Gold/acid-co-catalyzed direct microwave-assisted synthesis of fused azaheterocycles from propargylic hydroperoxides

Article abstract of DOI:10.1002/chem.201304509

The gold-acid-co-catalyzed synthesis of nine series of fused azaheterocycles with structural diversity starting from the same synthons as readily available propargylic hydroperoxides and aromatic amines has been achieved. The overall tandem process consists in a gold-catalyzed hydroperoxide rearrangement/Michael reaction followed by a final acid-catalyzed cyclization.

Full text of DOI:10.1002/chem.201304509

DOI: 10.1002/chem.201304509
Full Paper
&
Synthetic Methods
Gold/Acid-Co-catalyzed Direct Microwave-Assisted Synthesis of
Fused Azaheterocycles from Propargylic Hydroperoxides
Benito Alcaide,*[a] Pedro Almendros,*[b] and M. Teresa Quirꢀs[a]
Abstract: The gold–acid-co-catalyzed synthesis of nine series
of fused azaheterocycles with structural diversity starting
from the same synthons as readily available propargylic hy-
droperoxides and aromatic amines has been achieved. The
overall tandem process consists in a gold-catalyzed hydro-
peroxide rearrangement/Michael reaction followed by a final
acid-catalyzed cyclization.
Introduction
condensation in situ was by using a Brønsted acid. In this arti-
cle we report that the gold-catalyzed[9] reaction of propargylic
hydroperoxides with a variety of aromatic amines in the pres-
ence of catalytic amounts of a protic acid results in the prepa-
ration of a small library of fused azaheterocycles.
Despite that a number of organic hydroperoxides are natural
products of relevant biological activity,[1] this functionality at-
tracted attention in industry,[2] and several approaches have
been reported for the synthesis of the hydroperoxide moiety,[3]
its synthetic utility has been somewhat limited.[4] In this con-
text, we have recently described the preparation of stable and
easily handling propargylic hydroperoxides 1 together with
their gold-catalyzed rearrangements to ketones and concomi-
tant alcoholic trapping.[5] Following our above-mentioned in-
vestigation, we became interested in the direct transformation
of propargylic hydroperoxides into fused azaheterocycles[6]
through a tandem sequence.[7] We recognized that the ability
to employ aromatic amines in the rearrangement of propargyl-
ic hydroperoxides would provide an attractive alternative to
a stepwise azaheterocycle synthesis. In addition, it would pro-
vide a platform to further expand the synthetic utility of the
propargylic hydroperoxide rearrangement, since there are no
examples with amine nucleophiles. The reaction between hy-
droperoxides and aromatic amines should afford an aminoke-
tone intermediate, aza-Michael-type adduct, which are relevant
building blocks.[8] We thought that the most convenient
manner to activate the aminoketone towards an intramolecular
Results and Discussion
Encouraged by our previous results, we envisioned that 3,5-di-
methoxyaniline would react with propargylic hydroperoxides
1 through a tandem process to furnish substituted quinolines
under gold-catalyzed conditions. Quinoline derivatives are
pharmacologically active compounds.[10] Initially, we chose 1-(3-
hydroperoxyprop-1-ynyl)-4-methoxybenzene 1a as the starting
hydroperoxide. At the outset, the use of [AuCl3] and [AuCl]
were tested, but both failed to catalyze the reaction in the
presence or absence of any additive. Happily, a different proto-
col afforded the desired quinoline 2a in 72% yield by expo-
sure to the system [AuCl(PPh3)] (2.5 mol%)/[AgOTf] (2.5 mol%)/
p-toluenesulfonic acid (PTSA; 10 mol%)/H2O (200 mol%) in di-
chloromethane at room temperature for 42 h (Scheme 1). As
such, the propargylic hydroperoxide functionality would
behave as a latent carbonyl group giving a reactive a,b-unsa-
turated ketone, which is doubly trapped by the aromatic
amine. Disappointingly, under the above conditions propargyl-
ic hydroperoxides 1b–e gave low yields of the corresponding
[a] Prof. Dr. B. Alcaide, M. T. Quirꢀs
Grupo de Lactamas y Heterociclos Bioactivos
Departamento de Quꢁmica Orgꢂnica I
Unidad Asociada al CSIC, Facultad de Quꢁmica
Universidad Complutense de Madrid
28040 Madrid (Spain)
Fax: (+34)91-3944103
E-mail: alcaideb@quim.ucm.es
[b] Dr. P. Almendros
Instituto de Quꢁmica Orgꢂnica General
Consejo Superior de Investigaciones Cientꢁficas
IQOG-CSIC, Juan de la Cierva 3
28006 Madrid (Spain)
Fax: (+34)91-5644853
E-mail: palmendros@iqog.csic.es
Scheme 1. Controlled gold-catalyzed reaction of propargylic hydroperoxides
with 3,5-dimethoxyaniline. Synthesis of 5,7-dimethoxy-2,4-disubstituted
quinolines.
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/chem.201304509.
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heterocyclic reaction products, because total consumption of
the starting material could not be achieved after several days
of reaction. Nicely, a gentle heating at 508C on a sealed tube
both considerably decreased the reaction time and positively
affected the yield. For example, the soft thermal treatment
raised the yield of 2b from 33 up to 67% (Scheme 1). Thus,
our protocol allowed the direct preparation of quinolines 2b–
e in reasonable yields (Scheme 1).
The above combination of the p-acid gold catalyst with
a Brønsted acid resulted in a dual activation mode of the
latent alkenyl ketone. We can envision that a,b-unsaturated ke-
tones, as intermediates, can be transferred in situ from propar-
gylic hydroperoxides to a variety of azacycles in a one-pot pro-
cedure. Worthy of note, this is not a minor point because vinyl
ketone substrates are toxic, volatile, and have a high propensi-
ty to polymerization. On the other hand, pyrazolo[1,5-a]pyrimi-
dines play an important role in medicinal chemistry.[11] Based
on our above protocol for quinoline synthesis, we optimized
the tandem sequence for the reaction of hydroperoxides
1 with 3-aminopyrazole (Table 1). Nicely, from 1a this protocol
prop-1-ynyl)-4-methoxybenzene 1a was treated with 3-amino-
pyrazole under [Au(OTf)PPh3] catalysis in 1,2-dichloroethane
(DCE) at 1208C under microwave irradiation for 2.5 h, pyrazolo-
[1,5-a]pyrimidine 3a was isolated in 76% yield. A screening of
solvents (toluene, tetrahydrofuran, 1,4-dioxane) revealed that
the reaction is best performed in DCE. Other counterions has
little effect in the reaction, because ([AgSbF6], [AgBF4], and
[AgNTf2]) in combination with AuI delivered similar yields of
the product. Other Au-catalysts were less effective; that is,
[AuCl(IPr)]
(IPr=1,3-bis(2,6-diisopropylphenyl)imidazol-2-yli-
dene) leads to considerable amounts of propargylic alcohol
coming from decomposition of the starting hydroperoxide.
Similarly, differently substituted propargylic hydroperoxides
1b, 1c, and 1e also delivered the corresponding bicycles 3 in
good yields (Scheme 2).
Table 1. Selective reaction between hydroperoxide 1a and 3-aminopyra-
zole under modified gold-catalyzed conditions.
Scheme 2. Controlled gold-catalyzed reaction of propargylic hydroperoxides
with 3-aminopyrazole. Synthesis of pyrazolo[1,5-a]pyrimidines.
Entry
Catalyst
T
[8C]
t
[h]
Solvent
Yield
[%][a]
1
2
3
4
5
6
7
[AuCl(PPh3)]/[AgOTf]
[AuCl(PPh3)]/[AgOTf]
[AuCl(PPh3)]/[AgSbF6]
[AuCl(PPh3)]/[AgBF4]
[AuCl(PPh3)]/[AgNTf2]
[AuCl(IPr)]/[AgOTf]
[AuCl(IPr)]/[AgSbF6]
50
384
CH2Cl2
DCE
DCE
DCE
DCE
DCE
DCE
72
sealed tube
120
microwave
120
microwave
120
microwave
120
microwave
120
microwave
120
2.5
76
2.5
3
70
65
Scheme 3. Controlled gold-catalyzed reaction of propargylic hydroperoxides
with 1H-indazol-3-amine. Synthesis of pyrimido[1,2-b]indazoles.
2.5
4
68
5[b]
65[b]
As depicted in Scheme 3, the pyrimido[1,2-b]indazole
motif.[13] could also be obtained adapting this acid-catalyzed
protocol to the use of the benzo analogue 1H-indazol-3-amine.
A variety of pyrimido[1,2-b]indazole derivatives 4 were formed
using our cyclative capture approach. When we performed the
same tandem addition/cyclization process on propargylic hy-
droperoxides 1 and imidazo[1,2-a]pyridin-3-amine, the corre-
sponding dipyrido[1,2-a:3’,2’-d]imidazoles 5 were smoothly ob-
tained, again as the only reaction products (Scheme 4). The
heterocyclic core of tricycles 5 is of potential pharmacological
relevance because of its intercalation ability with DNA.[14]
2.5
microwave
[a] Yield of pure, isolated product with correct analytical and spectral
data. [b] Appreciable decomposition of the starting hydroperoxide 1a
was observed.
afforded the desired pyrazolo[1,5-a]pyrimidine 3a in 72%
yield, but after prolonged exposure to the system [AuCl(PPh3)]
(2.5 mol%)/[AgOTf]
(2.5 mol%)/PTSA
(10 mol%)/H2O
(200 mol%) in dichloromethane at 508C on a sealed tube for
384 h. However, the conversion to the corresponding heterocy-
cle could not be satisfied at room temperature. Considering
the successful application of MW (microwave) irradiation in or-
ganic synthesis, we decided to perform this domino reaction
under MW irradiation.[12] Interestingly, when 1-(3-hydroperoxy-
The indole scaffold has been recognized as the fundamental
nucleus for a large number of natural and synthetic products
of biological significance.[15] Therefore, methods for the synthe-
sis of new indole derivatives are highly appreciated. We ex-
pected that the above methodology could be used for the
straightforward preparation of tricyclic indole derivatives.
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Scheme 4. Controlled gold-catalyzed reaction of propargylic hydroperoxides
with imidazo[1,2-a]pyridin-3-amine. Synthesis of dipyrido[1,2-a:3’,2’-d]imida-
zoles.
Based on this premise, we chose propargylic hydroperoxide 1a
and 1H-indol-2-amine[16] as substrates for this new type of
transformation. Interestingly, under gold catalysis hydroperox-
ide 1a delivered the a-carboline 6a in addition to the non-
linear tricycle 7a, which were easily separable by flash column
chromatography (Scheme 5). The present protocol was extend-
ed to hydroperoxides 1 f–h. Similarly, their gold-catalyzed reac-
tions with 1H-indol-2-amine furnished separable mixtures of a-
carbolines 6 and benzo[cd]indol-
Scheme 5. Controlled gold-catalyzed reaction of propargylic hydroperoxides
with 1H-indol-2-amine. Synthesis of a-carbolines and benzo[cd]indol-2-
amines.
2-amines 7 (Scheme 5). Despite
that signals of tricycle 7h could
1
be detected in the H NMR spec-
trum of the crude reaction mix-
ture, it decomposed under chro-
matographic separation. In the
case of 1H-indol-2-amine, the
nucleophilic attack of the highly
reactive indole C3 position on
the activated a,b-unsaturated
ketone occurs, which avoids the
aza-Michael event. The forma-
tion of adducts 6 and 7 can be
explained invoking
a Friedel–
Crafts-type reaction of the indole
nucleus to generate ketone 8,
a
common intermediate that
evolves either through amino- or
carbocyclization to afford tricy-
cles
6 or 7, respectively. Al-
though the selectivity is poor
under the conditions and efforts
for further improvements were
in vain, it is worthy of note that
fused heterocycles 6 and 7 are
easily separated, thus providing
readily two valuable indole-type
products.[17]
Scheme 6. Controlled gold-catalyzed reaction of propargylic hydroperoxides with N-benzoyliminopyridinium
ylides. Synthesis of fused pyrazoles.
single isomers (Scheme 6). The conversion of hydroperoxides
Natural products bearing an NÀN bond belong to a particular
group because of its interesting structural and biological char-
acteristics.[18] Besides, natural and synthetic pyrazole derivatives
are considered as drug candidates and are important synthetic
targets.[19] Thus, the reaction of propargylic hydroperoxides
with several N-benzoyliminopyridinium ylides was also ex-
plored.[20] Following the previous gold-catalyzed procedure,
the reaction of ylides with hydroperoxides 1 worked well to
provide a series of pyrazole-embedded polycycles 9–11 as
1 into pyrazolyl based fused heterocycles 9–11 should initially
consist of a regioselective 1,3-dipolar capture approach in
which the generated a,b-unsaturated ketone serves as a dipo-
larophile to afford intermediates 12–14. Under the reaction
conditions, tricycles 12–14 evolve to fused pyrazoles through
debenzoylation with concomitant aromatization.
The crucial role of the hydroperoxide functionality was ex-
amined in several experiments (Scheme 7): 1) Propargylic hy-
droperoxide 1a was treated with 3-bromoaniline to give b-
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under PTSA-free reaction conditions, tricycle 4a was obtained
after slightly prolonged time (from 2.5 to 5 h). This would sug-
gest that PTSA is not necessary for the reaction to proceed, be-
cause this process is catalyzed by gold. However, the consider-
able decrease of yield in the formation of tricycle 4a (from 71
to 47%) may point to a Brønsted acid cocatalysis. Indeed, gold
salts are readily hydrolizable in presence of water and are
a possible source of catalytic protons as recognized by Hashmi
and others.[21]
A possible pathway for the gold–acid-co-catalyzed synthesis
of fused azaheterocycles from propargylic hydroperoxides and
aromatic amines may or may not involve a b-aminoketone in-
termediate. The obtention of aza-Michael type adducts 15a
and 18O-15b (Scheme 7) leads us to propose a mechanism,
which is illustrated in Scheme 8, and occurs through b-amino-
ketone species. A tentative explanation for the gold–acid-co-
catalyzed synthesis of fused azaheterocycles from propargylic
hydroperoxides and aromatic amines is exemplified with the
reaction using 3-aminopyrazole by the obtention of pyrazolo-
[1,5-a]pyrimidines 3 (Scheme 8). The reaction may tentatively
be classified as cooperative concurrent catalysis, involving a cat-
alytic action by the AuI salt on the alkynic site (Scheme 8, right
catalytic cycle), and by the Brønsted acid on the activation of
the transient aminoketonic intermediate (Scheme 8, left cata-
lytic cycle).
Scheme 7. Control experiments.
aminoketone 15a in good yield;
2) Propargylic hydroperoxide 1b
was treated with p-anisidine in
presence of H218O to give b-ami-
noketone 18O-15b with 40% 18O
content; 3) Propargylic alcohol
16a did not react neither with 3-
bromoaniline nor with 3,5-di-
methoxyaniline, because b-hy-
droxyketone 17a was formed
during standard treatment but
nothing else; 4) compound 18a,
the acetate of 16a, was nearly
unreactive to the exposure with
3,5-dimethoxyaniline. In short,
propargylic alcohols as well as
their acetates are not suitable
substrates. Under otherwise
identical conditions, the particu-
Scheme 8. Mechanistic explanation for the gold–acid-co-catalyzed reaction of propargylic hydroperoxides with 3-
aminopyrazole.
Conclusion
lar characteristics of the OOH functional group allow a different
mechanism to happen, which cannot apply to propargylic al-
cohol derivatives.
We report that hydroperoxy alkynes were directly transformed
into a wide diversity of fused azaheterocycles under acidic con-
ditions. This transformation involved an interesting gold-cata-
lyzed hydroperoxide rearrangement/Michael reaction followed
by a final acid-catalyzed cyclization. The methodology could
be valuable for the construction of structurally new heterocy-
clic systems using propargylic hydroperoxides and aromatic
amines as the starting materials.
The last task was to examine the effect of the Brønsted acid.
A control experiment that would clarify the participation of
protons as the active catalysts in the reaction was undertaken
(Scheme 7). No strong difference of reactivity using gold salts
or gold/PTSA as catalysts was observed, because when propar-
gylic hydroperoxide 1a was treated with 1H-indazol-3-amine
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(Ar), 1206 (CÀO), 824 cmÀ1 (Ar); HRMS (ES): m/z calcd for
C18H17NO3: 295.1208 [M]+; found: 295.1212.
Experimental Section
General methods
1H NMR and 13C NMR spectra were recorded on a Bruker Avance
AVIII-700 with cryoprobe, Bruker Avance-300, or Varian VRX-300S.
NMR spectra were recorded in CDCl3 solutions, except otherwise
stated. Chemical shifts are given in ppm relative to TMS (1H, d=
0.0 ppm), or CDCl3 (13C, d=76.9 ppm). Low- and high-resolution
mass spectra were taken on an AGILENT 6520 Accurate-Mass QTOF
LC/MS spectrometer using the electronic impact (EI) or electro-
spray modes (ES) unless otherwise stated. All commercially avail-
able compounds were used without further purification.
Quinoline 2b: From propargylic hydroperoxide 1b (60 mg,
0.41 mmol), and after chromatography of the residue using ethyl
acetate/dichloromethane (0.5:9.5) as eluent gave the quinoline 2b
1
(72 mg, 67%) as a pale-brown oil. H NMR (300 MHz, CDCl3, 258C):
d=3.98 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 6.52 (d, 1H, J=2.2 Hz,
Ar), 7.12 (d, 1H, J=2.1 Hz, Ar), 7.50 (m, 3H, Ph), 7.71 (d, 1H, J=
8.6 Hz, Ar), 8.14 (m, 2H, Ph), 8.50 ppm (dd, 1H, J=8.6, 0.8 Hz, Ar);
13C NMR (75 MHz, CDCl3, 258C): d=161.5 (OCq), 158.1 (OCq), 156.0
(Cq), 150.5 (Cq), 139.9 (Cq), 131.4 (CH Ar), 129.1 (CH Ph), 128.8 (2CH
Ph), 127.5 (2CH Ph), 115.9 (CH Ar), 115.6 (Cq), 100.1 (CH Ar), 98.0
(CH Ar), 55.8 (OCH3), 55.6 ppm (OCH3); IR (CHCl3): n˜ =2929 (Ar),
1207 (CÀO), 831 cmÀ1 (Ar); HRMS (ES): m/z calcd for C17H15NO2:
265.1103 [M]+; found: 265.1101.
CAUTION! Organic peroxides are potentially hazardous compounds
and should be handled very carefully. If elementary precautions are
taken, the work with propargylic hydroperoxides 1 is safe; we have
never experienced any difficulties working with compound 1. Hy-
droperoxides 1 are stable compounds because: 1) 0.1m solutions
(around 50 mg) in 1,2-dichloroethane (DCE) can be safely heated at
1208C for several hours under microwave irradiation; 2) 10 mg of
hydroperoxide 1b (neat product) can be heated at 2508C with de-
composition but not explosion; 3) They did not decompose under
strong light; and 4) They are not friction/shock-sensitive because
hydroperoxides 1 are not altered after gentle scratching with
a spatula. Although we did not suffer any explosion, only a small
amount of material should be prepared at a time, and it should be
handled with great care. When handling organic peroxides, expo-
sure to heat, light, or redox-active metal salts should be avoided.
Reactions were performed on small scale and behind a safety
shield.[22] Additional appropriate safety precautions such as face
shields and protective clothing should be taken when dealing with
large quantities
Quinoline 2c: From propargylic hydroperoxide 1c (60 mg,
0.26 mmol), and after chromatography of the residue using hex-
anes/ethyl acetate (4:1) as eluent gave the quinoline 2c (55 mg,
61%) as a pale-brown solid. M.p. 103–1048C; 1H NMR (300 MHz,
CDCl3, 258C): d=3.98 (s, 3H, OCH3), 4.00 (s, 3H, OCH3), 6.53 (d, 1H,
J=2.2 Hz, Ar), 7.09 (d, 1H, J=2.0 Hz, Ar), 7.64 (d, 2H, J=8.6 Hz,
Ph), 7.66 (d, 1H, J=8.6 Hz, Ar), 8.03 (d, 2H, J=8.6 Hz, Ph),
8.50 ppm (dd, 1H, J=8.7, 0.6 Hz, Ar); 13C NMR (75 MHz, CDCl3,
258C): d=161.6 (OCq), 156.0 (OCq), 150.4 (Cq), 142.2 (Cq), 138.7 (Cq),
136.1 (Cq), 131.9 (2CH 4-BrPh), 131.6 (CH Ar), 129.0 (2CH 4-BrPh),
115.7 (Cq), 115.4 (CH Ar), 100.0 (CH Ar), 98.2 (CH Ar), 55.8 (OCH3),
55.7 ppm (OCH3); IR (CHCl3): n˜ =3003 (Ar), 1206 (CÀO), 819 cmÀ1
(Ar); HRMS (ES): m/z calcd for C17H14NO2Br: 343.0208 [M]+; found:
343.0212.
General procedure for the gold-catalyzed reaction of prop-
argylic hydroperoxides 1 with 3,5-dimethoxyaniline: Prepa-
ration of quinolines 2
Quinoline 2d: From propargylic hydroperoxide 1d (60 mg,
0.39 mmol), and after chromatography of the residue using hex-
anes/ethyl acetate (4:1) as eluent gave the quinoline 2d (59 mg,
56%) as a pale-brown solid. M.p. 105–1068C; 1H NMR (300 MHz,
CDCl3, 258C): d=3.96 (s, 3H, OCH3), 3.98 (s, 3H, OCH3), 6.48 (d, 1H,
J=2.2 Hz, Ar), 7.03 (d, 1H, J=2.1 Hz, Ar), 7.16 (dd, 1H, J=5.0,
3.7 Hz, thiophene), 7.45 (dd, 1H, J=5.0, 0.9 Hz, thiophene), 7.63 (d,
1H, J=8.7 Hz, Ar), 7.72 (dd, 1H, J=3.7, 1.0 Hz, thiophene),
8.42 ppm (d, 1H, J=8.7 Hz, Ar); 13C NMR (75 MHz, CDCl3, 258C):
d=161.6 (OCq), 156.0 (OCq), 153.0 (Cq), 150.3 (Cq), 145.6 (Cq), 131.3
(CH Ar), 128.2 (CH thiophene), 128.0 (CH thiophene), 125.6 (CH
thiophene), 115.5 (Cq), 114.4 (CH Ar), 99.8 (CH Ar), 97.9 (CH Ar), 55.8
(OCH3), 55.7 ppm (OCH3); IR (CHCl3): n˜ =1202 (CÀO), 820 cmÀ1 (Ar);
HRMS (ES): m/z calcd for C15H13NO2S: 271.0667 [M]+; found:
271.0678.
[AuCl(PPh3)] (4 mg, 0.0084 mmol), [AgOTf] (2.2 mg, 0.0084 mmol),
p-toluenesulfonic acid (5.9 mg, 0.034 mmol), 3,5-dimethoxyaniline
(104.2 mg, 0.68 mmol), and water (12.2 mg, 0.68 mmol) were se-
quentially added to a stirred solution of the corresponding propar-
gylic hydroperoxide 1 (0.34 mmol) in dichloromethane (2.7 mL).
The resulting mixture was stirred at RT or was heated in a sealed
tube at 508C until the disappearance of the starting material (TLC).
The reaction was allowed to cool to room temperature and filtered
through a pack of Celite. Saturated ammonium chloride (0.7 mL)
was added, before being partitioned between dichloromethane
and water. The organic extract was washed with brine, dried
(MgSO4), concentrated under vacuum, and purified by flash
column chromatography eluting with ethyl acetate/hexanes or
ethyl acetate/dichloromethane mixtures. Spectroscopic and analyti-
cal data for pure forms of compound 2 follow.
Quinoline 2e: From propargylic hydroperoxide 1e (60 mg,
0.37 mmol), and after chromatography of the residue using hex-
anes/ethyl acetate (6:1) as eluent gave the quinoline 2e (47 mg,
45%) as a pale-brown solid. M.p. 116–1178C; 1H NMR (300 MHz,
CDCl3, 258C): d=2.90 (s, 3H, Me), 3.94 (s, 3H, OCH3), 3.98 (s, 3H,
OCH3), 6.50 (d, 1H, J=2.4 Hz, Ar), 7.14 (s, 1H, Ar), 7.44 (s, 1H, Ar),
7.51 (m, 3H, Ph), 8.12 ppm (m, 2H, Ph); 13C NMR (75 MHz, CDCl3,
258C): d=161.7 (OCq), 160.5 (OCq), 158.6 (Cq), 148.1 (Cq), 140.2 (Cq),
129.1 (Cq), 129.0 (CH Ar), 128.7 (2CH Ph), 128.3 (CH Ph), 127.4 (2CH
Ph), 119.1 (CH Ar), 115.6 (Cq), 98.4 (CH Ar), 55.5 (OCH3), 55.5 (OCH3),
24.5 ppm (CH3); IR (CHCl3): n˜ =2922 (Ar), 1205 (CÀO), 696 cmÀ1
(Ar); HRMS (ES): m/z calcd for C18H17NO2: 279.1259 [M]+; found:
279.1261.
Quinoline 2a: From propargylic hydroperoxide 1a (60 mg,
0.34 mmol), and after chromatography of the residue using hex-
anes/ethyl acetate (4:1) as eluent gave the quinoline 2a (72 mg,
72%) as a pale-brown solid. M.p. 120–1218C; 1H NMR (300 MHz,
CDCl3, 258C): d=3.96 (s, 3H, OCH3), 3.97 (s, 3H, OCH3), 3.99 (s, 3H,
OCH3), 6.50 (d, 1H, J=2.2 Hz, Ar), 7.04 (d, 2H, J=8.9 Hz, PMP), 7.09
(d, 1H, J=2.0 Hz, Ar), 7.66 (d, 1H, J=8.7 Hz, Ar), 8.12 (d, 2H, J=
8.8 Hz, PMP), 8.45 ppm (dd, 1H, J=8.6, 0.6 Hz, Ar); 13C NMR
(75 MHz, CDCl3, 258C): d=161.4 (OCq), 160.7 (OCq), 157.6 (OCq),
156.0 (Cq), 150.5 (Cq), 132.5 (Cq), 131.2 (CH Ar), 128.8 (2CH PMP),
115.4 (CH Ar), 115.2 (Cq), 114.2 (2CH PMP), 100.0 (CH Ar), 97.7 (CH
Ar), 55.7 (OCH3), 55.6 (OCH3), 55.4 ppm (OCH3); IR (CHCl3): n˜ =2935
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(CH3); IR (CHCl3): n˜ =765 cmÀ1 (Ar); HRMS (ES): m/z calcd for
C13H11N3: 209.0953 [M]+; found: 209.0955.
General procedure for the gold-catalyzed reaction of prop-
argylic hydroperoxides 1 with 3-aminopyrazole: Preparation
of pyrazolo[1,5-a]pyrimidines 3
[AuCl(PPh3)] (4 mg, 0.0084 mmol), [AgOTf] (2.2 mg, 0.0084 mmol),
p-toluenesulfonic acid (5.9 mg, 0.034 mmol), 3-aminopyrazole
(56.5 mg, 0.68 mmol), and water (12.2 mg, 0.68 mmol) were se-
quentially added to a stirred solution of the corresponding propar-
gylic hydroperoxide 1 (0.34 mmol) in 1,2-dichloroethane (2.7 mL).
The resulting mixture was stirred at 1208C under microwave irradi-
ation until disappearance of the starting material (TLC). The reac-
tion was allowed to cool to room temperature and filtered through
a pack of Celite. Saturated ammonium chloride (0.7 mL) was
added, before being partitioned between dichloromethane and
water. The organic extract was washed with brine, dried (MgSO4),
concentrated under vacuum, and purified by flash column chroma-
tography eluting with ethyl acetate/hexanes mixtures. Spectro-
scopic and analytical data for pure forms of compounds 3 follow.
General procedure for the gold-catalyzed reaction of prop-
argylic hydroperoxides 1 with 1H-indazol-3-amine: Prepara-
tion of pyrimido[1,2-b]indazoles 4
[AuCl(PPh3)] (4 mg, 0.0084 mmol), [AgOTf] (2.2 mg, 0.0084 mmol),
p-toluenesulfonic acid (5.9 mg, 0.034 mmol), 1H-indazol-3-amine
(90.5 mg, 0.68 mmol), and water (12.2 mg, 0.68 mmol) were se-
quentially added to a stirred solution of the corresponding propar-
gylic hydroperoxide 1 (0.34 mmol) in 1,2-dichloroethane (2.7 mL).
The resulting mixture was stirred at 1208C under microwave irradi-
ation until disappearance of the starting material (TLC). The reac-
tion was allowed to cool to room temperature and filtered through
a pack of Celite. Saturated ammonium chloride (0.7 mL) was
added, before being partitioned between dichloromethane and
water. The organic extract was washed with brine, dried (MgSO4),
concentrated under vacuum, and purified by flash column chroma-
tography eluting with ethyl acetate/hexanes mixtures. Spectro-
scopic and analytical data for pure forms of compounds 4 follow.
Pyrazolo[1,5-a]pyrimidine 3a: From propargylic hydroperoxide
1a (50 mg, 0.28 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (4:1) as eluent gave the pyrazolo[1,5-
a]pyrimidine 3a (48 mg, 76%) as a yellow solid. M.p. 106–1078C;
1H NMR (300 MHz, CDCl3, 258C): d=3.91 (s, 3H, OCH3), 6.78 (d, 1H,
J=2.4 Hz, Ar), 6.89 (d, 1H, J=4.4 Hz, Ar), 7.09 (d, 2H, J=9.0 Hz,
PMP), 8.08 (d, 2H, J=9.0 Hz, PMP), 8.18 (d, 1H, J=2.3 Hz, Ar),
8.51 ppm (d, 1H, J=4.4 Hz, Ar); 13C NMR (75 MHz, CDCl3, 258C):
d=161.8 (Cq), 149.9 (Cq), 148.9 (CH Ar), 144.6 (CH Ar), 130.9 (2CH
PMP), 129.0 (Cq), 123.2 (Cq), 114.1 (2CH PMP), 106.5 (CH Ar), 96.8
(CH Ar), 55.5 ppm (OCH3); IR (CHCl3): n˜ =1255 (CÀO), 777 cmÀ1 (Ar);
HRMS (ES): m/z calcd for C13H11N3O: 225.0902 [M]+; found:
225.0909.
Pyrimido[1,2-b]indazole 4a: From propargylic hydroperoxide 1a
(100 mg, 0.56 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (3:1) as eluent gave the pyrimido[1,2-
b]indazole 4a (109 mg, 71%) as a yellow solid. M.p. 145–1468C;
1H NMR (300 MHz, CDCl3, 258C): d=3.93 (s, 3H, CH3), 7.13 (d, 2H,
J=8.9 Hz, PMP), 7.28 (d, 1H, J=4.6 Hz, Ar), 7.32 (m, 1H, Ar), 7.64
(ddd, 1H, J=8.5, 6.6, 1.0 Hz, Ar), 7.88 (d, 1H J=8.7 Hz, Ar), 8.25 (d,
2H, J=8.9 Hz, PMP), 8.36 (d, 1H, J=8.3 Hz, Ar), 8.66 ppm (d, 1H,
J=4.5 Hz, Ar); 13C NMR (75 MHz, CDCl3, 258C): d=161.8 (OCq),
151.0 (Cq), 145.0 (2Cq), 145.0 (CH Ar), 131.1 (2CH PMP), 129.8 (CH
Ar), 123.4 (Cq), 120.8 (CH Ar), 120.7 (CH Ar), 116.4 (CH Ar), 114.2
(2CH PMP), 113.4 (Cq), 110.4 (CH Ar), 55.5 ppm (OCH3); IR (CHCl3):
n˜ =1255 (CÀO), 750 cmÀ1 (Ar); HRMS (ES): m/z calcd for C17H13N3O:
275.1059 [M]+; found: 275.1068.
Pyrazolo[1,5-a]pyrimidine 3b: From propargylic hydroperoxide
1b (50 mg, 0.34 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (4:1) as eluent gave the pyrazolo[1,5-
a]pyrimidine 3b (45 mg, 67%) as a pale-brown oil; 1H NMR
(300 MHz, CDCl3, 258C): d=6.80 (d, 1H, J=2.4 Hz, Ar), 6.91 (d, 1H,
J=4.3 Hz, Ar), 7.59 (m, 3H, Ph), 8.05 (d, 2H, Ph), 8.19 (d, 1H, J=
2.3 Hz, Ar), 8.55 ppm (d, 1H, J=4.3 Hz, Ar); 13C NMR (75 MHz,
CDCl3, 258C): d=149.9 (Cq), 149.0 (CH Ar), 145.6 (Cq), 144.7 (CH Ar),
131.1 (Cq), 131.0 (CH Ph), 129.2 (2CH Ph), 128.7 (2CH Ph), 107.3 (CH
Ar), 97.1 ppm (CH Ar); IR (CHCl3): n˜ =772 cmÀ1 (Ar); HRMS (ES): m/z
calcd for C12H9N3: 195.0796 [M]+; found: 195.0799.
Pyrimido[1,2-b]indazole 4b: From propargylic hydroperoxide 1b
(30 mg, 0.20 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (5:1) as eluent gave the pyrimido[1,2-
b]indazole 4b (29 mg, 69%) as a yellow solid. M.p. 146–1478C;
1H NMR (300 MHz, CDCl3, 258C): d=7.33 (d, 1H, J=4.5 Hz, Ar), 7.36
(m, 1H, Ar), 7.63 (m, 3H, Ph), 7.67 (m, 1H, Ar), 7.89 (dt, 1H J=8.7,
0.8 Hz, Ar), 8.22 (m, 2H, Ph), 8.38 (dt, 1H, J=8.3, 1.1 Hz, Ar),
8.71 ppm (d, 1H, J=4.5 Hz, Ar); 13C NMR (75 MHz, CDCl3, 258C):
d=151.0 (Cq), 145.3 (Cq), 145.0 (CH Ar), 134.2 (Cq), 134.0 (Cq), 131.2
(CH Ph), 129.9 (CH Ar), 129.4 (2CH Ph), 128.9 (2CH Ph), 121.0 (CH
Ar), 120.8 (CH Ar), 116.5 (CH Ar), 113.4 (Cq), 111.2 ppm (CH Ar); IR
(CHCl3): n˜ =759 cmÀ1 (Ar); HRMS (ES): m/z calcd for C16H11N3:
245.0953 [M]+; found: 245.0958.
Pyrazolo[1,5-a]pyrimidine 3c: From propargylic hydroperoxide 1c
(70 mg, 0.31 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (4:1) as eluent gave the pyrazolo[1,5-
a]pyrimidine 3c (73 mg, 86%) as a yellow solid. M.p. 153–1548C;
1H NMR (300 MHz, CDCl3, 258C): d=6.81 (d, 1H, J=2.4 Hz, Ar), 6.90
(d, 1H, J=4.3 Hz, Ar), 7.72 (d, 2H, J=8.6 Hz, 4-BrPh), 7.95 (d, 2H,
J=8.6 Hz, 4-BrPh), 8.18 (d, 1H, J=2.4 Hz, Ar), 8.55 ppm (d, 1H, J=
4.3 Hz, Ar); 13C NMR (75 MHz, CDCl3, 258C): d=149.8 (Cq), 148.9 (CH
Ar), 145.7 (Cq), 144.8 (CH Ar), 132.0 (2CH 4-BrPh), 130.7 (2CH 4-
BrPh), 129.9 (Cq), 125.6 (Cq), 107.1 (CH Ar), 97.3 ppm (CH Ar); IR
(CHCl3): n˜ =770 cmÀ1 (Ar); HRMS (ES): m/z calcd for C12H8N3Br:
272.9902 [M]+; found: 272.9915.
Pyrimido[1,2-b]indazole 4c: From propargylic hydroperoxide 1c
(50 mg, 0.22 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (5:1) as eluent gave the pyrimido[1,2-
b]indazole 4c (61 mg, 85%) as a yellow solid. M.p. 136–1478C;
1H NMR (300 MHz, CDCl3, 258C): d=7.31 (d, 1H, J=4.5 Hz, Ar), 7.35
(ddd, 1H, J=8.2, 6.7, 0.8 Hz, Ar), 7.66 (ddd, 1H, J=8.8, 6.7, 1.1 Hz,
Ar), 7.77 (d, 2H, J=8.6 Hz, 4-BrPh), 7.88 (d, 1H J=8.7 Hz, Ar), 8.12
(d, 2H, J=8.6 Hz, 4-BrPh), 8.37 (dt, 1H, J=8.3, 1.0 Hz, Ar), 8.70 ppm
(d, 1H, J=4.5 Hz, Ar); 13C NMR (75 MHz, CDCl3, 258C): d=151.0
(Cq), 145.1 (Cq), 145.0 (CH Ar), 144.0 (Cq), 132.1 (2CH 4-BrPh), 130.9
(2CH 4-BrPh), 130.0 (CH Ar), 128.3 (Cq), 125.7 (Cq), 121.2 (CH Ar),
120.8 (CH Ar), 116.5 (CH Ar), 113.5 (Cq), 110.9 ppm (CH Ar); IR
(CHCl3): n˜ =750 cmÀ1 (Ar); HRMS (ES): m/z calcd for C16H10N3Br:
323.0058 [M]+; found: 323.0045.
Pyrazolo[1,5-a]pyrimidine 3e: From propargylic hydroperoxide
1e (50 mg, 0.31 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (5:1) as eluent gave the pyrazolo[1,5-
a]pyrimidine 3e (38 mg, 61%) as
a
pale-brown oil. 1H NMR
(300 MHz, CDCl3, 258C): d=2.67 (s, 3H, CH3), 6.66 (d, 1H, J=2.3 Hz,
Ar), 6.78 (s, 1H, Ar), 7.57 (m, 3H, Ph), 8.12 (m, 2H, Ph), 8.12 ppm (d,
1H, J=2.3 Hz, Ar); 13C NMR (75 MHz, CDCl3, 258C): d=158.7 (Cq),
149.4 (Cq), 146.3 (Cq), 144.7 (CH Ar), 131.1 (Cq), 130.9 (CH Ph), 129.2
(2CH Ph), 128.7 (2CH Ph), 108.3 (CH Ar), 95.8 (CH Ar), 24.7 ppm
Chem. Eur. J. 2014, 20, 3384 – 3393
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Pyrimido[1,2-b]indazole 4e: From propargylic hydroperoxide 1e
(50 mg, 0.31 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (6:1) as eluent gave the pyrimido[1,2-
b]indazole 4e (63 mg, 78%) as a yellow solid. M.p. 157–1588C;
1H NMR (300 MHz, CDCl3, 258C): d=2.83 (s, 3H, CH3), 7.18 (s, 1H,
Ar), 7.27 (ddd, 1H, J=8.4, 6.8, 0.8 Hz, Ar), 7.61 (m, 4H, 3H Ph+1H
Ar), 7.83 (dt, 1H J=8.8, 0.8 Hz, Ar), 8.17 (m, 2H, Ph), 8.34 ppm (dt,
1H, J=8.3, 1.0 Hz, Ar); 13C NMR (75 MHz, CDCl3, 258C): d=155.4
(Cq), 151.2 (Cq), 144.9 (Cq), 144.6 (Cq), 131.4 (Cq), 131.0 (CH Ph),
129.6 (CH Ar), 129.4 (2CH Ph), 128.8 (2CH Ph), 120.9 (CH Ar), 120.4
(CH Ar), 116.4 (CH Ar), 112.8 (Cq), 112.1 (CH Ar), 24.5 ppm (CH3); IR
(CHCl3): n˜ =757 cmÀ1 (Ar); HRMS (ES): m/z calcd for C17H13N3:
259.1109 [M]+; found: 259.1108.
due using ethyl acetate/dichloromethane (0.5:9.5) as eluent gave
the dipyrido[1,2-a:3’,2’-d]imidazole 5e (35 mg, 43%) as a pale-
1
brown solid. M.p. 158–1598C; H NMR (700 MHz, CDCl3, 258C): d=
5.19 (s, 3H, CH3), 7.42 (m, 1H, Ph), 7.51 (t, 1H, J=6.9 Hz, Ar), 7.60
(t, 1H, J=7.5 Hz, Ph), 7.70 (t, 1H, J=7.7 Hz, Ph), 7.73 (s, 1H, Ar),
7.86 (d, 1H, J=8.3 Hz, Ph), 8.02 (d, 1H, J=7.7 Hz, Ph), 8.07 (t, 1H,
J=7.7 Hz, Ar), 8.94 (d, 1H, J=8.8 Hz, Ar), 9.14 ppm (d, 1H, J=
6.6 Hz, Ar); 13C NMR (175 MHz, CDCl3, 258C): d=153.9 (Cq), 146.2
(Cq), 143.6 (Cq), 138.8 (Cq), 137.4 (Cq), 131.0 (CH Ar), 130.3 (2CH Ph),
129.9 (CH Ph), 127.5 (2CH Ph), 125.1 (CH Ar), 123.7 (CH Ar), 121.4
(Cq), 116.4 (CH Ar), 115.5 (CH Ar), 24.4 ppm (CH3); IR (CHCl3): n˜ =
756 cmÀ1 (Ar); HRMS (ES): m/z calcd for C17H13N3: 259.1109 [M]+;
found: 259.1115.
Pyrimido[1,2-b]indazole 4 f: From propargylic hydroperoxide 1 f
(50 mg, 0.22 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (4:1) as eluent gave the pyrimido[1,2-
b]indazole 4 f (50 mg, 70%) as a yellow solid. M.p. 139–1418C;
1H NMR (300 MHz, CDCl3, 258C): d=7.25 (d, 1H, J=4.3 Hz, Ar), 7.36
(ddd, 1H, J=8.5, 6.8, 0.9 Hz, Ar), 7.58 (m, 4H, Ar), 7.83 (dd, 1H, J=
7.9, 1.0 Hz, Ar), 7.88 (dt, 1H, J=8.8, 0.8 Hz, Ar), 8.39 ppm (dt, 1H,
J=8.2, 1.0 Hz, Ar), 8.74 (d, 1H, J=4.3 Hz, Ar); 13C NMR (75 MHz,
CDCl3, 258C): d=151.1 (Cq), 144.5 (CH Ar+Cq), 144.3 (Cq), 133.6 (CH
2-BrPh), 133.0 (Cq), 131.9 (CH 2-BrPh), 131.2 (CH 2-BrPh), 129.9 (CH
Ar), 127.7 (CH 2-BrPh), 123.0 (Cq), 121.2 (CH Ar), 120.8 (CH Ar), 116.8
(CH Ar), 113.6 (Cq), 112.9 ppm (CH Ar); IR (CHCl3): n˜ =753 cmÀ1 (Ar);
HRMS (ES): m/z calcd for C16H10N3Br: 323.0058 [M]+; found:
323.0047.
Dipyrido[1,2-a:3’,2’-d]imidazole 5g: From propargylic hydroper-
oxide 1g (40 mg, 0.16 mmol), and after chromatography of the res-
idue using hexanes/ethyl acetate (3:1) as eluent gave the dipyri-
do[1,2-a:3’,2’-d]imidazole 5g (27 mg, 49%) as a pale-brown solid.
M.p. 162–1648C; 1H NMR (700 MHz, CDCl3, 258C): d=5.19 (s, 2H,
OCH2), 7.31 (d, 2H, J=7.8 Hz, PMP), 7.36 (t, 1H, J=7.4 Hz, Ph), 7.43
(t, 2H, J=7.5 Hz, Ph), 7.49 (d, 2H, J=7.2 Hz, Ph), 7.55 (t, 1H, J=
6.8 Hz, Ar), 7.83 (d, 1H, J=4.9 Hz, Ar), 8.07 (d, 2H, J=8.1 Hz, PMP),
8.12 (t, 1H, J=7.7 Hz, Ar), 8.71 (d, 1H, J=4.9 Hz, Ar), 9.00 (d, 1H,
J=7.4 Hz, Ar), 9.16 ppm (d, 1H, J=6.6 Hz, Ar); 13C NMR (175 MHz,
CDCl3, 258C): d=162.2 (OCq), 146.1 (CH Ar), 143.8 (Cq), 139.3 (Cq),
138.5 (Cq), 137.9 (Cq) 136.4 (CH Ar), 135.1 (Cq), 130.6 (2CH PMP),
128.6 (2CH Ph), 128.1 (CH Ph), 127.7 (2CH Ph), 125.2 (CH Ar), 124.7
(Cq), 122.8 (CH Ar), 116.6 (CH Ar), 116.3 (2CH PMP), 115.5 (CH Ar),
70.2 ppm (OCH2); IR (CHCl3): n˜ =1251 (CÀO), 750 cmÀ1 (Ar); HRMS
(ES): m/z calcd for C23H17N3O: 351.1372 [M]+; found: 351.1377.
General procedure for the gold-catalyzed reaction of prop-
argylic hydroperoxides 1 with imidazo[1,2-a]pyridin-3-
amine: Preparation of dipyrido[1,2-a:3’,2’-d]imidazoles 5
General procedure for the gold-catalyzed reaction of prop-
argylic hydroperoxides 1 with 1H-indol-2-amine: Prepara-
tion of a-carbolines 6 and benzo[cd]indol-2-amines 7
[AuCl(PPh3)] (4 mg, 0.0084 mmol), [AgOTf] (2.2 mg, 0.0084 mmol),
p-toluenesulfonic acid (5.9 mg, 0.034 mmol), imidazo[1,2-a]pyridin-
3-amine (90.5 mg, 0.68 mmol), and water (12.2 mg, 0.68 mmol)
were sequentially added to a stirred solution of the corresponding
propargylic hydroperoxide 1 (0.34 mmol) in 1,2-dichloroethane
(2.7 mL). The resulting mixture was stirred at 1208C under micro-
wave irradiation until disappearance of the starting material (TLC).
The reaction was allowed to cool to room temperature and filtered
through a pack of Celite. Saturated ammonium chloride (0.7 mL)
was added, before being partitioned between dichloromethane
and water. The organic extract was washed with brine, dried
(MgSO4), concentrated under vacuum, and purified by flash
column chromatography eluting with ethyl acetate/hexanes or
ethyl acetate/dichloromethane mixtures. Spectroscopic and analyti-
cal data for pure forms of compounds 5 follow.
[AuCl(PPh3)] (2.7 mg, 0.0054 mmol), [AgOTf] (1.4 mg, 0.0054 mmol),
p-toluenesulfonic acid (3.8 mg, 0.022 mmol), 1H-indol-2-amine
(58.2 mg, 0.44 mmol), and water (7.9 mg, 0.44 mmol) were sequen-
tially added to a stirred solution of the corresponding propargylic
hydroperoxide 1 (0.22 mmol) in 1,2-dichloroethane (1.8 mL). The
resulting mixture was stirred at 1208C under microwave irradiation
until disappearance of the starting material (TLC). The reaction was
allowed to cool to room temperature and filtered through a pack
of Celite. Saturated ammonium chloride (0.5 mL) was added,
before being partitioned between dichloromethane and water. The
organic extract was washed with brine, dried (MgSO4), concentrat-
ed under vacuum, and purified by flash column chromatography
eluting with ethyl acetate/hexane mixtures. Spectroscopic and ana-
lytical data for pure forms of compounds 6 and 7 follow.
Dipyrido[1,2-a:3’,2’-d]imidazole 5a: From propargylic hydroperox-
ide 1a (50 mg, 0.28 mmol), and after chromatography of the resi-
due using hexanes/ethyl acetate (4:1) as eluent gave the dipyri-
do[1,2-a:3’,2’-d]imidazole 5a (42 mg, 55%) as a pale-brown solid.
M.p. 126–1288C; 1H NMR (700 MHz, CDCl3, 258C): d=3.93 (s, 3H,
CH3), 7.23 (d, 2H, J=7.2 Hz, PMP), 7.55 (t, 1H, J=6.6 Hz, Ar), 7.84
(d, 1H, J=4.5 Hz, Ar), 8.07 (d, 2H, J=7.0 Hz, PMP), 8.12 (m, 1H, Ar),
8.71 (d, 1H, J=4.5 Hz, Ar), 9.01 (d, 1H, J=6.4 Hz, Ar), 9.16 ppm (d,
J=6.4 Hz, Ar); 13C NMR (175 MHz, CDCl3, 258C): d=162.0 (OCq),
146.1 (CH Ar), 143.9 (Cq), 139.3 (Cq), 138.6 (Cq), 137.9 (CH Ar), 132.1
(Cq), 130.6 (2CH PMP), 125.2 (CH Ar), 124.5 (Cq), 122.7 (CH Ar), 116.6
(CH Ar), 115.5 (2CH PMP+CH Ar), 55.6 ppm (OCH3); IR (CHCl3): n˜ =
1255 (CÀO), 759 cmÀ1 (Ar); HRMS (ES): m/z calcd for C17H13N3O:
275.1059 [M]+; found: 275.1055.
Treatment of hydroperoxide 1a with 1H-indol-2-amine
From hydroperoxide 1a (40 mg, 0.22 mmol), and after chromatog-
raphy of the residue using hexanes/ethyl acetate (4:1) as eluent,
18 mg (30%) of the less polar compound 6a and 17 mg (28%) of
the more polar compound 7a were obtained.
a-Carboline 6a: Red solid. M.p. 143–1458C; 1H NMR (700 MHz,
CDCl3, 258C): d=3.91 (s, 3H, OCH3), 7.14 (d, 2H, J=8.8 Hz, PMP),
7.44 (m, 1H, Ar), 7.63 (m, 2H, Ar), 7.68 (d, 1H, J=8.1 Hz, Ar), 8.10
(d, 1H, J=7.8 Hz, Ar), 8.16 (d, 2H, J=8.8 Hz, PMP), 8.67 (d, 1H, J=
8.1 Hz, Ar), 11.65 ppm (brs, 1H, NH); 13C NMR (175 MHz, CDCl3,
258C): d=162.7 (OCq), 145.6 (Cq), 145.1 (Cq), 138.7 (Cq), 135.0 (CH
Ar), 130.2 (Cq), 129.4 (CH Ar), 129.3 (2CH PMP), 122.8 (CH Ar), 121.2
(CH Ar), 119.4 (Cq), 119.3 (Cq), 115.5 (2CH PMP), 113.1 (CH Ar), 111.7
Dipyrido[1,2-a:3’,2’-d]imidazole 5e: From propargylic hydroperox-
ide 1e (50 mg, 0.31 mmol), and after chromatography of the resi-
Chem. Eur. J. 2014, 20, 3384 – 3393
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ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

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(CH Ar), 55.6 ppm (OCH3); IR (CHCl3): n˜ =3223 (NH), 1254 (CÀO),
748 cmÀ1 (Ar); HRMS (ES): m/z calcd for C18H14N2O: 274.1106 [M]+;
found: 274.1102.
Benzo[cd]indol-2-amine 7g: Red solid. M.p. 139–1418C; 1H NMR
(700 MHz, CDCl3, 258C): d=5.22 (s, 2H, OCH2), 7.18 (t, 1H, J=
7.6 Hz, Ar), 7.21 (d, 2H, J=8.4 Hz, BnOPh), 7.37 (m, 1H, Ar), 7.39
(m, 1H, Ph), 7.45 (t, 2H, J=7.5 Hz, Ph), 7.52 (d, 2H, J=8.1 Hz, Ph),
7.53 (m, 1H, Ar), 7.67 (d, 2H, J=8.3 Hz, BnOPh), 7.82 (d, 1H, J=
8.0 Hz, Ar), 8.34 ppm (brs, 1H, Ar); 13C NMR (175 MHz, CDCl3, 258C):
d=164.9 (NCq), 160.2 (OCq), 149.3 (Cq), 145.0 (Cq), 138.8 (CH Ar),
136.4 (Cq), 133.0 (Cq), 130.1 (2CH BnOPh), 128.7 (2CH Ph), 128.4 (CH
Ar), 128.3 (CH Ph), 127.6 (2CH Ph), 122.7 (CH Ar), 121.3 (CH Ar),
119.9 (Cq), 116.3 (Cq), 116.2 (Cq), 115.4 (2CH BnOPh), 112.3 (CH Ar),
70.2 ppm (OCH2); IR (CHCl3): n˜ =3210 (NH2), 1244 (CÀO), 745 cmÀ1
(Ar); HRMS (ES): m/z calcd for C24H18N2O: 350.1419 [M]+; found:
350.1410.
Benzo[cd]indol-2-amine 7a: Red solid. M.p. 137–1388C; 1H NMR
(700 MHz, CDCl3, 258C): d=3.95 (s, 3H, OCH3), 7.13 (d, 2H, J=
8.7 Hz, PMP), 7.16 (d, 1H, J=5.4 Hz, Ar), 7.48 (t, 1H, J=7.3 Hz, Ar),
7.56 (d, 1H, J=8.1 Hz, Ar), 7.66 (d, 2H, J=8.6 Hz, PMP), 7.79 ppm
(d, 1H, J=8.0 Hz, Ar), 8.39 (d, 1H, J=5.3 Hz, Ar); 13C NMR
(175 MHz, CDCl3, 258C): d=161.3 (NCq), 160.6 (OCq), 149.7 (Cq),
147.8 (Cq), 140.7 (CH Ar), 138.7 (Cq), 130.0 (2CH PMP), 127.7 (CH Ar),
122.7 (CH Ar), 120.6 (CH Ar), 120.3 (Cq), 115.6 (Cq), 114.6 (Cq), 114.3
(2CH PMP), 111.7 (CH Ar), 55.4 ppm (OCH3); IR (CHCl3): n˜ =3145
(NH2), 1252 (CÀO), 746 (Ar) cmÀ1; HRMS (ES): m/z calcd for
C18H14N2O: 274.1106 [M]+; found: 274.1094.
a-Carboline 6h: From propargylic hydroperoxide 1h (50 mg,
0.25 mmol), and after chromatography of the residue using hex-
anes/ethyl acetate (4:1) as eluent gave the a-carboline 6h (23 mg,
34%) as a pale-brown solid. M.p. 115–1528C; 1H NMR (700 MHz,
CDCl3, 258C): d=4.64 (d, 2H, J=5.3 Hz, OCH2), 5.35 (dd, 1H, J=
10.5, 1.3 Hz, =CHH), 5.47 (dd, 1H, J=17.3, 1.4, Hz, =CHH), 6.09 (ddt,
1H, J=17.2, 10.6, 5.3 Hz, =CH), 7.13 (d, 2H, J=8.8 Hz, allylO-Ph),
7.41 (m, 1H, Ar), 7.58 (m, 2H, Ar), 7.66 (d, 1H, J=8.1 Hz, Ar), 8.09
(d, 1H, J=7.8 Hz, Ar), 8.13 (d, 2H, J=8.8 Hz, allylO-Ph), 8.60 ppm
(d, 1H J=8.1 Hz, Ar); 13C NMR (175 MHz, CDCl3, 258C): d=161.1
(OCq), 147.5 (Cq), 146.7 (Cq), 138.7 (Cq), 133.5 (CH Ar), 132.5 (=CH),
132.4 (Cq), 129.0 (2CH allylO-Ph), 128.7 (CH Ar), 122.2 (CH Ar), 121.1
(CH Ar), 119.8 (Cq), 118.3 (=CH2), 118.0 (Cq), 115.9 (2CH allylO-Ph),
112.6 (CH Ar), 111.9 (CH Ar), 69.0 ppm (OCH2); IR (CHCl3): n˜ =3207
(NH), 1247 (CÀO), 745 cmÀ1 (Ar); HRMS (ES): m/z calcd for
C20H16N2O: 300.1263 [M]+; found: 300.1257.
Treatment of hydroperoxide 1 f with 1H-indol-2-amine
From hydroperoxide 1 f (50 mg, 0.22 mmol), and after chromatog-
raphy of the residue using hexanes/ethyl acetate (5:1) as eluent,
18 mg (26%) of the less polar compound 6 f and 16 mg (23%) of
the more polar compound 7 f were obtained.
1
a-Carboline 6 f: Red solid. M.p. 97–988C; H NMR (700 MHz, CDCl3,
258C): d=7.40 (m, 2H, Ar+2-BrPh), 7.50 (d, 1H, J=8.1 Hz, 2-BrPh),
7.52 (t, 1H, J=7.4 Hz, Ar), 7.58 (t, 1H, J=8.1 Hz, Ar), 7.61 (d, 1H,
J=7.8 Hz, Ar), 7.72 (dd, 1H, J=6.4, 1.3 Hz, 2-BrPh), 7.78 (d, 1H, J=
8.0 Hz, 2-BrPh), 8.13 (d, 1H, J=7.8 Hz, Ar), 8.61 ppm (d, 1H, J=
7.8 Hz, Ar); 13C NMR (175 MHz, CDCl3, 258C): d=144.4 (Cq), 144.2
(Cq), 139.1 (Cq), 134.0 (CH Ar), 133.5 (CH 2-BrPh), 132.4 (CH 2-BrPh),
131.8 (2-BrPh), 129.7 (CH Ar), 128.2 (Cq), 127.0 (CH 2-BrPh), 125.4
(Cq), 124.6 (Cq), 122.2 (CH Ar), 121.4 (CH Ar), 116.7 (CH Ar),
112. ppm (CH Ar); IR (CHCl3): n˜ =3210 (NH), 751 cmÀ1 (Ar); HRMS
(ES): m/z calcd for C17H11N2Br: 322.0106 [M]+; found: 322.0107.
Benzo[cd]indol-2-amine 7 f: Red solid. M.p. 128–1298C; 1H NMR
(700 MHz, CDCl3, 258C): d=7.07 (t, 1H, J=7.5 Hz, 2-BrPh), 7.14 (m,
1H, Ar), 7.44 (m, 1H, Ar), 7.47 (m, 2H, 2-BrPh), 7.52 (td, 1H, J=7.4,
0.8 Hz, 2-BrPh), 7.56 (d, 1H, J=8.1 Hz, Ar), 7.84 (d, 1H, J=7.7 Hz,
Ar), 8.56 ppm (d, 1H, J=4.8 Hz, Ar); 13C NMR (175 MHz, CDCl3,
258C): d=151.4 (NCq), 144.5 (Cq), 143.5 (CH Ar), 139.2 (Cq), 138.9
(Cq), 133.2 (CH 2-BrPh), 130.4 (CH 2-BrPh), 130.1 (CH 2-BrPh), 127.7
(CH Ar), 127.2 (CH 2-BrPh), 122.5 (CH Ar), 122.3 (Cq), 120.4 (Cq),
120.3 (CH Ar), 116.4 (Cq), 115.3 (Cq), 111.4 ppm (CH Ar); IR (CHCl3):
n˜ =3156 (NH2), 747 cmÀ1 (Ar); HRMS (ES): m/z calcd for C17H11N2Br:
322.0106 [M]+; found: 322.0102.
General procedure for the gold-catalyzed reaction of prop-
argylic hydroperoxides 1 with N-benzoyliminopyridinium
ylides: Preparation of fused pyrazoles 9–11
[AuCl(PPh3)] (4 mg, 0.0084 mmol), [AgOTf] (2.2 mg, 0.0084 mmol),
p-toluenesulfonic acid (5.9 mg, 0.034 mmol), the appropriate N-
benzoyliminopyridinium ylide (0.68 mmol), and water (12.2 mg,
0.68 mmol) were sequentially added to a stirred solution of the
corresponding propargylic hydroperoxide 1 (0.34 mmol) in 1,2-di-
chloroethane (2.7 mL). The resulting mixture was stirred at 1208C
under microwave irradiation until disappearance of the starting
material (TLC). The reaction was allowed to cool to room tempera-
ture and filtered through a pack of Celite. Saturated ammonium
chloride (0.7 mL) was added, before being partitioned between di-
chloromethane and water. The organic extract was washed with
brine, dried (MgSO4), concentrated under vacuum, and purified by
flash column chromatography eluting with ethyl acetate/hexanes
or ethyl acetate/dichloromethane mixtures. Spectroscopic and ana-
lytical data for pure forms of compounds 9–11 follow.
Treatment of hydroperoxide 1g with 1H-indol-2-amine
From hydroperoxide 1g (45 mg, 0.18 mmol), and after chromatog-
raphy of the residue using hexanes/ethyl acetate (6:1) as eluent,
15 mg (24%) of the less polar compound 6g and 16 mg (25%) of
the more polar compound 7g were obtained.
Pyrazolo[1,5-a]pyridine 9: From propargylic hydroperoxide 1b
(50 mg, 0.34 mmol), and after chromatography of the residue
using ethyl acetate/dichloromethane (1:9) as eluent gave the fused
pyrazole 9 (31 mg, 41%) as a pale-brown solid. M.p. 98–1008C;
1H NMR (300 MHz, CDCl3, 258C): d=7.22 (dd, 1H, J=7.7, 0.9 Hz,
Ar), 7.62 (m, 5H, 3H Ph+2H Ar), 7.95 (m, 2H, Ph), 8.40 (brs, 1H,
Ar), 8.64 ppm (d, 1H, J=8.4 Hz, Ar); 13C NMR (75 MHz, CDCl3,
258C): d=190.3 (C=O), 146.9 (Cq), 140.7 (CH Ar), 134.4 (CH Ar),
133.7 (Cq), 132.7 (CH Ar), 132.2 (CH Ph), 129.1 (2CH Ph), 127.2 (2CH
Ph), 124.2 (CH Ar), 122.8 (Cq), 121.0 ppm (CH Ar); IR (CHCl3): n˜ =
1661 (C=O), 709 cmÀ1 (Ar); HRMS (ES): m/z calcd for C14H10N2O:
222.0793 [M]+; found: 222.0787.
1
a-Carboline 6g: Red solid. M.p. 87–898C; H NMR (700 MHz, CDCl3,
258C): d=5.18 (s, 2H, OCH2), 7.21 (d, 2H, J=8.8 Hz, BnOPh), 7.43
(m, 6H, Ph+Ar), 7.65 (m, 2H, Ar), 7.68 (d, 1H, J=8.1 Hz, Ar), 8.11
(d, 1H, J=7.8 Hz, Ar), 8.16 (d, 2H, J=8.8 Hz, BnOPh), 8.69 (d, 1H,
J=8.1 Hz, Ar), 11.83 ppm (brs, 1H, NH); 13C NMR (175 MHz, CDCl3,
258C): d=161.9 (OCq), 145.4 (Cq), 145.0 (Cq), 138.8 (Cq), 136.0 (Cq),
135.1 (CH Ar), 129.5 (CH Ar), 129.3 (2CH BnOPh), 128.8 (2CH Ph),
128.3 (CH Ph), 127.5 (2CH Ph), 127.5 (Cq), 122.9 (CH Ar), 121.2 (CH
Ar), 119.6 (Cq), 119.3 (Cq), 116.3 (2CH BnOPh), 113.1 (CH Ar), 111.7
(CH Ar), 70.3 ppm (OCH2); IR (CHCl3): n˜ =3220 (NH), 1249 (CÀO),
744 cmÀ1 (Ar); HRMS (ES): m/z calcd for C24H18N2O: 350.1419 [M]+;
found: 350.1424.
Pyrazolo[1,5-a]quinoline 10: From propargylic hydroperoxide 1a
(50 mg, 0.28 mmol), and after chromatography of the residue
Chem. Eur. J. 2014, 20, 3384 – 3393
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3391
ꢁ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim

Full Paper
11744; For a photooxygenation approach, see: e) A. G. Griesbeck, A.
de Kiff, Org. Lett. 2013, 15, 2073; For gold-catalyzed homogeneous oxi-
dations with hydroperoxides as oxidants, see: f) A. S. K. Hashmi, C. Loth-
schꢂtz, M. Ackermann, R. Doepp, S. Anantharaman, B. Marchetti, H. Ber-
tagnolli, F. Rominger, Chem. Eur. J. 2010, 16, 8012.
using ethyl acetate/dichloromethane (0.5:9.5) as eluent gave the
fused pyrazole 10 (40 mg, 48%) as a pale-brown solid. M.p. 127–
1
1288C; H NMR (300 MHz, CDCl3, 258C): d=3.93 (s, 3H, OCH3), 7.04
(d, 2H, J=8.8 Hz, PMP), 7.58 (ddd, 1H, J=8.0, 7.3, 1.2 Hz, Ar), 7.79
(d, 1H, J=9.2 Hz, Ar), 7.79 (ddd, 1H, J=8.5, 7.3, 1.5 Hz, Ar), 7.89 (d,
1H, J=7.8 Hz, Ar), 7.95 (d, 2H, J=8.8 Hz, PMP), 8.31 (d, 1H J=
9.3 Hz, Ar), 8.36 (s, 1H, Ar), 8.68 ppm (d, 1H, J=8.5 Hz, Ar);
13C NMR (75 MHz, CDCl3, 258C): d=188.4 (C=O), 162.8 (OCq), 144.4
(CH Ar), 139.9 (Cq), 134.2 (Cq), 132.4 (Cq), 131.2 (2CH PMP), 130.3
(CH Ar), 128.9 (CH Ar), 128.5 (CH Ar), 125.8 (CH Ar), 124.1 (Cq), 117.5
(CH Ar), 116.1 (CH Ar), 114.2 (Cq), 113.8 (2CH PMP), 55.5 ppm
(OCH3); IR (CHCl3): n˜ =1604 (C=O), 1255 (CÀO), 686 cmÀ1 (Ar);
HRMS (ES): m/z calcd for C19H14N2O2: 302.1055 [M]+; found:
302.1045.
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Pyrazolo[5,1-a]isoquinoline 11a: From propargylic hydroperoxide
1a (50 mg, 0.28 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (4:1) as eluent gave the fused pyrazole
´
chacka-Cwikła, J. Am. Chem. Soc. 2013, 135, 898.
[6] Azaheterocycles are an extensive family of biologically active molecules
that have also been incorporated into a large number of medicinal
chemistry designs and clinical products and as such have been consid-
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of Heterocyclic Chemistry: Importance in Nature and in the Synthesis of
Pharmaceuticals, Wiley, New York, 2010; b) A. Mieczkowski, V. Roy, L. A.
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1
11 a (58 mg, 69%) as a pale-brown solid. M.p. 134–1358C; H NMR
(300 MHz, CDCl3, 258C): d=3.92 (s, 3H, OCH3), 7.03 (d, 2H, J=
8.9 Hz, PMP), 7.27 (d, 1H, J=7.3 Hz, Ar), 7.66 (m, 2H, Ar), 7.81 (m,
1H, Ar), 7.96 (d, 2H, J=8.8 Hz, PMP), 8.17 (s, 1H, Ar), 8.36 (d, 1H,
J=7.3 Hz, Ar), 9.21 ppm (m, 1H, Ar); 13C NMR (75 MHz, CDCl3,
258C): d=189.2 (C=O), 163.1 (OCq), 146.2 (CH Ar), 146.0 (Cq), 132.6
(Cq), 132.1 (2CH PMP), 131.0 (Cq), 130.5 (Cq), 129.6 (CH Ar), 128.0
(CH Ar), 127.1 (CH Ar), 127.0 (CH Ar), 126.1 (CH Ar), 124.5 (Cq), 115.1
(CH Ar), 113.7 (2CH PMP), 55.5 ppm (OCH3); IR (CHCl3): n˜ =1634 (C=
O),1256 (CÀO), 764 cmÀ1 (Ar); HRMS (ES): m/z calcd for C19H14N2O2:
302.1055 [M]+; found: 302.1047.
Pyrazolo[1,5-a]quinoline 11b: From propargylic hydroperoxide
1b (50 mg, 0.34 mmol), and after chromatography of the residue
using hexanes/ethyl acetate (6:1) as eluent gave the fused pyrazole
1
11 b (49 mg, 53%) as a pale-brown solid. M.p. 158–1608C; H NMR
(700 MHz, CDCl3, 258C): d=7.31 (d, 1H, J=7.2 Hz, Ar), 7.55 (t, 2H,
J=7.7 Hz, Ph), 7.63 (t, 1H, J=7.4 Hz, Ph), 7.70 (m, 2H, Ar), 7.84 (m,
1H, Ar), 7.94 (m, 1H, Ph), 8.17 (s, 1H, Ar), 8.37 (d, 1H, J=7.2 Hz,
Ar), 9.49 ppm (d, 1H, J=7.9 Hz, Ar); 13C NMR (175 MHz, CDCl3,
258C): d=190.3 (C=O), 147.0 (CH Ar+Cq), 140.2 (Cq), 132.2 (CH Ph),
131.7 (Cq), 130.7 (Cq), 129.8 (CH Ar), 129.7 (2CH Ph), 128.4 (2CH Ph),
128.1 (CH Ar), 127.3 (CH Ar), 127.1 (CH Ar), 126.2 (CH Ar), 124.5
(Cq), 115.4 ppm (CH Ar); IR (CHCl3): n˜ =1641 (C=O), 697 cmÀ1 (Ar);
HRMS (ES): m/z calcd for C18H12N2O: 272.0950 [M]+; found:
272.0955.
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Acknowledgements
Support for this work by MINECO (projects CTQ2012–33664-
C02–01 and CTQ2012–33664-C02–02) and Comunidad Autꢀno-
ma de Madrid (project S2009/PPQ-1752) are gratefully ac-
knowledged. M.T.Q. thanks the MEC for a predoctoral grant.
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Keywords: alkynes · amines · gold · heterocycles · peroxides
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Received: November 18, 2013
[19] a) M. Aghazadeh Tabrizi, P. G. Baraldi, G. Saponaro, A. R. Moorman, R.
Romagnoli, D. Preti, S. Baraldi, E. Ruggiero, C. Tintori, T. Tuccinardi, F.
Published online on February 13, 2014
Chem. Eur. J. 2014, 20, 3384 – 3393
www.chemeurj.org
3393
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