Microwave-assisted synthesis of pyrazino[2,1-b]quinazolines and 3-indolyl-2(1H)-pyrazinones employing a chemoselective silver(I)- and gold(I)-catalyzed reaction

Article abstract of DOI:10.1002/adsc.201100881

Novel microwave-assisted syntheses of pyrazino[2,1-b]quinazolines and 3-indolyl-2(1H)-pyrazinones employing silver(I)- or gold(I)-catalyzed protocols have been elaborated. The scope and limitations of these processes have been investigated. Copyright

Full text of DOI:10.1002/adsc.201100881

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DOI: 10.1002/adsc.201100881
Microwave-Assisted Synthesis of Pyrazino[2,1-b]quinazolines
G
and 3-Indolyl-2(1H)-pyrazinones Employing a Chemoselective
Silver(I)- and Gold(I)-Catalyzed Reaction
Dipak D. Vachhani,a Vaibhav P. Mehta,a,b Sachin G. Modha,a Kristof Van Hecke,c,d
Luc Van Meervelt,c and Erik V. Van der Eyckena,*
a
Laboratory for Organic & Microwave-Assisted Chemistry (LOMAC), University of Leuven (KU Leuven),
Celestijnenlaan 200F, B-3001 Leuven, Belgium
E-mail: erik.vandereycken@chem.kuleuven.be
Present address: C-5, Rushikesh Apartment, Near Viral Baug, Opp. Pratap Palace, Jamnagar, 361008 Gujurat, India
b
c
Biomolecular Architecture, Department of Chemistry, University of Leuven (KU Leuven), Celestijnenlaan 200F, B-3001,
Leuven, Belgium
d
Present address: Department of Inorganic and Physical Chemistry, Ghent University, Krijgslaan 281, Building S3, B-9000
Gent, Belgium
Received: November 12, 2011; Revised: February 4, 2012; Published online: && &&, 0000
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201100881.
Abstract: Novel microwave-assisted syntheses of protocols have been elaborated. The scope and limi-
pyrazinoACHTUNGTRENNUNG[2,1-b]quinazolines and 3-indolyl-2(1H)-pyr- tations of these processes have been investigated.
azinones employing silver(I)- or gold(I)-catalyzed
Keywords: gold; heteroannulation; homogenous cat-
alysis; hydroamination; microwave irradiation; pyra-
zinones; silver
Introduction
Pursuant to our long-standing interest in the syn-
thesis, decoration and application of the 2(1H)-pyrazi-
Heterocyclic compounds, especially nitrogen fused none scaffold,[5l,m,7,8,9] we were keen to establish condi-
heterocycles, are major constituents in the field of the tions for the generation of the oxazepinopyrazine
pharmaceutical and agrochemical industry. A large skeleton (Scheme 1) employing an annulation strat-
number of studies has been performed to develop egy.
new approaches for the synthesis of heterocycles,
which can be evaluated for their potential biological
activity.[1] The transition metal-catalyzed[2] inter- or in- Results and Discussion
tramolecular cyclization or heteroannulation strategy
has recently attracted vast attention owing to its selec- Our strategy started from the 1-PMB(p-methoxyben-
tivity and mild conditions. In these transformations p- zyl)-3,5-dichloro-2(1H)-pyrazinone 1a,[10] which was
systems, especially alkynes, are being activated to- substituted with 2-iodoaniline 2a at its C-3 position
wards inter- or intramolecular hydroamination or hy- using NaH in THF under reflux for 4 h affording 3a
droarylation to construct fused heterocycles.[3] Among in 55% yield (Scheme 1). This was subjected to Sono-
the diverse types of catalysts applied, typically silver gashira cross-coupling reaction employing phenylace-
salts and/or gold complexes have attracted great at- tylene 4a, PdACHTUNGTRNEG(UN PPh3)2Cl2 and CuI in a mixture of TEA
tention.[4,5] Large numbers of fused heterocycles can and DMSO at 458C for 30 min yielding 5a in 92%.
be synthesized via cationic heteroannulation of com- This was further treated with a mixture of AgOTf
pounds tethered with a nucleophilic substituent.[6] (5 mol%) and TFA (trifluoroacetic acid) (10 equiv.)
However, chemists keep on searching for ameliora- in dichloromethane (DCM). Compound 5a was en-
tion in terms of substrate scope, ease of operation and tirely consumed after 18 h at room temperature. Ac-
most importantly, regioselectivity.
cording to GC/MS and TLC analyses two different
products were formed. After purification and
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Scheme 1. Attempted synthesis of the oxazepino-pyrazinone skeleton.
1H NMR and MS analyses we realized to our surprise wave irradiation. Increasing the reaction temperature
that the PMB-group was still intact and that com- to 608C under microwave irradiation improved the
pounds with similar molecular weight as the starting yield of compound 6a to 83% while the yield of com-
material 5a were formed. X-ray crystallographic anal- pound 7a dropped to 5% (Table 1, entry 2). Decreas-
ysis[11] proved that a pyrazino-quinazoline 6a was ing the catalyst loading to 2 mol% of AgOTf afforded
formed in 75% yield via a 6-exo-dig cyclization with only 31% yield of 6a, while 10 mol% of AgOTf under
the (Z)-configuration around the exocyclic double conventional heating for 7 h at 608C afforded 6a as
bond (Figure 1), besides
2(1H)-pyrazinone 7a which is formed via a 5-endo-dig 4). Next, using 10 mol% of AgOTf catalyst in combi-
cyclization in 18% yield[12] (Scheme 1).
nation with microwave irradiation for 35 min at a ceil-
a 3-indolyl substituted the sole product in 82% yield (Table 1, entries 3 and
Surprised by these initial findings and intrigued by ing temperature of 608C and 100 W maximum power,
the highly regioselective outcome of the reaction ap- afforded 6a in an excellent yield of 87% (Table 1,
plying these mild conditions, we further investigated entry 5). Interestingly only traces of indolyl-2(1H)-
this protocol. The results are summarized in Table 1.
pyrazinone 7a were observed applying these condi-
To identify the optimal reaction conditions and to tions. No reaction occurred in the absence of TFA
obtain selectively compounds 6a or 7a, we evaluated even after prolonged microwave irradiation for
several reaction parameters like different silver or 45 min. (Table 1, entry 6). Switching to alternative
gold catalysts in combination with various tempera- Ag(I) salts like AgOCOCF3, AgNO3, AgSbF6 or
tures, solvents, reaction times and the use of micro- other metal salts like CuACTHNUGTRENNUG(OTf)2, CuI or YbACHUTTGNREN(NUGN OTf)3 re-
sulted in lower yields of 6a (Table 1, entries 7–12).
Next we also explored the use of AuCl and were sur-
prised to see the consumption of all the starting mate-
rial after merely 25 min of microwave irradiation
(Table 1, entry 13). This solely afforded the 3-indolyl-
2(1H)-pyrazinone 7a in 70% yield with only traces of
pyrazino-quinazoline 6a. Hence we have been able to
achieve complete regioselectivity of the ring closure
by employing different catalysts (Table 1, entry 5 and
13). Among the solvents tested, the initially used di-
choloromethane proved to be the solvent of choice.
No reaction or partial conversions were observed
when using polar solvents in combination with elevat-
ed temperatures under microwave irradiation
(Table 1, entries 15–18). In addition, omitting the
metal salt resulted in no conversion and all starting
material was recovered (Table 1, entry 19). Finally, as
Figure 1. X-ray structure of compound 6a. Thermal displace-
ment ellipsoids are shown at the 50% probability level.
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Microwave-Assisted Synthesis of PyrazinoCAHTUNGTRENNNUG
Table 1. Optimization study for the synthesis of pyrazinoACHTUNGTRENNUNG
Entry
Catalyst (mol%)
Solvent (2 mL)
Temperature [oC]
Time
Yield of 6a [%]
Yield of 7a [%]
1[b]
2
AgOTf (5)
AgOTf (5)
AgOTf (2)
AgOTf (10)
AgOTf (10)
AgOTf (5)
AgOCOCF3 (5)
AgNO3 (5)
AgSbF6 (5)
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
MeOH
THF
30
60
60
60
60
60
60
60
60
60
60
60
60
60
80
70
100
110
60
60
60
60
18 h
1 h
1 h
7 h
75
83
31
82
87
NR
60
30
28
traces
6
NR
traces
14
traces
traces
20
traces
NR
58
traces
35
18
5
3
traces
traces
traces
NR
5
4[b]
5
35 min
45 min
45 min
1 h
45 min
50 min
1 h
45 min
25 min
1 h
45 min
1 h
1 h
1 h
45 min
45 min
35 min
35 min
6[c]
7
8
9
8
traces
traces
5
NR
70
10
11
12
13
14
15
16
17
18
19
20
21[d]
22[e]
Cu
A
Yb
ACHTUNGTRENNUNG
CuI (5)
AuCl (5)
Au
N
50
AgOTf (5)
AgOTf (5)
AgOTf (5)
AgOTf (5)
–
AgOTf(5)/AuCl(5)
AgOTf (10)
AgOTf (10)
traces
traces
9
traces
NR
32
CH3CN
water
DCM
DCM
DCM
DCM
NR
traces
[a]
Unless otherwise stated all reactions were carried out in a microwave reactor (CEMꢁ Discover) operating at a frequency
of 2.45 GHz and using a 100 W maximum power setting. Reactions were run using 5a (0.2 mmol) and TFA (10 equiv.).
Yields reported are for compounds isolated via column chromatography. In case of incomplete conversions starting mate-
rial 5a was observed. NR=No reaction.
Conventional heating.
Reaction was carried out without TFA.
[b]
[c]
[d]
[e]
0.2 equiv. of TFA used.
2.0 equiv. of TFA used. A conversion of 35% to compound 6a was observed via GC-MS analysis.
expected the combination of AgOTf and AuCl cata- (1.5 equiv.), PdACHTUNGTRNEG(UN PPh3)2Cl2 (2 mol%) and CuI
lysts lead to poor regioselectivity (Table 1, entry 20). (3 mol%) in a mixture of triethylamine/DMSO (4:1)
Reducing the amount of TFA from 10 equiv. to at 458C for 30 min. The resulting C-3-(ortho-alkyny-
0.2 equiv. or even 2 equiv. resulted in the formation of lated anilino)-substituted 2(1H)-pyrazinones 5b–
traces and 35% of 6a respectively (Table 1, entries 21
and 22).
u
were obtained in good to excellent yields
(Scheme 2).
Having optimized the reaction conditions we next
Next we explored the newly optimized Ag(I)-cata-
synthesized a set of diversely substituted starting com- lyzed[13] protocol for the synthesis of diversely func-
pounds 5b–u to evaluate the scope and the limitations tionalized pyrazino-quinazolines (Table 2). In most
of the process. Readily synthesized 3,5-dicholoro- cases, complete conversion was obtained using micro-
2(1H)-pyrazinones[10] 1a–e, were reacted with 2-iodo- wave irradiation for 35 min yielding the correspond-
4-substituted anilines 2a–c using NaH under reflux ing pyrazino-quinazolines 6b–r in good to excellent
conditions in THF for 4–6 h affording compounds 3b– yields, regardless of the substitution pattern of the
k in good yields of 48–66%. The thus obtained iodoa- pyrazinone or the aniline. Slightly lower yields were
nilines 3b–k were subjected to Sonogashira cross-cou- obtained for the pyrazino-quinazolines 6s–u when
pling reaction, employing various acetylenes 4a–f starting from aliphatic alkyne-substituted compounds
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Scheme 2. Synthesis of diversely substituted C-3-(ortho-alkynylated anilino)-substituted 2(1H)-pyrazinones 5.
Table 2. Evaluation and scope of the Ag(I)-catalyzed[13] protocol for the generation of pyrazino-quinazolines.[a]
Entry
Code
R1
R2
R3
R4
Yield[b] [%]
1
2
3
4
5
6
7
8
6b
6c
6d
6e
6f
6g
6h
6i
Me
Me
Me
Me
Me
Me
Me
Me
Ph
Ph
Ph
Ph
Ph
Ph
Ph
Ph
H
H
H
H
Me
Me
Me
Cl
Cl
H
Ph
84
92
88
85
91
81
75
82
4-Me-C6H4
4-t-Bu-C6H4
Ph
3-F-C6H4
4-Me-C6H4
4-Me-C6H4
Ph
9
6j
Bn
Ph
90
10
11
12
13
14
15
16
17
18
19
20
21
6k
6l
Bn
Bn
Bn
Bn
H
H
H
H
H
H
4-t-Bu-C6H4
3-Me-C6H4
Ph
83
80
81
74
85
72
74
74
6m
6n
6o
6p
6q
6r
6s
6t
6u
6v
Me
Cl
Cl
Me
H
H
Me
H
4-Me-C6H4
4-t-Bu-C6H4
4-t-Bu-C6H4
4-Me-C6H4
4-Me-C6H4
n-propyl
n-propyl
n-propyl
4-Me-C6H4
Bn
H
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
PMP
H
H
H
61[c,d]
63[c,d]
61[c,d]
60[e]
PMP
H
H
CF3
[a]
Unless otherwise stated all reactions were carried out in microwave reactor (CEMꢁ Discover) operating at a frequency
of 2.45 GHz and using a 100 W maximum power setting. Reactions were run using 5 (0.2 mmol), AgOTf (10 mol%), TFA
(10 equiv.) and DCM (2 mL) at 608C for 35 min. PMP=p-methoxyphenyl.
Isolated yields, single run.
AgOTf (20 mol%) and 45 min irradiation time were used.
C3-indolyl-substituted pyrazinones were the major side products.
[b]
[c]
[d]
[e]
60 min irradiation time was used.
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Microwave-Assisted Synthesis of Pyrazino
ACHTUNGTREN[NUGN 2,1-b]quinazolines and 3-Indolyl-2(1H)-pyrazinones
Table 3. AuCl-catalyzed intramolecular hydroamination[14] leading to C-3-indolyl-substituted 2(1H)-pyrazinones.[a]
Entry
Code
R1
R2
R3
R4
Yield[b] [%]
1
2
3
4
7b
7c
7d
7e
Me
Me
Bn
Ph
Ph
H
Me
Me
Me
Me
Ph
62
69
68
60
4-Me-C6H4
4-Me-C6H4
n-proyl
PMP
H
[a]
Unless otherwise stated all reactions were carried out in a microwave reactor (CEMꢁ Discover) operating at a frequency
of 2.45 GHz and using a 100 W maximum power setting. Reactions were run using 5 (0.2 mmol), AuCl (5 mol%), TFA
(10 equiv.), DCM (2 mL) at 608C for 25–30 min. PMP=p-methoxyphenyl.
[b]
Isolated yields, single run.
5s–u, giving C-3-indolyl substituted pyrazinones as the
While we have no explanation why different prod-
major side product. In the case of a strong electron ucts 6 vs. 7 were obtained using Ag(I) or Au(I) salts,
withdrawing R3-group a longer reaction time was re- respectively, a plausible mechanism for the serendipi-
quired to synthesize 6v.
tously discovered reactions is depicted in Scheme 3.
Subsequently, we explored our previously opti- Upon coordination, with Ag(I) the 6-exo-dig cycliza-
mized protocol (Table 1, entry 13) for the AuCl-cata- tion is favoured while coordination with Au(I) the p-
lyzed[14] synthesis of C-3-indolyl substituted 2(1H)- system becomes prone to nucleophilic addition lead-
pyrazinones 7b–e (Table 3). All compounds were ob- ing to 5-endo-dig cyclization.
tained in good yields, with only traces of the corre-
sponding pyrazino-quinazolines 6.
Scheme 3. A plausible mechanism for the 6-endo-dig vs. 5-exo-dig heteroannulation via Ag(I) or Au(I) catalysis.
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Conclusions
EMECW, lot 13 (Erasmus Mundus External Cooperation
Window, Lot-13) for providing a doctoral scholarship. The
authors thank Ir. B. Demarsin for HR-MS measurements.
In conclusion, we have elaborated a mild and efficient
microwave-assisted methodology for the synthesis of
pyrazinoACHTUNGTRENNUNG[2,1-b]quinazolines and 3-indolyl-2(1H)-pyra-
zinones applying an Ag(I)-catalyzed 6-exo-dig or an
Au(I)-catalyzed 5-endo-dig cyclization. High yields
and tolerance towards a range of functional groups
are the merits of these protocols. The applicability of
the newly developed methodology allows the rapid
generation of these heterocycles, which are currently
under investigation for their biological activity.
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In a oven-dried, argon-flushed 10-mL reaction vial contain-
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1 equiv.), Au(I)Cl (5 mol%) and TFA (300 mL) under argon.
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Research
–
Flanders (Belgium)]. DDV is thankful to
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Adv. Synth. Catal. 0000, 000, 0 – 0
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asc.wiley-vch.de
7
ÞÞ
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FULL PAPERS
8 Microwave-Assisted Synthesis of PyrazinoACTHNUGTRNEUNG[2,1-
b]quinazolines and 3-Indolyl-2(1H)-pyrazinones Employing
a Chemoselective Silver(I)- and Gold(I)-Catalyzed Reaction
Adv. Synth. Catal. 2012, 354, 1 – 8
Dipak D. Vachhani, Vaibhav P. Mehta, Sachin G. Modha,
Kristof Van Hecke, Luc Van Meervelt,
Erik V. Van der Eycken*
8
asc.wiley-vch.de
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Adv. Synth. Catal. 0000, 000, 0 – 0
ÝÝ
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