One-potfour-component synthesis of pyrimidyl and pyrazolyl substituted azulenes by glyoxylation-decarbonylative alkynylationcyclocondensation sequences

Article abstract of DOI:10.3762/bjoc.7.136

A novel one-pot four-component synthesis of pyrimidyl-and pyrazolylazulenes through the use of glyoxylation-decarbonylative alkynylation-cyclocondensation sequences starting from azulene or guaiazulene as substrates, gives rise to the formation of the target compounds in moderate to good yields.

Full text of DOI:10.3762/bjoc.7.136

One-pot four-component synthesis of
pyrimidyl and pyrazolyl substituted azulenes
by glyoxylation–decarbonylative alkynylation–
cyclocondensation sequences
Charlotte F. Gers, Julia Rosellen, Eugen Merkul and Thomas J. J. Müller*
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2011, 7, 1173–1181.
Institut für Organische Chemie und Makromolekulare Chemie,
Heinrich-Heine-Universität Düsseldorf, Universitätsstr. 1, D-40225
Düsseldorf, Germany
doi:10.3762/bjoc.7.136
Received: 01 June 2011
Accepted: 29 July 2011
Published: 26 August 2011
Email:
Charlotte F. Gers - Charlotte.Gers@uni-duesseldorf.de;
Julia Rosellen - Julia.Rosellen@uni-duesseldorf.de; Eugen Merkul -
E.Merkul@uni-duesseldorf.de; Thomas J. J. Müller* -
ThomasJJ.Mueller@uni-duesseldorf.de
This article is part of the Thematic Series "Multicomponent reactions".
Associate Editor: I. Marek
* Corresponding author
© 2011 Gers et al; licensee Beilstein-Institut.
License and terms: see end of document.
Keywords:
azulenes; catalysis; decarbonylation; multicomponent reactions;
ynones
Abstract
A novel one-pot four-component synthesis of pyrimidyl- and pyrazolylazulenes through the use of glyoxylation–decarbonylative
alkynylation–cyclocondensation sequences starting from azulene or guaiazulene as substrates, gives rise to the formation of the
target compounds in moderate to good yields.
Introduction
Diversity-oriented synthesis has become an important field in parison to traditional multistep syntheses. Thus, they can be
organic chemistry, initiated by the increasing demand for new considered to be economically and ecologically efficient [9,10].
scaffolds for pharmaceuticals and biologically active com-
pounds over the past decades [1-3]. Herein, multicomponent In particular, multicomponent syntheses of heterocycles initi-
reactions adopt a central position since each component can be ated by transition metal catalysis received increasing attention
varied within a wide range of functionalities and substituents in the past decade [11]. As a one-pot synthetic methodology,
[4-8]. Furthermore, these one-pot processes are highly advanta- this novel concept combines the unique reactivity patterns of
geous because they combine shortened reaction times and transition metal catalysis with fundamental organic reactivity, in
resource efficiency with diminished waste production in com- a sequential or consecutive fashion. Over the years, we have
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Beilstein J. Org. Chem. 2011, 7, 1173–1181.
contributed to this concept through Pd/Cu-catalyzed accesses to Friedel–Crafts-type reactions, generally occurs in the 1-posi-
enones and ynones and the in situ transformation of these tion [24]. Interestingly, the azulene motif is also found in
intermediates into many classes of heterocycles [12-15]. These terpenoids [27,28]. Guaiazulene (1b) (Scheme 1), a commonly
novel MCRs nicely correspond with diversity-oriented strate- known derivative of azulene (1a), is a naturally occurring
gies towards functional organic chromophores [1,2].
sesquiterpene [29]. Guaiazulene (1b) has found entry in a wide
range of cosmetic formulations [30]. In addition, numerous
The striking blue color of azulene (1a) (from the Spanish word azulene derivatives display appealing properties for material
“azul” = blue) has aroused scientific attention for a long time [31-33] and pharmaceutical sciences [34-38]. Furthermore, the
[16,17]. This prominent appearance results from the electronic use of the azulene moiety as part of a protecting group chro-
transition between the S0 and S1 state [18], as a consequence of mophore in carbohydrate chemistry has recently been reported
low energy frontier molecular orbital transitions [19]. The [39].
bicyclic structure of this nonbenzoid hydrocarbon results from a
five–seven ring annulation with a planar, cyclic conjugation of N-Heteroaryl-substituted azulenes can be accessed by stoichio-
10 π-electrons. The dipole moment of 1a at μ = 1.08 D [20] is metric [40,41] as well as Pd-catalyzed cross-coupling processes
astoundingly large in comparison to that of naphthalene at μ = [42-44]. However, these methods have only delivered a narrow
0 D and can be rationalized by a significant contribution of range of derivatives. Prior to application in Pd-catalyzed
cyclopentadienyl anion/tropylium cation resonance structures processes, azulenes must be functionalized, either by halogena-
(Scheme 1) [19].
tion or borylation, and some of these derivatives were found to
be quite unstable [45,46]. To the best of our knowledge, no
diversity-oriented multicomponent syntheses of azulenyl
heterocycles have been reported so far. Here, we report the
development of one-pot four-component syntheses toward
pyrimidyl- and pyrazolylazulenes.
Results and Discussion
Recently, we reported a three-component synthesis leading to
the formation of ynones by a conceptually novel glyoxylation–
decarbonylative Sonogashira coupling sequence (Scheme 2)
[47]. The Lewis acid free glyoxylation of electron rich N-het-
erocycles, such as indoles and pyrroles, leads to the formation
of glyoxylyl chlorides, which can be reacted without isolation
by decarbonylative Sonogashira coupling to form the desired
ynones. So far, only one example of the synthesis of azulenyl-
ynones has been described [48].
Scheme 1: Selected resonance structures of azulene (1a) and struc-
ture of the sesquiterpene guaiazulene (1b).
Our retrosynthetic analysis (Scheme 3) suggests that a wide
Since the elucidation of the structure and the first synthesis of range of N-heterocycle-substituted azulenes should be acces-
the azulene skeleton by Pfau and Plattner [21,22], its reactivity sible through Michael addition–cyclocondensation of azulenyl-
has been intensively studied [23-26]. The aromatic system is ynones with binucleophiles. Azulenylynones in turn could be
susceptible to nucleophilic addition in the 4-, 6- and 8-positions simply disconnected by our glyoxylation–decarbonylative
[23], whereas electrophilic aromatic substitution, such as alkynylation transform [47] back to azulenes.
Scheme 2: Synthesis of ynones by glyoxylation–decarbonylative Sonogashira coupling.
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Beilstein J. Org. Chem. 2011, 7, 1173–1181.
Scheme 3: Retrosynthetic analysis of N-heterocyclic substituted azulenes by a one-pot four-component approach.
Previously, glyoxylation of azulene (1a), with oxalyl chloride in Encouraged by our smooth glyoxylation–alkynylation
1-position was reported to be essentially complete within 5 min sequences with a variety of unfunctionalized π-nucleophiles,
[39]. Oxalyl bromide could be equally used as a glyoxylating such as pyrazoles, thiophenes, furans, and even the hydro-
agent [49,50]. Likewise, the glyoxylation of 1b has been carbon azulene (1a) [53], we decided to perform optimization
reported to proceed in 3-position with both reagents, yet with studies of the glyoxylation–decarbonylative alkynylation with
lower reactivity, and its conversion was found to be incomplete guaiazulene (1b), a commercially available and inexpensive
even after 2 h. In addition, the formation of side products [51] azulene derivative, and 1-hexyne (2b) as model substrates
and decarbonylation [52] was observed, presumably caused by (Table 1) (for experimental details, see Supporting Information
the steric hindrance of the methyl group in 4-position.
File 1).
Table 1: Optimization studies for the synthesis of ynone 3k.a
Glyoxylation step
Sonogashira coupling step
Entry NEt3 [equiv]
T [°C]
t [h]
PdCl2(PPh3)2 [mol %]
CuI [mol %] NEt3 [equiv]
t [h]
Yield 3k [%]b
1
2
1.0
-
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
0 °C to rt
rt to 50 °C
0 °C to rt
rt
4
4
1
1
1
1
1
1
2
2
1
1
1
1
1
1
2
2
1.0
2.0
1.0
1.0
1.0
2.0
2.0
2.0
1
1
1
1
2
1
1
1
40
43
36
25
41
19
56
55
3
1.0
1.0
1.0
-
24
2
4
5
4
6c
7
4
-
4
8c
-
4
aThe reactions were performed on a 2.00 mmol scale in 10 mL of THF as a solvent (c (1b) = 0.2 M); bisolated yield; c1,4-Dioxane was used as a
solvent (c (1b) = 0.2 M).
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Beilstein J. Org. Chem. 2011, 7, 1173–1181.
Initially, the optimized conditions for the glyoxylation–decar- Table 2) (for experimental details, see Supporting Information
bonylative alkynylation of indoles were applied [47], except for File 1). Their structures were unambiguously supported by
the addition of one equivalent of triethylamine in the glyoxyla- NMR spectroscopy, mass spectrometry, and combustion
tion step for scavenging the generated hydrogen chloride analysis.
(Table 1, entry 1). However, the use of the amine base in the
first step was unsatisfactory (Table 1, entry 2). Prolonged reac- Azulene (1a) and guaiazulene (1b) were both applied as
tion times in the first step did not affect the yield. According to substrates in the reaction sequence, giving rise to azulenyl-
monitoring by TLC, glyoxylation of guaiazulene (1b) was and guaiazulenylynones 3. The azulenyl derivatives 3a and 3b
incomplete even after 24 h reaction time (Table 1, entry 3). were obtained in higher yields compared to the guaiazulenyl-
Shorter reaction times in the first step caused a substantial ynones 3c–n. A variety of substituted arylacetylenes were
decrease of the yield (Table 1, entry 4), whereas longer reac- utilized in the reaction sequence. Electron neutral (Table 2,
tion times in the Sonogashira coupling had no effect on the entries 1 and 3), electron withdrawing (Table 2, entries 5–7),
yield (Table 1, entry 5). Rising the reaction temperature of the and electron donating (Table 2, entries 4 and 8) substituents
glyoxylation step to 50 °C considerably diminished the yield were equally well tolerated. In addition, heteroaryl-substituted
(Table 1, entry 6). However, doubling the catalyst loading acetylenes (Table 2, entries 9 and 10) as well as simple ali-
furnished significantly higher yields (Table 1, entry 7). 1,4- phatic acetylenes (Table 2, entries 2, 11, and 12) were success-
Dioxane was equally well employed as a solvent (Table 1, fully employed. Finally, propargylaldehyde diethylacetal
entry 8). From this optimization study, the conditions of entry 7 (Table 2, entry 13) and TIPS-protected acetylene (Table 2,
(Table 1) were considered to be optimal and were applied in the entry 14) also participated in the sequence, although relatively
three-component synthesis of the azulenylynones 3 (Scheme 4, low yields were achieved.
Scheme 4: Three-component synthesis of azulenyl- and guaiazulenylynones 3 by glyoxylation–decarbonylative Sonogashira coupling sequence.
Table 2: Three-component synthesis of azulenyl- and guaiazulenylynones 3.a
Entry
Azulene 1
Alkyne 2
Azulenylynone 3
[%]b
1
1a (R1 = R2 = R3 = H)
2a (R4 = Ph)
65c
3a
3b
2
3
1a
2b (R4 = n-Bu)
66c
55
1b (R1 = iPr, R2 = R3 = Me)
2a
3c
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Beilstein J. Org. Chem. 2011, 7, 1173–1181.
Table 2: Three-component synthesis of azulenyl- and guaiazulenylynones 3.a (continued)
4
5
1b
1b
1b
1b
1b
1b
1b
1b
1b
2c (R4 = p-tolyl)
2d (R4 = p-CNC6H4)
2e (R4 = p-NO2C6H4)
2f (R4 = m-FC6H4)
2g (R4 = 3,5-(MeO)2C6H3)
2h (R4 = 2-C4H3S)
2i (R4 = 3-pyridyl)
2b
57
3d
60
3e
6
76
3f
7
51
3g
8
47
3h
9
55
3i
10
11
12
31
3j
56
3k
2j (R4 = cyclopropyl)
42
3l
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Beilstein J. Org. Chem. 2011, 7, 1173–1181.
Table 2: Three-component synthesis of azulenyl- and guaiazulenylynones 3.a (continued)
13
14
1b
1b
2k (R4 = CH(OEt)2)
30
3m
2l (R4 = TIPS)
26
3n
aThe reactions were performed on a 2.00 mmol scale in 10 mL of THF as a solvent (c (1) = 0.2 M); bIsolated and purified compounds; cThe reactions
were performed on a 1.00 mmol scale in 5 mL THF as a solvent (c (1) = 0.2 M).
With this versatile three-component synthesis of azulenyl- with oxalyl chloride, followed by Pd/Cu-catalyzed decarbonyla-
ynones in hand, the stage was set to expand the sequence to a tive alkynylation with terminal alkynes 2, and finally by cyclo-
four-component access to pyrimidyl- and pyrazolyl-substituted condensation of the ynone intermediates with substituted
azulenes. Hence, the conditions for the terminating Michael amidine hydrochlorides 4, pyrimidylazulenes 5 were obtained in
addition–cyclocondensation step, adopted from a recent work moderate to good yields in a one-pot fashion (Scheme 5) (for
[54], were only slightly adjusted as a consequence of the lower experimental details, see Supporting Information File 1).
electrophilicity of azulenylynones in comparison to aryl- and
heteroaryl-substituted ynones that we have previously synthe- The diversity-oriented nature of this four-component approach
sized. Therefore, upon the subsequent reaction of the azulenes 1 to pyrimidylazulenes 5 is underlined by flexible variation of the
Scheme 5: Four-component synthesis of pyrimidylazulenes 5 by glyoxylation–decarbonylative Sonogashira coupling–cyclocondensation sequence
(yields refer to isolated and purified compounds).
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Beilstein J. Org. Chem. 2011, 7, 1173–1181.
Scheme 6: Four-component synthesis of pyrazolylazulenes 7 by glyoxylation–decarbonylative Sonogashira coupling–cyclocondensation sequence
(yields refer to isolated and purified compounds).
azulenyl, the alkynyl, and the amidinyl substrates. In particular,
Supporting Information
the amidine component 4 leads to the formation of aryl (com-
pounds 5a, 5d–5f), heteroaryl (compound 5b) or alkyl (com-
Supporting Information File 1
pound 5c) pyrimidylazulene derivatives.
Experimental procedures, spectroscopic and analytical data,
and copies of NMR spectra of compounds 3, 5, and 7.
[http://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-7-136-S1.pdf]
Likewise, pyrazolylazulenes were obtained in the course of a
consecutive glyoxylation–decarbonylative Sonogashira
coupling, followed by a cyclocondensation with methylhy-
drazine (6) to furnish two N-methylpyrazoles 7 in moderate
yields (Scheme 6) (for experimental details, see Supporting
Information File 1).
Acknowledgements
The authors cordially thank Merck KGaA, Darmstadt, and the
Fonds der Chemischen Industrie for their generous support.
Attempts to employ phenylhydrazine, N-Boc-hydrazine, and
hydrazine hydrate under standard conditions were met with
failure. Based upon previous syntheses of N-methylpyrazoles
from ynones and methylhydrazine [55,56] and the appearance
of a single set of resonances in the proton and carbon NMR
spectra, it is obvious that only a single regioisomer was formed.
Although the synthesis of similarly substituted pyrazolylazu-
lenes has already been described [57], our one-pot four-compo-
nent approach utilizes readily available starting materials as
well as a simple catalyst system. In addition, it avoids tedious
multiple workup and purification operations.
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