tampere
University of Technology,
Korkeakoulunkatu 8, 33101 Tampere, Finland
E-mail: nuno.rafaelcandeias@tut.fi
Homepage: http://www.ff.ul.pt/~pedrogois/index.html
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201300796.
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Ring-Expansion Reaction of Isatins En Route to Viridicatin Alkaloids
Scheme 1. General structures of 4-arylquinolin-2(1H)-ones and 3-hydroxy-4-arylquinolin-2(1H)-ones.
Scheme 2. Retrosynthetic analyses for the 3-hydroxy-4-arylquinolin-2(1H)-ones proposed in this work.
drochloric acid or zinc chloride to catalyze the ring expan- ring expansion reaction could be achieved by inducing for-
sion reaction, though this method proved incompatible with mation of a metallocarbene using this family of complexes.
more sensitive functionalities.[14] Aware of these limitations, To test this hypothesis, diazo compound 5 was prepared
Pellicciari et al. studied the ability of several Lewis acids and reacted with Rh2(OAc)4 in dichloromethane. To our
(LA) to promote the ring-expansion reaction, and observed delight, these conditions enabled 5 to smoothly undergo
formation of different reaction products depending on the ring-expansion to afford ethyl 3-hydroxy-2(1H)-oxoquino-
specific LA used.[20]
line-4-carboxylates 6 in 81% yield. This reaction was fur-
ther improved by the use of EtOH as solvent and the appli-
cation of 0.5 mol-% Rh2(OAc)4. Under these conditions,
compound 6 was isolated by simple filtration in 90% yield
Results and Discussion
Based on our long standing interest on the use of dirho- (Scheme 3). Impressed by the efficiency of this transforma-
dium(II) complexes to promote transformations of diazo tion, the ring expansion-reaction was repeated with the ob-
compounds,[21] we envisioned that a more regioselective jective of recycling the catalyst. Therefore, after filtration of
Scheme 3. EDA addition to isatin followed by Eistert ring expansion reaction catalyzed by Rh2(OAc)4. Molecular structures of compounds
5 and 6 determined by single-crystal X-ray diffraction are shown.
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Scheme 4. A metal-organic catalytic system for the synthesis of ethyl 3-hydroxy-2(1H)-oxoquinoline-4-carboxylate core.
6, the ethanolic solution containing dirhodium(II) complex studied, DBU was found to be the most efficient, affording
was charged with more diazo compound 5 which was then the expected product in 78% yield after 24 h at room tem-
efficiently converted into 6. The catalytic system was then perature. This result was further improved by performing
reused for 6 reaction cycles with an average isolated yield the reaction in EtOH; under these conditions, diazo com-
of 90% (Scheme 3).
pound 5 was isolated in 82% yield just after 3h at room
After confirming that Rh2(OAc)4 was indeed an efficient temperature (Table 1, Entries 6–10).
catalyst for the Eistert ring expansion reaction, we turned
Following optimization trials the EDA addition to isatin
our attention towards the possibility of implementing a as well as the compatibility between Rh2(OAc)4 and DBU
one-pot metal-organic catalyzed protocol for the prepara- was further tested by adding 1 mol-% of this complex to
tion ethyl 3-hydroxy-2(1H)-oxoquinoline-4-carboxylates as the reaction mixture. Gratifyingly, the sequential protocol
shown in Scheme 4. One of the main challenges to develop- afforded the expected compounds in good to excellent
ment of a one-pot metal-organic catalyzed systems is to pre- yields confirming the possibility of combining, in the same
vent self-quenching of both metal and organo catalysts.[22] pot, both catalysts. As shown in Table 2, the methodology
This is particularly true when using dirhodium(II) com-
Table 2. Eistert ring expansion of isatins with EDA using a sequen-
plexes as they are known to be, in some cases, easily inacti-
tial DBU/Rh2(OAc)4 system.[a]
vated upon coordination of Lewis bases at the complex ax-
ial coordination sites.[23]
With this objective in mind, the formation of diazo com-
pound 5 was initially evaluated in the presence of 15 mol-
% of different bases (Table 1, Entries 1–5). Of the bases
Table 1. Base and solvent screening for addition of EDA to isatin.[a]
Entry
Compound R1
R2
Yield (%)
1
2
3
4
5
6
7
8
6
7
H
H
H
H
H
F
F3CO
Cl
Br
H
F
F3CO
Cl
Br
H
F
63
64
74
92
90
75
75
81
81
78
73
93
87
72
8
9
10
11
12
13
14
15
16[b]
17
18
19
H
Entry
Base
Solvent
React. temp. (h) Yield (%)
CH3
CH3
CH3
CH3
CH3
CH2Ph
CH2Ph
CH2Ph
CH2Ph
1
2
3
4
5
6
7
8
9
TEA
DCM
DCM
DCM
DCM
DCM
toluene
Et2O
THF
C6H5Cl
EtOH
24
24
24
24
24
2
2
2
2
2
Ͻ 14
15
traces
DEA
DIPEA
tBuOK
DBU
DBU
DBU
DBU
DBU
DBU
9
17
10
11
12
13
14
78(Ͻ 25)[b]
51
68
38
Cl
Br
47
[a] Isatin (0.3 mmol), EDA (1.2 equiv.), DBU (15 mol-%) and
EtOH (1.5 mL); 1 mol-% of Rh2(OAc)4 was added to the reaction
mixture after 3 h. [b] The molecular structure of compound 16 de-
termined by single-crystal X-ray diffraction is presented in the Sup-
porting Information.
10
73 (82)[c]
[a] Isatin (0.3 mmol), EDA (1.5 equiv.), base (15 mol-%) and sol-
vent (1.5 mL). [b] After 2 h. [c] After 3h at room temperature with
1.2 equiv. of EDA.
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Ring-Expansion Reaction of Isatins En Route to Viridicatin Alkaloids
was quite tolerant of substituents present in the aromatic Table 3. Eistert ring expansion of isatins with EDA using a one-
pot DBU/Rh2(OAc)4 system.[a]
ring. Furthermore, good to excellent yields were obtained
when using N–H (Table 2, Entries 1–5), N–CH3 (Table 2,
Entries 6–10) and N–CH2Ph (Table 2, Entries 11–14)-sub-
stituted isatins.
Entry Solvent
Catalyst Product (%) Diazo (%) Isatin
(%)
1
2
3
4
5
6
7
8
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
Toluene
DCE
20
21
22
23
24
25
26
27
26
26
26
27
32
35
25
35
46
43
44
35
51
49
80
45
Ͻ 16
Ͻ 14
Ͻ 7
Ͻ 17
Ͻ 19
Ͻ 20
Ͻ 9
13
3
2
1
10
51
50
67
47
34
35
45
53
44
44
19
43
Having established the optimized sequence and condi-
tions for sequential transformation, we considered the pos-
sibility of having both catalysts present in one-pot from the
start of the reaction. This is quite an interesting system that
presents some important challenges such as i) the potential
self-quenching of dirhodium(II) with DBU, and ii) the
probable competition between EDA and the 3-hydroxyin-
dole-diazo intermediate for the metal catalyst (Scheme 4).
Aware of these potential difficulties, the reaction between
N-methyl-isatin and EDA was performed in the presence of
DBU and Rh2(OAc)4. As anticipated, the reaction proved
considerably more problematic and compound 11 was
formed in just 32% (Table 3, Entry 1). Based on this result,
the catalytic activity of dirhodium(II) complexes 21–28 was
evaluated with the aim of minimizing detrimental DBU–
metal complex interactions (Scheme 5). In evaluating con-
versions on the basis of 1H-NMR spectra of the crude reac-
tion mixture, complex 26, with its electron-donating axial
NHC ligand,[21a,24] was found to be the most efficient cata-
lyst affording product 11 in 44% while allowing only 9% of
the diazo compound to remain unreacted (Table 3, Entry
7). Analogous to the sequential protocol, EtOH proved to
be the best solvent for the one-pot protocol affording de-
sired product 11 in 80% yield (Table 3, Entries 9–12). Once
optimized, the reaction conditions and protocol was ex-
tended to other substrates with similar or better yields than
those observed when performing the reaction in a sequen-
tial manner (Table 4).
9
10
11
12
EtOH
DME
[a] N-methyl isatin (0.3 mmol), EDA (1.2 equiv.), DBU (15 mol-%),
dirhodium complex (1 mol-%), solvent (1.5 mL).
Table 4. Eistert ring expansion of isatins with EDA using a one-
pot relay DBU/Rh2(OAc)4 system.[a]
Entry
Compound R1
R2
Yield (%)
1
2
3
4
5
6
6
H
CH3
CH3
CH3
CH2Ph
CH2Ph
H
F3CO
Cl
Br
H
63
81
92
90
85
68
13
14
15
16
18
Cl
After establishing the ring expansion protocol, we ad-
dressed the complex preference for decomposition of the
isatin–diazo intermediate instead of EDA. To understand
this issue and get further insight into the reaction mecha-
[a] Isatin derivative (0.3 mmol), absolute EtOH (1.5 mL), ethyl di-
azoacetate (1.2 equiv.), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU)
(15 mol-%) and Rh2(OAc)4 (1 mol-%).
Scheme 5. Dirhodium(II) catalyst evaluation in the one-pot Eistert ring expansion of isatins with EDA.
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nism, the ring expansion reaction catalyzed by dirhodium are represented in Figure 1 and Figure 2, and a general
complexes was studied by Density Functional Theory working model of the mechanism is shown in Scheme 6.
(DFT).[25] Hence, the diazo compound resulting from the
Metallocarbene formation proceeds through a concerted
addition of EDA to isatin (5) was used as the model reac- mechanism in which the transition state (ts1) accounts for
tant, and the mechanism was subsequently investigated C–Rh formation with synchronous release of nitrogen. This
starting from the formation of the metallocarbene and sub- aspect of the mechanism is evident by the C–Rh bond
sequent ring expansion. The free energy profiles obtained length decrease from 2.39 Å in the optimal 5-Rh2(OAc)4
Figure 1. Free energy profiles calculated for the metallocarbene formation between the 3-substituted 3-hydroxy-oxindole (5, top) or ethyl
diazoacetate (EDA, bottom) and dirhodium(II) tetraacetate. The relevant bond lengths (Å) are indicated, as well as the respective Wiberg
indices (WI, italics). The minima and the transition states were optimized and the energy values (kcal/mol) are referred to as a pair of
starting materials in each case, and include the thermal correction to Gibbs Free Energy in EtOH. H-atoms are omitted for clarity.
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Ring-Expansion Reaction of Isatins En Route to Viridicatin Alkaloids
Figure 2. Energy profiles calculated for the 1,2-aryl migration of the metallocarbene formed between 3-substituted 3-hydroxy-oxindole
(5) and dirhodium(II) tetraacetate. The relevant bond lengths (Å) are indicated, as well as the respective Wiberg indices (WI, italics). The
minima and the transition states were optimized and the energy values (kcal/mol) are referred to as a pair of starting materials [5 +
Rh2(OAc)4] after thermal correction to Gibbs Free Energy in EtOH. H-atoms are omitted for clarity.
pair to 2.10 Å in ts1, whereas the corresponding Wiberg kcal/mol higher than the one previously discussed, which
index (WI)[26] increases from 0.17 to 0.43. In the metallocar- corroborates the selectivity of the dirhodium catalyst
bene (mc1) formed after liberation of N2, the C–Rh bond towards reaction with oxindole starting material.
is fully formed as shown by a distance of 1.98 Å and a Wib-
After formation of the metallocarbene, the path proceeds
erg index of 0.71. The metallocarbene is further stabilized (see Scheme 6 and Figure 2) with a rearrangement of this
by the presence of an intramolecular H-bond formed be- intermediate, from mc1 to mc2, with concomitant weaken-
tween the hydroxy group of the oxindole moiety and one of ing of the Rh–C bond, as shown by the corresponding Wib-
the carboxylates of the metallic complex. In fact, mc1Ј (the erg indices, 0.7 in mc1 and 0.4 in mc2. The geometry
metallocarbene without the neighbouring N2 molecule) is 7 changes that occur in going from mc1 to mc2 allow mi-
kcal/mol more stable than is the conformer with the O–H gration of the aryl ring in the following step, through transi-
kept away from the carboxylate ligands of the dirhodium tion state ts2. This transformation proceeds through a three
complex (see Figure S1, Supporting Information.).
membered ring and in the corresponding transition state,
For the one-pot variation of this transformation to be ts2, the process is halfway through, as shown by two
successful, ethyl diazoacetate cannot react with Rh2(OAc)4 roughly equal Caryl–C bonds (d = 1.6–1.7 Å, and WI = 0.7).
to form the corresponding metallocarbene. After the obser- On the other hand, the third C–C bond of the three mem-
vation of preferential formation of the ethyl diazoacetate bered ring is kept unchanged during the process. The Caryl
–
addition to isatin, the mechanism for formation of the C bond migration step, from mc2 to mc3, is thermodynami-
metallocarbene derived from that diazo compound was cally favored by over 18 kcal/mol. In mc3, there is a fused
studied, for comparison purposes. Analogously to the for- four membered ring formed by the interaction of the free
mation of the metallocarbene derived from 5, the one de- electron pair of the carbonyl oxygen with the 3-carbon of
rived from ethyl diazoacetate also proceeds through a con- the quinolone moiety thus stabilizing the electronic de-
certed nitrogen extrusion and C–Rh bond formation as ficiency of that position. Interestingly, although the dirho-
indicated by the strengthening of the C–Rh bond and weak- dium catalyst is determinant for extrusion of molecular ni-
ening of the C–N bond from the EDA+Rh2(OAc)4 pair to trogen and consequent formation of the metallocarbene,
tsEDA. However, this process is thermodynamically unfavor- its role along the rest of the pathway is diminished. Proba-
able (ΔG298 = 2.6 kcal/mol) and has an energy barrier 4 bly due to the bulkiness of the quinolone ring, the C–Rh
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Scheme 6. Mechanistic representation of the dirhodiumcatalyzed ring expansion reaction of 3-hydroxy oxindole (5).
bond length remains in excess of 2.3 Å after this stage, be- the rate-determining step in Rh-carbenoid C–H inser-
ing accompanied by a low Wiberg index (0.2 in mc3) com- tions.[27]
pared with that of mc1 (WIRh–C = 0.7).
Lewis acids are known to catalyze the expansion ring of
The following step in the mechanism, progressing from 3-hydroxyindoles bearing a diazoethoxycarbonyl at the 3-
mc3 to 6, corresponds to C–Rh bond cleavage and synchro- position, as previously reported by Pellicciari and co-
nous formation of the C=C bond, going through transition workers.[20] Taking this into consideration, and despite the
state ts3, with an energy barrier of 6 kcal/mol. After prod- rather weak Lewis acidity of dirhodium complexes,[23] we
uct formation, an intramolecular hydrogen bond between explored alternative mechanisms for the ring expansion re-
the hydroxy group at the 3 position and the carboxylic ester action. This was achieved considering coordination of the
stabilizes the molecule whereas the dirhodium complex is substrate to Rh through the carbonyl group of the carbox-
liberated to reenter in the catalytic cycle. In the Rh2- ylic ester moiety or by the carbonyl of the 3-oxindole func-
(OAc)4–product pair obtained at the end of the reaction tion. In both cases, substrate coordination stabilizes the ini-
path (Figure 2) there is only a very weak interaction be- tial pair of reactants. However, the mechanisms calculated
tween the two molecules, and the geometry calculated for 6 for those starting species are not competitive with the one
is in very good agreement with the X-ray structure deter- presented above (see Supporting Information for complete
mined for the product (with deviations smaller than energetic profiles).
0.06 Å).
In addition, alternative mechanisms accounting for prod-
The mechanism discussed above represents a thermody- uct formation without the intervention of the dirhodium
namically favorable process (ΔG298 = –77 kcal/mol) with complex were also considered (see Supporting Information
metallocarbene formation as the rate-determining step (i.e., for the energy profiles). Two paths were envisaged; one pro-
the first step) and an energy barrier of 13 kcal/mol. Metall- ceeds through a free carbene intermediary and the other is
ocarbene formation has been previously determined to be a concerted 1,2-aryl migration with nitrogen extrusion. In
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Ring-Expansion Reaction of Isatins En Route to Viridicatin Alkaloids
Scheme 7. Synthesis of viridicatin alkaloid derivatives based on the Suzuki–Miyaura coupling reaction of arylboronic acids with 4-bromo-
3-hydroxyquinolin-2(1H)-ones.
both cases the calculated energy barriers are considerably ethyl 3-hydroxy-2(1H)-oxoquinoline-4-carboxylate in yields
higher than the ones associated with the mechanism dis- up to 92%. Finally, the 4-bromo-3-hydroxyquinolin-2(1H)-
cussed above.
one core was simply coupled with arylboronic acid to yield
Finally, having established the efficient regioselective ring expected viridicatin alkaloids in up to 80% yield.
expansion reaction of isatins with EDA, we evaluated the
synthesis of the viridictin core through application of a Su-
zuki–Miyaura coupling of arylboronic acids with 3-hy-
droxy-4-bromoquinolin-2(1H)-ones. Therefore, 3-hydroxy-
4-bromoquinolin-2(1H)-one was simply prepared by decar-
Experimental Section
General Methods: Dimethoxyethane (DME) as reaction solvent
was freshly distilled from calcium hydride whereas EtOH and DMF
boxylation of 6 and reaction with NBS and then reacted
were used without any purification. All reactions were performed
with phenylboronic acids using microwave irradiation and
in oven-dried glassware. Open to air microwave reactions were car-
in the presence of several palladium complexes. After exten-
ried out with a CEM Discover 908010 in oven dried 10 mL reaction
vessels. Reaction mixtures were analyzed by TLC using ALUG-
sive screening of reaction conditions (see Supporting Infor-
mation), we found that, by using 10 mol-% of Pd(PPh3)4,
RAM® SIL G/UV254from MN (Ref. 818133, silica gel 60), and
expected compound 28 could be obtained in 80% yield.
visualisation of TLC spots was effected using ultraviolet (UV).
Very gratifyingly, the optimized reaction conditions were
Flash chromatography was carried out on silica gel 60 m Merck
successfully used in the coupling of 3-hydroxy-4-bromoqui- (Ref. 107734) in a Combiflash Rf teledyne isco system. Nuclear
magnetic resonance (NMR) spectra were recorded with a Bruker
AMX 400 and a BrukerAvance II 300 using CDCl3, CD3OD and
(CD3)2SO as solvents and (CH3)4Si (1H) as the internal standard.
All coupling constants are expressed in Hz. Electrospray ionization
(ESI) mass spectra were recorded with a mass spectrometer (Micro-
mass Quattro Micro API, Waters, Ireland) with a Triple Quadru-
pole (TQ) and with an electrospray ion source operating in positive
mode. Electrospray ionization (ESI) mass spectra were recorded
using a mass spectrometer (Micromass Quattro Micro API, Waters,
Ireland) with a Triple Quadrupole (TQ) and with an electrospray
ion source operating in positive mode. Elemental analyses were per-
formed using a Flash 2000 CHNS-O analyzer (ThermoScientific,
UK). Melting points were measured with a Stuart SMP10 digital
melting point apparatus.
nolin-2(1H)-one with arylboronic acids yielding viridicatin
alkaloids 30–33 in good yields as shown in Scheme 7.
Conclusions
In summary, herein is disclosed an efficient synthesis of
viridicatin alkaloids based on Suzuki–Miyaura coupling re-
action of arylboronic acids with 3-hydroxy-4-bromoquino-
lin-2(1H)-ones prepared from ethyl 3-hydroxy-2(1H)-ox-
oquinoline-4-carboxylates. The ethyl 3-hydroxyquinoline-4-
carboxylate was simply prepared by a regioselective ring ex-
pansion reaction of isatins with EDA catalyzed by dirhodi-
um(II) complexes. The reaction mechanism was studied by
DFT calculations highlighting metallocarbene formation
between the 3-hydroxyindole-diazo intermediate and the di-
rhodium(II) complex as the rate-limiting step of the mecha-
nism. The discovered compatibility of the NHC-dirhodi-
um(II) complex 26 and DBU, enabled implementation of
one-pot addition of EDA to isatin followed by NHC-dirho-
General Method for the Sequential Synthesis of Ethyl 3-Hydroxy-
2(1H)-oxoquinoline-4-carboxylates: (Table 2) EDA (1.2 equiv.) and
DBU (15 mol-%) were added to a stirred solution of isatin
(0.3 mmol) in absolute EtOH (1.5 mL). The reaction mixture was
stirred for 3 h at room temperature and then Rh2(OAc)4 (1 mol-
%) was added to afford the ring expansion product, which readily
precipitated from the reaction mixture and was isolated by fil-
dium(II)-catalyzed ring expansion enabling generation of tration. The collected solid was washed with Et2O, and dry under
Eur. J. Org. Chem. 2013, 6280–6290
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
6287

N. Candeias and P. M. P. Gois et al.
FULL PAPER
reduced pressure to furnish the expected ethyl 3-hydroxy-2(1H)-
oxoquinoline-4-carboxylates described in Table 2.
b1 level. Basis b2 consisted of the same base (b1) for Rh and a
standard 6-311++G(d,p)[37] for the remaining elements. Solvent ef-
fects (ethanol) were considered in the PBE1PBE/b2//PBE1PBE/b1
energy calculations using the Polarizable Continuum Model (PCM)
initially devised by Tomasi and coworkers[38] as implemented on
Gaussian 03.[39] The molecular cavity was based on the united atom
topological model applied on UAHF radii, optimized for the HF/
6-31G(d) level.
General Method for the Tandem Synthesis of Ethyl 3-Hydroxy-
2(1H)-oxoquinoline-4-carboxylates: (Table 4) A round-bottomed
flask equipped with a magnetic stirrer was charged with a solution
of isatin (0.3 mmol) in absolute EtOH (1.5 mL), ethyl diazoacetate
(1.2 equiv.), 1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU) (15 mol-%)
and Rh2(OAc)4 (1 mol-%). The mixture was then stirred for 3 hours
at room temperature after which the reaction mixture was centri-
fuged and the product isolated by filtration. The collected solid
was washed with water, Et2O, and dry under reduced pressure to
furnishing the expected ethyl ester described in Table 4.
The free energy values presented along the text (Gb2soln) were de-
rived from the electronic energy values obtained at the PBE1PBE/
b2//PBE1PBE/b1 level, including solvent effects (Eb2soln), according
soln
soln
to the following expression: Gb2
= Eb2
+ Gb1 – Eb1
3-Hydroxyquinolin-2(1H)-one 28: (Scheme 6) Compound
6
Single Crystal X-ray Diffraction for Compounds 5, 6 and 16: Crys-
tals of 5, 6 and 16 suitable for X-ray diffraction studies were
mounted on a loop with protective oil. X-ray data were collected
at 150 K on a Bruker AXS-KAPPA APEX II diffractometer using
graphite monochromated Mo-Kα radiation (λ = 0.71069 Å) and
operating at 50 kV and 30 mA. Cell parameters were retrieved
using Bruker SMART software and refined using Bruker SAINT[40]
on all observed reflections. Absorption corrections were applied
using SADABS.[41] Structure solution and refinement were per-
formed using direct methods with program SIR97[42] and
SHELXL97,[43] both included in the package of programs
WINGX-Version 1.80.05.[44] A full-matrix least-squares refinement
was used for the non-hydrogen atoms with anisotropic thermal pa-
rameters. All hydrogen atoms connected to carbons were inserted
in idealized positions and allowed to refine riding in the parent
carbon atom; hydrogen atoms bonded to nitrogen atoms were lo-
cated in a difference map.
(5 mmol) was added to a solution of NaOH (10 mmol) in H2O
(50mL). The reaction was then stirred at reflux for 7 h. The formed
precipitate after acidification until pH 1–2 with aqueous HCl solu-
tion (2 m), was filtered, washed with water and dried under reduced
pressure to yield the 3-hydroxyquinolin-2(1H)-one in 92%
(74.4 mg).
4-Bromo-3-hydroxyquinolin-2(1H)-one (29): (Scheme 6) The synthe-
sis was performed according to the protocol described in the litera-
ture.[28] 1H NMR (400 MHz, DMSO): δ = 7.44–7.15 (m, 3 H), 7.70
(d, J = 8.0 Hz, 1 H), 10.40 (d, J = 14.5 Hz, 1 H), 12.32 (s, 1 H) ppm.
13C NMR [101 MHz, (CD3)2SO]: δ = 157.11, 145.45, 132.93,
127.93, 125.66, 123.42, 120.19, 115.74, 109.75 ppm.
Optimization of the Microwave-Assisted Suzuki–Mayura Reaction:
An oven-dried 10 mL microwave reaction vessel was charged with
4-bromo-3-hydroxyquinolin-2(1H)-one (0.4 mmol), phenylboronic
acid (2.2 equiv.) and freshly dried DME (1.1 mL). Then a Pd source
and a solution 2 m of Na2CO3/H2O (0.4 mL) were added to the
reaction mixture. The vessel was capped and the mixture was
stirred for 5 min at room temperature. The sealed vessel was then
heated by microwave irradiation at 150 C for 2 h. After cooling
to the room temperature, the resulting dark-colored mixture was
purified by flash chromatography using a Combiflash Rf teledyne
isco system and 1:1 mixture of Hexane/EtOAc to afford 3-hydroxy-
4-phenylquinolin-2(1H)-one.
CCDC-939410 (for 5), -939411 (for 6) and -939640) (for 16) contain
the supplementary crystallographic data for this paper. These data
can be obtained free of charge from The Cambridge Crystallo-
graphic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
Crystallographic Data for 5: C12H11N3O4, fw = 261.24, monoclinic,
space group P21/c, a = 19.2024(16) Å, b = 11.8604(8) Å, c =
11.0525(10) Å, β = 105.828(4) °, V = 2421.8(3) Å3, Z = 8, T =
150K, dcalc = 1.433 Mgm–3, μ = 0.110 mm–1, F(000) = 1088, yellow
block crystal (0.22ϫ0.10ϫ0.08 mm). Of 19885 reflections col-
lected, 5328 were independent (Rint = 0.0430); 345 variables refined
with 5328 reflections to final R indices R1[IϾ2σ(I)] = 0.0472, wR2[I
Ͼ 2σ(I)] = 0.1163, R1(all data) = 0.0724, wR2(all data) = 0.1255,
GOF = 1.054. A disorder model was applied to one methyl group.
Computational Details: All calculations were performed using the
Gaussian 03 software package[29], and the PBE1PBE functional,
without symmetry constraints. That functional uses a hybrid gener-
alized gradient approximation (GGA), including 25 % mixture of
Hartree-Fock[30] exchange with DFT[31] exchange-correlation, given
by Perdew, Burke and Ernzerhof functional (PBE).[32] The opti-
mized geometries were obtained with the lanl2dz basis set[33] aug-
mented with a f-polarization function[34] for Rh, and a standard 6-
31G(d,p)[35] for the remaining elements (basis b1). Transition state
optimizations were performed with the Synchronous Transit-
Guided Quasi-Newton Method (STQN) developed by Schlegel et
al.,[36] following extensive searches of the Potential Energy Surface.
Frequency calculations were performed to confirm the nature of
the stationary points, yielding one imaginary frequency for the
transition states and none for the minima. Each transition state
was further confirmed by following its vibrational mode downhill
on both sides and obtaining the minima presented on the energy
profile. The electronic energies (Eb1)obtained at the PBE1PBE/b1
level of theory were converted to free energy at 298.15 K and 1 atm
(Gb1) by using zero point energy and thermal energy corrections
based on structural and vibration frequency data calculated at the
same level.
Crystallographic Data for 6: C12H11NO4, fw = 233.22, trigonal,
¯
space group R3, a = 25.034(5) Å, b = 25.034(5) Å, c = 8.926(5) Å,
V = 4856(3) Å3, Z = 18, T = 150K, dcalc = 1.435 mgm–3, μ =
0.109 mm–1,
F(000)
=
2196,
colourless
needle
(0.2ϫ0.02ϫ0.02 mm). Of 10137 reflections collected, 1972 were
independent (Rint = 0.1573); 158 variables refined with 1972 reflec-
tions to final R indices R1[IϾ2σ(I)] = 0.0483, wR2[I Ͼ 2σ(I)] =
0.0795, R1(all data) = 0.1650, wR2(all data) = 0.0938, GOF =
0.749.
Crystallographic Data for 16: C19H17NO4, fw = 323.34, triclinic,
¯
space group P1,
a = 6.8034(6) Å, b = 10.6251(8) Å, c =
11.2680(8) Å, α = 92.853(4), β = 102.984(4) °, γ = 95.613(4), V =
787.73(11) Å3, Z = 2, T = 150K, dcalc = 1.363 mgm–3, μ =
0.096 mm–1, F(000)
=
340, colourless block crystal
(0.20ϫ0.04ϫ0.02 mm). Of 9515 reflections collected, 3236 were
independent (Rint = 0.0413); 219 variables refined with 3236 reflec-
tions to final R indices R1[IϾ2σ(I)] = 0.0451, wR2[I Ͼ 2σ(I)] =
0.1123, R1(all data) = 0.0807, wR2(all data) = 0.1255, GOF =
1.059.
Single point energy calculations were performed using an improved
basis set (basis b2) and the geometries optimized at the PBE1PBE/
6288
www.eurjoc.org
© 2013 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Eur. J. Org. Chem. 2013, 6280–6290

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Supporting Information (see footnote on the first page of this arti-
cle): Detailed experimental procedures, computational details and
spectroscopy data for above-mentioned compounds.
Acknowledgments
Fundação do Ministério de Ciência e Tecnologia (FCT) is ac-
knowledged for funding (grant numbers PEst-OE/SAU/UI4013/
2011; PTDC/QUIQUI/099389/2008; SFRH/BD/78301/2011).
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Received: May 29, 2013
Published Online: August 20, 2013
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