Pd-catalyzed and copper assisted regioselective sequential C2 and C7 arylation of thiazolo[5,4-f]quinazolin-9(8H)-one with aryl halides

Article abstract of DOI:10.1021/acs.orglett.6b01552

A selective functionalization of thiazolo[5,4-f]quinazolin-9(8H)-one has been developed through sequential activation of C-H bonds to furnish diarylated compounds. This strategy allows the regioselective C2 and C7 arylation by a judicious choice of coupling partners and bases, requiring no additional ligands or directing groups. Differently substituted N⁸-benzylated-2,7-diaryl-thiazoloquinazolin-9(8H)-ones were thereby obtained in a facile manner. A one-pot procedure was also performed. These protocols provide a synthetically useful route for late-stage functionalization of this highly valuable scaffold, required in drug discovery.

Full text of DOI:10.1021/acs.orglett.6b01552

Letter
pubs.acs.org/OrgLett
Pd-Catalyzed and Copper Assisted Regioselective Sequential C2 and
C7 Arylation of Thiazolo[5,4‑f ]quinazolin-9(8H)‑one with Aryl Halides
Marine Harari, Florence Couly, Corinne Fruit,* and Thierry Besson*
Normandie Univ, UNIROUEN, INSA Rouen, CNRS, COBRA, 76000 Rouen, France
S
* Supporting Information
ABSTRACT: A selective functionalization of thiazolo[5,4-f ]quinazolin-9(8H)-one has been developed through sequential
activation of C−H bonds to furnish diarylated compounds. This strategy allows the regioselective C2 and C7 arylation by a
judicious choice of coupling partners and bases, requiring no additional ligands or directing groups. Differently substituted N8-
benzylated-2,7-diaryl-thiazoloquinazolin-9(8H)-ones were thereby obtained in a facile manner. A one-pot procedure was also
performed. These protocols provide a synthetically useful route for late-stage functionalization of this highly valuable scaffold,
required in drug discovery.
he development of a process for selective and sequential
building of C−C bonds remains a significant challenge for
that is essential for drug discovery. Since both the linear and
angular isomers have pharmacological activity, general synthetic
strategies are highly desirable for functionalization of theses
valuable heterocycles. The synthesis of a series of diarylated
thiazolo[5,4-f]quinazolin-9(8H)-ones as potential kinase in-
hibitors described by structure A is envisioned (Figure 1).
Despite their obvious synthetic interest, there are signifi-
cantly less examples reported of diarylation of heteroarenes
involving a stepwise or one-pot sequential strategy using aryl
halides.7 Given that selective C−H arylation is an ideal strategy
for late-stage functionalization, we opted to use the N8-
benzylated-thiazolo-quinazolin-9(8H)-one 1 as the substrate, a
key structural unit in the DYRK1 kinase inhibitor series. At the
start of our study, the reaction was based on our reported
results on C2−H arylation of quinazolin-4-ones and pyridopyr-
imidin-ones8 under microwave irradiation.9 Under these
conditions, no selective C7−H phenylated product was
observed (Table 1, entry 1). These reaction conditions afforded
a mixture of C2-mono- and C2/C7-bis-phenylated products 2a
and 3a, among starting material 1. However, when the loading
of aryl iodide was increased and the reaction time was
prolonged to 5 h, diphenylated product 3a was interestingly
obtained in up to 68% yield (Table 1, entry 6). Notably,
products 2a and 3a are readily separated by flash column
chromatography on silica gel.
T
organic chemists, especially for the functionalization of N-
bearing ubiquitous cyclic frameworks.1 In this context,
transition-metal-catalyzed C−C coupling of a heteroarene
through C−H arylation represents an extremely attractive
approach.2 This methodology has emerged as an important tool
for incorporating structural diversity into complex nitrogen
containing heterocycles, without the need for prefunctionalized
starting materials, useful in drug discovery.3 The emergence of
direct functionalization strategies for heteroaromatics allows us
to assess the potential for selective C−H functionalization in
the 6,6,5-tricyclic-thiazolo[5,4-f ]-quinazolin-9(8H)-one scaf-
fold. This heterocycle was used as a versatile molecular
platform for the synthesis of various derivatives with broad
applications in biological sciences.4,5 Our research group was
focused on the synthesis of a novel thiazolo[5,4-f ]quinazolin-
9(8H)-one library as potential kinase inhibitors. We previously
reported that thiazolo[5,4-f ]quinazolin(-on)e derivatives dis-
played single-digit nanomolar IC50 values and are among the
most potent DYRK1A/1B inhibitors disclosed to date
(compounds I and II, Figure 1).6 The ability to perform
selective functionalization on thiazolo[5,4-f]quinazolin-9-one
derivatives would considerably facilitate novel library synthesis
In order to improve selective C2−H arylation on the thiazole
part, the reaction was performed without CuI (Table 1, entry
2). According to our previous study on arylation of quinazolin-
4-one,8 product 3a was effectively not obtained. However,
starting material was recovered as the major compound and 2a
was isolated in only 30% yield. To circumvent the limitation of
Received: May 30, 2016
Figure 1. Structures of molecule hits I and II.
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01552
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Organic Letters
Letter
Table 1. C−H Arylation of N3-Benzylated-Thiazolo[5,4-
When the reaction was conducted with 2,4-dichlorophenyl
iodide, the bis-arylated product was not obtained (entry 6). As
previously described,8a experimentation involving an ortho-
substituent with an electronic effect was unsuccessful on the
quinazolinone part.
a
f]quinazolin-9(8H)-one 1 with Aryl Halide
For structure−activity relationship (SAR) studies, the
development of an efficient regioselective functionalization
based on sequential C−H arylation is required. Despite the
clear interest in selective C2−H arylation, this developed
methodology is limited to aryl bromides as the coupling
partner. In this regard, a convenient protocol allowing the use
of aryl iodides as coupling partners is still required to extend
the scope of the reaction. Inspired by recent reported studies
on the arylation of benzothiazoles, we postulated that the
selective C2−H activation could be performed by using copper
and/or palladium catalysts.10 One of the most attractive
methods for C−H arylation of benzothiazole unit was reported
by Daugulis, who used a CuI catalyst in the presence of tBuOLi
as a base.10b Under these conditions, C2-phenylated product 2a
was obtained in only 28% yield. Whereas an increased amount
of CuI or addition of ligand did not improve the efficiency of
the reaction, better conversion was observed with a longer
time.11 Unfortunately, starting material 1 was not completely
consumed after 4 h under microwave irradiation making the
sequential CH arylation approach difficult to apply. Since only
tBuOLi was effective for the C−H arylation of the quinazolin-4-
one part,8a we finally improved the C2−H arylation of the azole
moiety by switching the base.
After the extensive screening of various reaction parameters,
it was found that addition of 1.0 equiv of CuI in the presence of
1,8-diazabicyclo[5.4.0]undec-7-ene (DBU)12 dramatically im-
proved the reaction efficiency.11 The selective arylation took
place at the most acidic C2−H site. A longer reaction time and
10 mol % Pd(OAc)2 are required for a total conversion of 1.
Under these conditions, both phenyl iodide and bromide are
effective as coupling partners to afford C2-phenylated
compound 2a in 87% and 92% yield, within 3 and 5 h,
respectively (Scheme 1). With the optimum reaction conditions
in hand, the scope of the stepwise arylation reaction of 1 was
examined. The results were depicted in Schemes 2 and 3.
b
b
entry
1
time (h)
PhX (x equiv)
2a (yield %)
3a (yield %)
c
0.5
1
PhI (2)
PhI (2)
PhI (2)
PhI (3)
PhI (3)
PhI (4)
PhBr (2)
PhCl (2)
27
30
28
32
31
27
93
0
45 (23)
d
c
2
0 (64)
c
3
4
4
53 (0)
c
4
59 (0)
e
c
5
4
62 (0)
c
6
7
8
5
68 (0)
c
3
0 (0)
c
3
0 (100)
a
Conditions: Reactions were performed in a sealed tube at 0.4 M with
premixing CuI (50 mol %), LiOtBu (2 equiv), and 1 (1 equiv) in a
microwave reactor, before adding PhX (x equiv), Pd(OAc)2 (5 mol
%). Reported yields are isolated yields. Yields of recovered starting
material 1. The reaction was performed without CuI. The reaction
b
c
d
e
was performed with 1 equiv of CuI.
C−H activation selectivity, we considered that switching the
coupling partner for phenyl bromide or chloride could lead
exclusively to a C2-phenylated compound. While compound 2a
was selectively obtained in excellent yield using phenyl
bromide, no reaction occurred with phenyl chloride (Table 1,
entries 7−8). The reaction was complete at 120 °C under
microwave irradiation within 3 h based on TLC monitoring.
With acceptable conditions established, we explored first the
scope of the bis-arylation reaction (Table 2) with various aryl
a
Table 2. Scope of Bis-arylation Reactions
Scheme 1. Regioselective C2−H Arylation with DBU
b
entry
Ar-
compd
yield (%)
c
1
2
3
4
5
6
4-Me-Ph-
4-MeO-Ph-
4-Cl-Ph-
3b
3c
3d
3e
3f
63 (30)
67 (29)
56 (41)
26 (58)
55 (38)
0 (88)
c
c
c
c
c
4-F-Ph-
4-CN-Ph-
2,4-Cl-Ph-
3g
a
Conditions: Reactions were performed in a sealed tube at 0.4 M with
premixing 1 (1 equiv), LiOtBu (2 equiv), and CuI (50 mol %) in a
The selective C2 arylation is effective for electron-neutral and
electron-rich aryl iodides or bromides, containing methyl,
methoxy, dimethylamino, fluorine, and chlorine substituents
(2b−e; 2h, 59−87%). Electron-deficient aryl iodides and azine
rings gave monoarylated products 2f and 2i−j in 47−69% yield.
In addition, we were pleased to see that β-bromostyrene was
also an effective coupling partner as demonstrated by the
alkenylation reaction leading to compound 2k (Scheme 3). The
moderate yield of compound 2k is arguably due to the
degradation of the bromostyrene reagent at high temperature in
highly polar DMF solvent.
microwave reactor, before adding ArI (3 equiv), Pd(OAc)2 (5 mol %).
Reported yields are isolated yields. Isolated yields of corresponding
compound 2b−g.
b
c
iodides. When aryl iodide was introduced, the resulting 2-aryl-
thiazolo[5,4-f ]quinazolin-9(8H)-ones were reactive enough to
perform a second arylation, yielding significant amounts of 2,7-
homodiarylated products 3b−f. This double C2/C7 arylation
protocol yielded targeted compounds in moderate yields.
Whatever the applied reaction conditions, the bis-arylation was
not complete and compounds 2a−g were isolated even with a
longer reaction time.
We then turned our attention to the synthesis of diarylated
compounds. For this purpose, compound 2a was submitted to
B
DOI: 10.1021/acs.orglett.6b01552
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Organic Letters
Letter
Scheme 2. Scope of the C2 Arylation of N3-Benzylated-
Thiazolo[5,4-f ]quinazolin-9(8H)-one 1 with Aryl Halides
Scheme 4. Regioselective C7 Arylation of 2-Aryl-N3-
Benzylated-Thiazolo[5,4-f]quinazolin-9(8H)-ones 2a−f
a
a
a
Premixing 2 (1 equiv), LiOtBu (2 equiv), and CuI (50 mol %),
before adding ArI (2 equiv), Pd(OAc)2 (5 mol %) for 5 h.
stepwise Pd-catalyzed C−H arylation of thiazolo[5,4-f ]-
quinazolin-9(8H)-one 1 with aryl bromides and iodides occurs
in an efficient manner with broad tolerance to substituents on
the coupling partners. The challenging removal of the
protecting group was investigated, but many of the standard
debenzylation strategies failed.4a,14
We then envisioned the dual C−H bond functionalization in
a one-pot process, allowing the chromatographic purification
step to be discarded. The first C2-arylation of compound 1 with
phenyl bromide was complete within 3 or 5 h, depending on
the base. The second arylation was finally achieved by the in situ
addition of tolyl iodide, CuI (50 mol %), and Pd(OAc)2 (5 mol
%) to the reaction mixture and led to the expected C2 and C7
diarylated thiazolo[5,4-f ]quinazolin-9(8H)-one 4a in accept-
able yield (Scheme 5).
a
Premixing 1 (1 equiv), DBU (2 equiv), and CuI (1 equiv), before
adding ArI or ArBr (2 equiv), Pd(OAc)2 (10 mol %) for 5 h.
Scheme 3. C2 Alkenylation of Thiazolo[5,4-f]quinazolin-
9(8H)-one 1 with β-Bromostyrene
the previously reported conditions for C−H arylation of
quinazolinones.8a Under these aforementioned conditions,
compound 2a was further successfully arylated at C7 on the
quinazolin-4-one (Scheme 4) to afford diarylated compound 4a
in 87% yield after 5 h. We subsequently carried out the C7-
arylation of compounds 2b−f with aryl iodides bearing a
methyl, methoxy, fluoro, or cyano substituent at the para- or
ortho-position (Scheme 4).
Scheme 5. Ligand Free One-Pot Sequential C2 and C7
Arylation of N3-Benzylated-Thiazolo[5,4-f ]quinazolin-9-
(8H)one 1
Diverse aryl groups are readily introduced into the
quinazolinone part of compounds 2a−f in acceptable yields.
The 4-cyano-phenyl iodide is of particular note and led to
compounds 4b−da in yields up to 73%. The arylation of
compound 2f was also efficient, and compounds 4fa and 4fb
were obtained in 69% and 78% yield, respectively. An electron-
neutral substituent such as methyl in the ortho-position of the
coupling partner was found to be suitable. In some cases, the
reaction is not complete and the starting material was also
recovered. In addition, compounds 4 are especially difficult to
purify owing to their low solubility. It was noted that the
arylation of the 2-arylbenzothiazole moiety of compounds 2b−f
that afforded an undesired product was not observed.13 The
In conclusion, we have developed a mild and efficient
functionalization of N3-benzylated-thiazoloquinazolin-9(8H)-
one based on sequential selective C−H arylation. This
procedure tolerates a wide variety of substituents on the aryl
halides. Electron-deficient heteroarenes are also readily
introduced at the C2 position, a notable feature with respect
to medicinal agent synthesis. Thiazoloquinazolin-9(8H)-one
proved to be a viable substrate for C−H (hetero)-arylation,
C
DOI: 10.1021/acs.orglett.6b01552
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b01552.
■
S
́
Soule, J. F.; Doucet, H. Adv. Synth. Catal. 2015, 357, 2869. (d) Fuse,
S.; Morita, T.; Johmoto, K.; Uekusa, H.; Tanaka, H. Chem. - Eur. J.
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Experimental procedures and characterization for all new
compounds (PDF)
AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: corinne.fruit@univ-rouen.fr.
*E-mail: thierry.besson@univ-rouen.fr.
Notes
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The authors declare no competing financial interest.
ACKNOWLEDGMENTS
Financial support from the MESR (Minister
■
̀
e de l’Enseignement
Super
́
ieur et de la Recherche) is gratefully acknowledged for the
doctoral fellowships to M.H. and F.C. We thank the LABEX
SynOrg (ANR-11-LABX-0029) for financial support and Anton
Paar GmbH (Graz, Austria) for provision of a single-mode
microwave reactor (Monowave 300) and for technical support.
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