Base-controlled selectivity in the synthesis of linear and angular fused quinazolinones by a palladium-catalyzed carbonylation/nucleophilic aromatic substitution sequence

Article abstract of DOI:10.1002/anie.201402779

A new approach for the facile synthesis of fused quinazolinone scaffolds through a palladium-catalyzed carbonylative coupling followed by an intramolecular nucleophilic aromatic substitution is described. The base serves as the key modulator: Whereas DBU gives rise to the linear isomers, Et ₃N promotes the preferential formation of angular products. Interestingly, a light-induced 4+4 reaction of the product was also observed.

Full text of DOI:10.1002/anie.201402779

Angewandte
Chemie
DOI: 10.1002/anie.201402779
Heterocycle Synthesis
Base-Controlled Selectivity in the Synthesis of Linear and Angular
Fused Quinazolinones by a Palladium-Catalyzed Carbonylation/
Nucleophilic Aromatic Substitution Sequence**
Jianbin Chen, Kishore Natte, Anke Spannenberg, Helfried Neumann, Peter Langer,
Matthias Beller,* and Xiao-Feng Wu*
Abstract: A new approach for the facile synthesis of fused
quinazolinone scaffolds through a palladium-catalyzed car-
bonylative coupling followed by an intramolecular nucleo-
philic aromatic substitution is described. The base serves as the
key modulator: Whereas DBU gives rise to the linear isomers,
Et3N promotes the preferential formation of angular products.
Interestingly, a light-induced 4+4 reaction of the product was
also observed.
organic synthesis,[7] and many efforts have been made to apply
these reactions in the synthesis of biologically active com-
Table 1: Model synthesis of pyridoquinazolones: Optimization of the
reaction parameters.[a]
T
he presence of N heterocycles as an essential structural
motif in a variety of biologically active substances has
stimulated the development of new strategies and technolo-
gies for their synthesis.[1] Among the various N-heterocyclic
scaffolds, quinazolinones form a privileged class of com-
pounds. Indeed, quinazolinone derivatives possess a wide
spectrum of biological and pharmacological activities, such as
anti-inflammatory, antioxidant, antimicrobial, antipsychotic,
and antihypertensive activity, strong analgesic activity, and
many effects on the central nervous system (CNS).[2] More
specifically, pyridoquinazolones exhibit strong tuberculostatic
activity. Since both the linear[3] and angular[4] fused isomers
have unique pharmacological and/or biological activity,
synthetic methodologies which can provide these two isomers
in a convenient and efficient manner are highly desired.
Although many attractive procedures have been devel-
oped for rapid access to quinazolinones,[2a,b,3,5] the related
synthesis of pyridoquinazolones is still very limited. So far,
known procedures require a high temperature (2108C),
multistep synthesis, or specific ortho-halogen-substituted
benzoyl derivatives as the substrates.[6] Naturally, only the
linear or the angular products can be produced.
Entry CO
[bar]
Ligand
Base (equiv)
K2CO3 (2.0)
K3PO4·H2O (2.0) DMF
K3PO4·H2O (2.0) NMP
Solvent
DMF
Yield [%][b]
3a/4a/5a
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18[c]
19[d]
20[d]
21[e]
22[e]
10
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
Ph3P
DPEphos DBU (3.0)
xantphos
dppp
BuPAd2
BuPAd2
BuPAd2
BuPAd2
BuPAd2
xantphos
0/0/0
23/0/0
22/0/0
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
15
15
15
1
K3PO4·H2O (2.0) dioxane 1/(20)/0
K3PO4·H2O (2.0) toluene
1/(22)/0
31/0/0
50/0/1
30/0/4
43/0/0
55/0/13
54/0/7
83(74)/0/6
0/0/0
2/0/9
7/0/33
58/0/10
68/0/0
70/0/7
90(80)/0/0
70/0/9
3/0/(60)
2/0/(56)
DIPEA (2.0)
DBN (2.0)
DABCO (2.0)
DBU (2.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DMF
DMF
DMF
DMF
DMF
DMSO
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DMA
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
DBU (3.0)
Et3N (3.0)
Et3N (3.0)
The development of novel and improved palladium-
catalyzed carbonylation reactions is an important topic in
15
15
[*] J. Chen, Dr. K. Natte, Dr. A. Spannenberg, Dr. H. Neumann,
Prof. Dr. P. Langer, Prof. Dr. M. Beller, Prof. Dr. X.-F. Wu
Leibniz-Institut fꢀr Katalyse an der Universitꢁt Rostock e.V.
Albert-Einstein-Strasse 29a, 18059 Rostock (Germany)
E-mail: matthias.beller@catalysis.de
[a] Reaction conditions: 1a (1 mmol), 2a (1.0 equiv), Pd(OAc)2
(2 mol%), ligand (6 mol%), solvent (2 mL), base (indicated amount),
CO (indicated pressure), 1208C, 16 h. [b] Yields were determined by GC
with hexadecane as an internal standard; yields in parentheses are for the
isolated product. [c] The reaction was carried out with 2a (1.2 equiv).
[d] The reaction was carried out with 2a (1.5 equiv). [e] Reaction
conditions: 1a (0.5 mmol), 2a (1.1 equiv), DMA (5 mL), 32 h. Ad=
adamantyl, DABCO=1,4-diazabicyclo[2.2.2]octane, DIPEA=N,N’-diiso-
propylethylamine, DMA=N,N-dimethylacetamide, DMF=N,N-dime-
thylformamide, DMSO=dimethyl sulfoxide, DPEphos=(oxybis(2,1-
phenylene))bis(diphenylphosphane), dppf=1,1’-bis(diphenylphospha-
nyl)ferrocene, dppp=1,3-bis(diphenylphosphanyl)propane, NMP=1-
methyl-2-pyrrolidinone, xantphos=4,5-bis(diphenylphosphanyl)-9,9-
dimethylxanthene.
xiao-feng.wu@catalysis.de
[**] We thank the State of Mecklenburg-Vorpommern, the Bundes-
ministerium fꢀr Bildung und Forschung (BMBF), and the Deutsche
Forschungsgemeinschaft for financial support. We also thank Dr. C.
Fischer, S. Schareina, and Dr. W. Baumann for their excellent
technical and analytical support. The useful discussion with Dr.
Haijun Jiao is appreciated.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201402779.
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Scheme 1. Formation of the postulated intermediate for the linear
products with DBU.
pounds.[8] In general, these procedures provide efficient
means to incorporate CO as a cheap C1 source into valuable
heterocyclic compounds. On the basis of our continuing
research in this area, we report herein a novel approach that
enables the synthesis of linear or angular fused pyridoquina-
zolones simply by changing the base.
At the start of our study, the model reaction of 2-
aminopyridine and 2-bromofluorobenzene was conducted in
the presence of Pd(OAc)2 (2 mol%) and BuPAd2 (6 mol%)
under typical conditions known for palladium-catalyzed
carbonylation reactions (CO: 10 bar, K2CO3: 2.0 equiv,
DMF, 1208C). Unfortunately, none of the desired product
was observed (Table 1, entry 1). However, when K3PO4 was
used as the base, the target product 3a was formed in 23%
Figure 1. Molecular structure of a derivative of 3b (cycloaddition
dimer) formed during X-ray crystallography. Displacement ellipsoids
correspond to 30% probability.
(GC) and isolated in 80% yield; Table 1, entries 17–19). This
procedure even produced 3a in reasonable yield at a CO
pressure of 1 bar (Table 1, entry 20). Surprisingly, when the
base DBU was simply changed to NEt3, the selectivity was
completely reversed to give 5a as
the major product in 60% yield
(Table 1, entry 21). In the presence
of NEt3, xantphos showed similar
efficiency to that of
BuPAd2 (Table 1,
entry 22). Several
chelating ligands
[dcype
(3a/5a
73:27), dppe (3a/
5a 70:30), dppm
Scheme 3. Iden-
tification of the
angular isomer
5e by NOESY
correlations.
(3a/5a
68:32),
dppp
(3a/5a
85:15), binap (3a/
5a 83:17)] were
Scheme 2. Control experiments.
yield (as determined by GC; Table 1, entry 2).
Unfortunately, variation of the solvent led to no
significant improvement. As well as inorganic
bases, some organic bases were added to the
reaction mixture. To our delight, 1,5-
diazabicyclo(4.3.0)non-5-ene (DBN) and 1,8-
diazabicyclo[5.4.0]undec-7-ene (DBU) gave
improved product yields of up to 55% (with
3.0 equivalents of DBU). Notably, the target
molecule was formed in 83% yield (as deter-
mined by GC) and isolated in 74% yield when
DMA was used as the solvent under these
conditions (Table 1, entries 10–12). Other phos-
phorus ligands were tested, and it was found that
dppf gave 3a in moderate yield (Table 1,
entries 13–16).
A further improvement was
observed when the reaction was performed at
elevated pressure (15 bar of CO) with 1.5 equiv-
alents of 2a and BuPAd2 as the ligand: Under
these conditions, 3a was formed in 90% yield Scheme 4. Proposed catalytic cycle.
2
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Table 2: Synthesis of linear fused pyridoquinazolones: Scope of the
tested in place of BuPAd2, but no improvement was detected.
To gain some insight into this interesting selectivity switch,
we conducted a set of control experiments. We suspected that
the strength of the base may play a pivotal role in this process
(the acidities of the conjugate acids are pKa = 12 and 10.8 for
DBU and NEt3, respectively). Indeed, NMR spectroscopic
experiments confirmed that DBU deprotonates 2-aminopyr-
idine (2a) to a major extent to afford the 2-imino-2H-pyridin-
1-ide, which was not observed in the presence of NEt3
(Scheme 1). This selectivity switch was also seen in the
presence of other strong bases, such as NaOH. Unfortunately,
in this case 3a was only obtained in low yield despite the
excellent chemoselectivity. In the presence of DBU and NEt3
(1:1), the procedure gave a mixture of the angular isomer 5a
and 3a (Scheme 2).
The linear and angular isomers were fully characterized
by NMR spectroscopy, and their structural assignment was
confirmed by X-ray crystallography (Figure 1 and Scheme 3).
The regiochemical outcome of the reactions was determined
by comparison of the products with previously reported
compounds (3a, 3j, 3m, 3n, 5e), by NOESYexperiments (e.g.
5e), and by X-ray crystallography on 3b. Interestingly, during
the X-ray crystallographic measurements, the isolated prod-
uct underwent a further [4+4] cycloaddition reaction induced
by light or the X-ray beam (Figure 1).[9]
We propose a catalytic cycle for the palladium-catalyzed
carbonylation/intramolecular nucleophilic aromatic substitu-
tion reaction in Scheme 4. The formation of the active catalyst
takes place by the reduction of PdII to Pd0 with CO or amines.
The oxidative addition of 1-bromo-2-fluorobenzene to Pd0
then leads to the corresponding organopalladium species A.
By the coordination and insertion of CO, the key intermediate
acyl palladium complex B is formed. In the presence of DBU,
2-imino-2H-pyridin-1-ide (6b) undergoes nucleophilic attack
on the acyl palladium complex with the elimination of C. On
the other hand, in the presence of NEt3 as the base, the
nucleophilic reaction of 2-aminopyridine with the acyl
palladium complex yields compound C’. Finally, intramolec-
ular nucleophilic aromatic substitution of intermediate C or
C’ affords the terminal linear or angular product, respectively.
The active Pd0 catalyst is regenerated with the assistance of
the base.
Next, we turned our attention to the scope and limitations
of this methodology. The results are summarized in Table 2
for linear products and Table 3 for angular products. Avariety
of analogues of 1-bromo-2-fluorobenzene were tolerated in
this procedure and delivered the corresponding products 3a–
l in moderate to good yields. Notably, 4- and 5-substituted
substrates gave better yields than 3-substituted substrates
(3b,c versus 3d). This observation is in line with the results
with electron-withdrawing fluoro substituents (3 f,g versus
3h). Interestingly, 2-bromo-4-(difluoromethyl)-1-fluoroben-
zene was successfully converted into the desired product 3i in
60% yield. These results are of general importance owing to
the current interest in fluoro-containing products.[10] Chloride
substituents and acetyl groups remained intact under our
conditions to provide valuable products in moderate to good
yields (products 3j–l). Subsequently, different kinds of 2-
aminopyridines were investigated. Methyl- and fluoro-sub-
reaction.[a]
Entry
Product
Entry
11
Product
1
2
3
4
12
13
14
5[c]
15
16
17
6
7
8
18
19
9
10
[a] Reaction conditions: 1 (1 mmol), 2 (1.5 equiv), Pd(OAc)2 (2 mol%),
BuPAd2 (6 mol%), DMA (2 mL), DBU (3.0 equiv), CO (15 bar), 1208C,
16 h. [b] Yield of the isolated product. [c] The reaction was carried out
with 1 (0.32 mmol) and Pd(OAc)2 (10 mol%). [d] Compound 3a was
also recovered in 30% yield. [e] Compound 3a was recovered in 65%
yield. [f] A trace amount of the product was detected by GC–MS.
stituted products 3m–o were isolated without any problem.
However, halides attached to the pyridine ring also reacted.
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Table 3: Synthesis of angular fused pyridoquinazolones: Scope of the
Hence, the dehalogenated products corresponding to 3o and
3p were isolated, and 3q was detected by GC–MS. Unfortu-
nately, in the case of more sterically hindered substrates, only
the corresponding amides were isolated (products 4r,s).
In the case of the angular products (Table 3), steric and
electronic modification of the substrates did not influence the
outcome of the reactions. Ortho-methyl- and cyano-substi-
tuted 2-aminopyridines delivered the corresponding products
5c and 5d in 72 and 64% yield. A methyl group at the para
position as a representative example of an electron-donating
group was tolerated well (product 5e). Substrates with
electron-deficient p-cyano, p-fluoro, and p-chloro substitu-
ents were also converted into the corresponding angular
isomers 5 f–h in moderate yields. The uncyclized amides
corresponding to 5 f,g were also isolated. Notably, besides
aminopyridines, even aminopyrimidine and aminopyridazine
could be applied as substrates under our conditions and gave
the desired products in good yields (products 5i,j).
reaction.[a]
Entry
Product
Yield [%][b]
1
5a
5b
5c
5d
60 (32 h)
2[c]
71 (19 h)
72 (32 h)
64 (32 h)
3
4
In summary, an efficient novel palladium-catalyzed car-
bonylation/intramolecular nucleophilic aromatic substitution
reaction to give pyridoquinazolones has been developed. The
selective formation of both linear and angular fused isomers
in moderate to good yields could simply be controlled by the
choice of base (NEt3 or DBU). Whereas in the presence of
DBU the linear products were obtained, NEt3 gave the
angular derivatives. This novel methodology is complemen-
tary to previously reported synthetic procedures and enables
straightforward access to this biologically interesting class of
compounds.
5
6
5e
5 f
67 (32 h)
40 (19 h)[d]
Received: February 25, 2014
Revised: April 22, 2014
Published online: && &&, &&&&
7
5g
5h
41 (19 h)[e]
Keywords: carbonylation · domino reactions ·
.
nucleophilic aromatic substitution · palladium catalysts ·
quinazolinones
8[f]
56 (32 h)
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4
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Communications
Heterocycle Synthesis
J. Chen, K. Natte, A. Spannenberg,
H. Neumann, P. Langer, M. Beller,*
X.-F. Wu*
&&&& — &&&&
First base, second base… home run! A
base-controlled palladium-catalyzed car-
bonylation/intramolecular nucleophilic
aromatic substitution reaction gave linear
and angular fused pyridoquinazolones:
1,8-Diazabicyclo[5.4.0]undec-7-ene
(DBU) yielded the linear products,
whereas NEt3 gave the angular derivatives
(see scheme; Ad=adamantyl, DMA=
dimethylacetamide). A light-induced
Diels–Alder reaction of the product was
also observed.
Base-Controlled Selectivity in the
Synthesis of Linear and Angular Fused
Quinazolinones by a Palladium-Catalyzed
Carbonylation/Nucleophilic Aromatic
Substitution Sequence
6
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Angew. Chem. Int. Ed. 2014, 53, 1 – 6
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