Highly efficient four-component synthesis of 4(3H)-quinazolinones: Palladium-catalyzed carbonylative coupling reactions

Article abstract of DOI:10.1002/anie.201308756

Given the importance of quinazolinones and carbonylative transformations, a palladium-catalyzed fourcomponent carbonylative coupling system for the synthesis of diverse 4(3H)-quinazolinone in a concise and convergent fashion has been developed. Starting from 2-bromoanilines (1 mmol), trimethyl orthoformate (2 mmol), and amines (1.1 mmol), under 10 bar of CO, the desired products were isolated in good yields in the presence of Pd(OAc)2 (2 mol%), BuPAd2 (6 mol%) in 1,4-dioxane (2 mL) at 1008C, using N,Ndiisopropylethylamine (2 mmol) as the base. Notably, the process tolerates the presence of various reactive functional groups and is very selective for quinazolinones, and was used in the synthesis of the precursor to the bioactive dihydrorutaempine.

Full text of DOI:10.1002/anie.201308756

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Communications
DOI: 10.1002/anie.201308756
Multicomponent Reactions
Highly Efficient Four-Component Synthesis of 4(3H)-Quinazolinones:
Palladium-Catalyzed Carbonylative Coupling Reactions**
Lin He, Haoquan Li, Helfried Neumann, Matthias Beller,* and Xiao-Feng Wu*
Abstract: Given the importance of quinazolinones and
carbonylative transformations, a palladium-catalyzed four-
component carbonylative coupling system for the synthesis of
diverse 4(3H)-quinazolinone in a concise and convergent
fashion has been developed. Starting from 2-bromoanilines
(1 mmol), trimethyl orthoformate (2 mmol), and amines
(1.1 mmol), under 10 bar of CO, the desired products were
isolated in good yields in the presence of Pd(OAc)2 (2 mol%),
BuPAd2 (6 mol%) in 1,4-dioxane (2 mL) at 1008C, using N,N-
diisopropylethylamine (2 mmol) as the base. Notably, the
process tolerates the presence of various reactive functional
groups and is very selective for quinazolinones, and was used
in the synthesis of the precursor to the bioactive dihydror-
utaempine.
Over the years, the transition-metal-catalyzed MCRs have
À
emerged as a powerful approach for the construction of C X
(X = C, N, O, etc.) bonds.[5] One representative example is the
palladium-catalyzed carbonylative reactions, which hold an
important status because of the high levels of selectivity
generally observed, and the variety of bond-forming process-
es available.[6] Furthermore, concomitant incorporation of
CO (one of the cheapest C1 source) into the final products
may contribute to increasing the diversity of accessible
compounds in many ways. Indeed, many elegant three-
component carbonylative coupling reactions have been
developed, thus providing rapid and convergent syntheses
of complex organic molecules from readily available starting
materials.[7] In this contribution, our laboratory and other
research groups have presented several strategic options for
the preparation of various heterocycles.[8,9] In pursuing our
interest in finding more sophisticated MCRs, we sought to use
palladium-catalyzed carbonylative reactions for the concise
one-pot, four-component synthesis of valuable N-containing
heterocyclic compounds. To date, only rare examples of such
reactions (mainly performed in two steps manner) have been
reported.[10]
T
he pursuit of sustainable chemistry has stimulated the
development of new strategies and technologies for the
synthesis of useful products in a safe, compact, and energy-
efficient manner. In this regard, multicomponent reactions
(MCRs)[1] which directly yield the target products by domino
or cascade reaction sequences offer significant advantages
over conventional linear-step syntheses. The resulting re-
duced number of synthetic and purification steps for a given
molecule increases the attractiveness and practicability of the
process.[2] In the ideal situation, a MCR occurs when the
different transformations are mediated by the same catalytic
precursor in a one-pot, one-step operation. Significant success
has been achieved under this paradigm as illustrated by the
growing number of processes for three-component reac-
tions.[3] In contrast, a rather limited number of MCRs
involving four or more reagents have thus far proved to be
reliable enough to be among the usual synthetic tools.[4] This
clearly demonstrates the increasing difficulty in finding
a suitable catalytic system when increasing the number of
components. Not surprisingly though, the balance between
activity and selectivity is generally hard to achieve, as a sharp
penalty has to be paid because of side reactions. Thus, the
implementation of a straightforward MCR strategy with
efficient catalytic control remains a formidable challenge.
As one of the most frequently encountered heterocycles
in medicinal chemistry, 4(3H)-quinazolinones are present in
a large family of products with broad pharmacological
properties including antimalarial, antitumor, anticonvulsant,
fungicidal, antimicrobial, and anti-inflammatory.[11] Further-
more, the heterocyclic core constitutes more than 40 alkaloids
isolated from natural products.[12] In view of their importance,
a number of methods for 4(3H)-quinazolinone preparation
have been developed. These routes, however, mainly rely on
using anthranilic acid or its derivatives as the starting
materials, and generally suffer from low yields, multistep
reactions, or harsh reaction conditions.[13] Recently, Willis and
co-workers reported a straightforward procedure for the
synthesis of quinazolinones.[14] They used N-(o-halophenyl)-
imidates as their substrates, and the desired products were
produced in good yields. Herein, we wish to report our new
achievement in the carbonylative synthesis of quinazolinones.
We started from commercially available 2-bromoanilines,
amines, and ortho-esters, and various 4(3H)-quinazolinones
were isolated in moderate to excellent yields from palladium-
catalyzed aminocarbonylation reactions (Scheme 1).
[*] Dr. L. He, H. Li, Dr. H. Neumann, Prof. Dr. M. Beller, 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
Initially, the reaction was carried out with 2-bromoaniline
(1 mmol), aniline (1.1 mmol), CO (10 bar), and triethyl
orthoformate (2 mmol) in the presence of Pd(OAc)2
(2 mol%), BuPAd2 (CataCXium A, 6 mol%) at 1208C for
16 hours. The expected four-component reaction occurred
and 3-phenyl-4(3H)-quinazolinone (1) was formed as the
major product (63% GC yield) by using NEt3 (2 mmol) as the
xiao-feng.wu@catalysis.de
[**] We thank the State of Mecklenburg-Vorpommern and the Bundes-
ministerium fꢀr Bildung und Forschung (BMBF) for financial
support.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201308756.
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Scheme 1. Concept of the catalytic multicomponent coupling reaction
for the synthesis of 4(3H)-quinazolinones.
base in 1,4-dioxane (2 mL). Among numerous by-products,
four of them, namely N-(2-bromophenyl)formamide (2), N-
phenylformamide (3), ethyl 2-aminobenzoate (4), and ethyl 2-
formamidobenzoate (5) were identified by GC-MS (6–9%
yield). This result was encouraging, since it is not easy to avoid
side reactions for a reaction of such complexity. To our
delight, by replacing triethyl orthoformate with trimethyl
orthoformate, the desired 4(3H)-quinazolinone can be
obtained in remarkably high yield (86% yield upon isolation,
94% GC yield). The yield of the isolated product could be
further improved to 92% by using 2 mmol of DIPEA (N,N-
diisopropylethylamine) as a base under milder reaction
conditions (1008C), whereas a decreased yield was observed
when either K3PO4 or Na2CO3 was used. In the presence of
DIPEA, the air-stable BuPAd2 showed superior performance
compared to ligands such as PPh3 and DPPP. The high
selectivity of the present four-component system, coupled
with its ability to react under mild reaction conditions,
significantly improves the economic and environmental
impacts of this palladium-catalyzed carbonylative coupling
process.
To gain insight into a reaction mechanism, control experi-
ments were conducted. It was confirmed that the direct
conversion of 2-bromoaniline and N-phenylformamide (2)
under 10 bar of CO afford the desired product, while the
combination of aniline, CO (10 bar), and N-(2-bromophe-
nyl)formamide (3), which is the condensation product of 2-
bromoaniline with trimethyl orthoformate through an ether
cleavage of the imidate motif, led to 1 in near quantitative
yield (95% GC yield) under the optimized reaction con-
ditions. On the basis of the above observations and the known
chemistry of the palladium-catalyzed carbonylative cycliza-
tions, a possible reaction mechanism has been proposed in
Scheme 2. Initially, the reaction of 2-bromoaniline with
trimethyl orthoformate gave 2 as the intermediate. Then,
oxidative addition of the in situ generated active Pd0 complex
to 2 results in the arylpalladium complex 6. After the
coordination and insertion of CO, the acylpalladium complex
7 is produced. After nucleophilic attack of aniline on the
acylpalladium complex, 8 was eliminated and gave the
terminal product 1 after intramolecular condensation. Pd0
can be regenerated with the assistance of a base and thus
starts the next catalytic cycle. A catalytic cycle involving (E)-
N’-(2-bromophenyl)-N-phenylformimidamide as an inter-
mediate cannot be excluded.
Scheme 2. Proposed reaction mechanism.
the desired products in good to excellent yields (Table 1,
entries 1–17). Various anilines, regardless of the presence of
electron-donating or electron-withdrawing groups reacted
smoothly to give 71–92% yields of the isolated products
(entries 2–7). Strikingly, a wide range of synthetically useful
functional groups including thioether, benzyloxy, halide, and
trifluoromethyl groups, as well as ketone moieties remained
intact during the reaction. Also, the present system shows
excellent promise for the transformation of heteroaromatic
amines (entries 8 and 9). Notably, the notoriously difficult
benzylamines were successfully converted into the corre-
sponding 4(3H)-quinazolinones (60–73% yields; entries 10–
15). When alkylamines were employed, it was found that N-
alkylquinazolinones could be obtained in excellent yields (80–
84%, entries 16 and 17). More importantly, this one-pot, four-
component synthesis of 4(3H)-quinazolinone could be easily
scaled up. For example, by using DIPEA (20 mmol) as a base,
the direct conversion of 2-bromoaniline (10 mmol), aniline
(11 mmol), triethyl orthoformate (20 mmol), and CO (10 bar)
in the presence of Pd(OAc)2 (2 mol%), and BuPAd2 (Cata-
CXium A, 6 mol%) proceeded smoothly in 1,4-dioxane
(20 mL) at 1208C, thus affording 3-phenyl-4(3H)-quinazoli-
none in 70% yield within 24 h (Table 1, entry 1).
To further demonstrate the general applicability of this
procedure, we then choose aniline as a standard substrate to
perform the test reactions with different 2-bromoanilines
(Table 2). Both electron-donating and electron-withdrawing
substituents are tolerable under the present reaction con-
ditions (Table 1, entries 1–9). Of particular note is the utility
of our method for the preparation of fluorinated 4(3H)-
quinazolinones from commercially available 2-bromoanilines.
It is well known that fluorine-containing functional groups
can drastically change both the biological and physical
properties of organic molecules.[15] We were pleased to find
With these findings in hand, we extended this straightfor-
ward synthesis of 4(3H)-quinazolinones to a wider range of
amines and 2-bromoanilines. As depicted in Table 1 and
Table 2, the present Pd(OAc)2/BuPAd2 catalytic system was
surprisingly versatile. Structurally diverse amines, including
aromatic and aliphatic ones react with 2-bromoaniline to give
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Table 1: Palladium-catalyzed carbonylative coupling of various amines
Table 2: Palladium-catalyzed carbonylative coupling of various 2-
with 2-bromoanilines, trimethyl orthoformate, and CO.[a]
bromoanilines with trimethyl orthoformate, aniline, and CO.[a]
Entry Amine
1
Product
Yield [%][b]
Entry
1
2-Bromoaniline
Product
Yield [%][b]
92
70
70[c]
2
3
73
72
2
3
4
5
81
82
71
83
4
5
6
84
69
65
6
7
8
9
85
79
68
80
7
8
9
75
80
85
[a] 2-Bromoaniline (1 mmol), trimethyl orthoformate (2 mmol), aniline
(1.1 mmol), Pd(OAc)2 (2 mol%), BuPAd2 (6 mol%), 1,4-dioxane (2 mL),
DIPEA (2 mmol), 1008C, CO (10 bar), 16 h. [b] Yields of isolated
products.
10
11
12
13
14
15
16
17
60[d]
71[d]
68[d]
67[d]
73[d]
69[d]
84[d]
80[d]
that all five 2-bromoanilines bearing fluoro, trifluoromethyl,
and trifluoromethoxyl groups are suitable substrates for this
procedure (65–84% yields of isolated products, entries 4–8).
As a representative example of a heterocycle, 3-bromopyr-
idin-2-amine can also be used as a substrate and resulted in
the desired products in 85% yield. This result is remarkable,
considering that the strong coordinating capability of such
generally makes the reaction more difficult to proceed.
Besides trimethyl orthoformate, other ortho esters includ-
ing trimethyl orthoacetate, trimethyl orthopropionate, and
trimethyl orthobenzoate can also be used in the process.
However, the yields of the corresponding 4(3H)-quinazoli-
nones were around 15% under standard reaction conditions.
The yields can be improved to 30–35% by using 2 equivalents
of 2-bromoaniline.
Given the importance of the 4(3H)-quinazolinone nucleus
in many natural products, we wanted to demonstrate the
utility of this method for the synthesis of a pharmaceutically
relevant alkaloids. One such target with fundamental biolog-
ical interest is dihydrorutecarpin, a quinazolino carboline
alkaloid which was used for more than 2000 years in Chinese
[a] 2-Bromoaniline (1 mmol), trimethyl orthoformate (2 mmol), amine
(1.1 mmol), CO (10 bar), Pd(OAc)2 (2 mol%), BuPAd2 (6 mol%), 1,4-
dioxane (2 mL), DIPEA (2 mmol), 1008C, 16 h. [b] Yields of isolated
products. [c] 10 mmol scale. [d] NEt3 (2 mmol), 1208C.
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Scheme 3. Palladium-catalyzed four-component carbonylative coupling
reaction for the synthesis of dihydrorutecarpin.
In summary, we have developed a novel palladium-
catalyzed four-component carbonylative coupling system for
the selective construction of 4(3H)-quinazolinones in a one-
pot fashion. The easy generation of molecular diversity along
with the importance of 4(3H)-quinazolinones in medicinal
chemistry makes the reaction described herein an appropriate
alternative for the synthesis of potentially bioactive com-
pounds. In this context, and considering the simplicity of the
starting materials, the reaction is suitable for the synthesis of
small libraries of functionalized 4(3H)-quinazolinones. Nota-
bly, this interesting procedure can be easily scaled up and its
application in the synthesis of the bioactive dihydrorutaem-
pine precursor was successful.
Received: October 8, 2013
Keywords: heterocycles · multicomponent reactions ·
.
palladium · synthesis design · synthetic methods
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Angew. Chem. Int. Ed. 2014, 53, 1420 –1424