Bronsted acid-promoted sequential hydroarylation-hydroamidation of arene-tethered 1-(2-alkynylphenyl)ureas: Direct access to 4,4-spiro-3,4-dihydro- 2-(1H)-quinazolinones

Article abstract of DOI:10.1002/adsc.201100223

A Bronsted acid-promoted approach to 4,4-sipro-3,4-dihydro-2-(1H)- quinazolinones from arene-tethered 1-(2-alkynylphenyl)ureas has been developed. The reaction is initiated by intramolecular hydroarylation followed by hydroamidation, assisted by intramole

Full text of DOI:10.1002/adsc.201100223

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DOI: 10.1002/adsc.201100223
Brønsted Acid-Promoted Sequential Hydroarylation–
Hydroamidation of Arene-Tethered 1-(2-Alkynylphenyl)ureas:
Direct Access to 4,4-Spiro-3,4-dihydro-2-(1H)-quinazolinones
Honggen Wang,a Jiaji Zhao,a Jiancun Zhang,a,* and Qiang Zhua,*
a
State Key Laboratory of Respiratory Disease, Guangzhou Institutes of Biomedicine and Health, Chinese Academy of
Sciences, 190 Kaiyuan Avenue, Guangzhou 510530, Peopleꢀs Republic of China
Fax : (+86)-020-3201-5299; phone: (+86)-020-32015287; e-mail: zhang_jiancun@gibh.ac.cn or zhu_qiang@gibh.ac.cn
Received: March 28, 2011; Revised: May 9, 2011; Published online: September 29, 2011
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/adcs.201100223.
Abstract: A Brønsted acid-promoted approach to
4,4-sipro-3,4-dihydro-2-(1H)-quinazolinones from
um intermediates [Eq. (1), Scheme 1].[7] Brønsted
acid-promoted hydroamination is less common be-
cause, in most cases, nitrogen is more basic than the
p-systems of alkynes or alkenes, which makes the ni-
trogen non-nucleophilic upon protonation.[3] The use
of Brønsted acid in cascade hydroamination–hydroar-
ylation is even more scarce in theliterature.[8] Herein,
we would like to disclose a Brønsted acid-promoted
synthesis of a unique spirocyclic N-heterocycle by lo-
cating the amide and the arene moieties at separate
ends of an alkyne [Eq. (2), Scheme 1].
arene-tethered 1-(2-alkynylphenyl)ureas has been
developed. The reaction is initiated by intramolecu-
lar hydroarylation followed by hydroamidation, as-
sisted by intramolecular proton transfer from the
protonated urea moiety. A variety of tethering
atoms, including carbon, oxygen, sulfur, and pro-
tected nitrogen are compatible with the reaction
conditions.
Keywords: acidity; alkynes; cyclization; heterocy-
cles; hydroamidation; hydroarylation
With this idea in mind, we designed compound
1a,[9] a phenol-tethered 1-(2-alkynylphenyl)urea using
the phenolic oxygen as the linker, to test our hypothe-
sis (Table 1). It was anticipated that both the low ba-
sicity of the urea nitrogen and the high electron densi-
ty of the tethered phenol will facilitate the process of
Considerable attention has been paid to cascade reac- Brønsted acid-promoted hydroamidation and hydro-
tions involving alkynes, in which multiple carbon- arylation. To our delight, a unique spiroquinazolinone
carbon and/or carbon-heteroatom bonds are formed derivative 2a was isolated in excellent yield (87%)
sequentially in one operation, enabling a fast assem- under the conditions involving 1.5 equivalents of
bly of complex and diversified molecular architec- TfOH in refluxing DCE (entry 1, Table 1). A series of
tures.[1] Transition metal- or Brønsted acid-promoted spiroquinazolinone derivatives were claimed as prom-
direct addition of Ar H bonds or N H bonds across ising PDE7 inhibitors.[10] Methods for the synthesis of
alkynes or alkenes, known as hydroarylation[2] and hy-
droamination[3], provides atom-economical and step-
efficient processes to functionalized arenes and N-
containing compounds. Compared with double hydro-
arylation[4] and double hydroamination[5], cascade hy-
droamination–hydroarylation or hydroarylation–hy-
droamination on the same carbon-carbon triple bond
is relatively undervalued. Recently, Patil and co-work-
ers reported Pt-catalyzed hydroamination–hydroaryla-
tion cascade reactions to construct complex multi-ring
N-heterocyclic compounds.[6] In a report by Dixon et
al, Au(I)-catalyzed a formal hydroamination–hydroar-
À
À
ylation reaction of alkynoic acids and pyrrole or
indole-substituted ethylamines through N-acylimini- droarylation–hydroamidation of alkynes.
Scheme 1. Cascade hydroamination–hydroarylation and hy-
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Table 1. Optimization of reaction conditions.[a]
our attention to the compatibility of different linkers.
Gratifyingly, carbon chain-linked 1j exhibited excel-
lent efficiency for cyclization under both acidic condi-
tions. Strangely, the cyclization efficiency of TfOH
and TFA was reversed in the case of using sulfur as a
linker, preferring TfOH (78%) way over TFA (33%).
Nitrogen could also be used as a tethering atom, de-
pending heavily on the protecting group on it.
Methyl- and acetyl-protecting groups were deteriori-
ous for the reaction, probably due to the basicity of
the nitrogen linker. As expected, the desired cycliza-
tion proceeded smoothly when a more electron-with-
drawing tosyl group was applied under the modified
TFA conditions (2l, 59%).
Having successfully established the intramolecular
cascade, we then explored an intermolecular variant
of this reaction. As shown in Table 3, 4,4-disubstituted
3,4-dihydro-2(1H)-quinazolinone 4a was produced re-
gioselectively in good yield (77%) upon treatment of
1-(2-alkynylphenyl)urea 3a with 1.5 equivalents of
TfOH in toluene as solvent under reflux. Notably, the
milder TFA was inert in this intermolecular cascade
reaction, forming 4-pentylquinazolin-2(1H)-one 5, the
Entry Catalyst (equiv.)
Solvent T
[oC]
Yield
[%][b]
1
2
3
4
TfOH (1.5)
TfOH (1.0)
TfOH (0.5)
TfOH (1.5)
TFA:DCE=1:2
PtCl4 (0.05)
DCE
DCE
DCE
DCE
reflux 87
reflux 60
reflux 20
60
reflux 93
toluene reflux 0
toluene 80
50
5
6[c]
7[c]
AuCl
G
0
(0.05/0.05)
[a]
[b]
[c]
1a (0.5 mmol), solvent (2 mL).
Isolated yield.
1a decomposed to unidentified mixtures.
this class of compounds are limited to condensation hydroamidation product, exclusively (Scheme 2).
of arylureas with cyclic ketones in polyphosphoric Alkyl substituents on the other end of triple bond,
acid (PPA) under heating.[10] Attempts to minimize such as cyclohexyl and tert-butyl were compatible
the amount of acid resulted in significant loss of yield with the reaction conditions (4e and f). However, a
(entries 2 and 3, Table 1). The reaction temperature phenyl substitution was not suitable for this transfor-
was also important to maintain the high yield. The mation. The reaction also proceeded well in other ar-
less acidic TFA gave even better result, albeit it had omatic solvents, such as benzene, p-xylene, and m-
to be used as a co-solvent (entry 5, Table 1). Surpris- xylene, furnishing 4b, 4c, and 4d in moderate yields,
ingly, Au and Pt, prevalent catalysts in alkyne chemis- respectively. Unfortunately, the desired product 4
try, exhibited no activity at all in this transformation cannot be obtained in electron-deficient arenes such
(entries 6 and 7, Table 1).[11]
as chlorobenzene and 1,2-dichlorobenzene. It was
Both of the reaction conditions, involving 1.5 equiv- noteworthy that a significant amount of 4-alkylquina-
alents of TfOH and an excess amount of TFA in zolin-2(1H)-ones, derived from intramolecular alkyne
DCE under reflux, were applied to probe the general- hydroamidation, were observed as major by-products
ity of this reaction. The effect of substituents on the in these reactions.[12]
tethered phenol was examined first. As shown in
To figure out the sequence of the cascade reaction,
Table 2, a variety of substituents ranging from elec- 4-pentylquinazolin-2(1H)-one 5 was exposed to the
tron-donating OMe and Et to electron-withdrawing F, TfOH/toluene condition (Scheme 2).[12] No further in-
Cl, and Br were all well-tolerated (1b–1i, Table 2). In termolecular hydroarylation occurred, indicating that
general, good to excellent yields were obtained, ex- 5 was not the reaction intermediate for the final prod-
hibiting the TFA-protocol as being superior to that uct 4a. In another words, the intermolecular hydroary-
with TfOH. It is noteworthy that functionalities, such lation was preferred and took place first. In the case
as chloro, bromo, and methoxy, provide handles for of phenyl-tethered substrates 1, the intramolecular
further elaboration on the scaffold. The electron-rich hydroarylation should proceed even faster, suggesting
para-methoxy-substituted 1f decomposed to unidenti- a hydroarylation–hydroamidation sequence as being
fied mixtures under the strong acidic TfOH condi- more likely. Moreover, the requisite for a stoichiomet-
tions. When meta-methyl-substituted 1h was used, two ric excess of acid suggested that the product existed
regioisomers were formed, favoring the less hindered in its protonated form under the reaction conditions.
site for hydroarylation to occur. In this case, the re-
Based on the above observations and Hartwigꢀs re-
gioselectivity was decreased from 4:1 to 2:1, but the search on Brønsted acid-catalyzed intramolecular hy-
yield was improved when the acid was switched from droamidation of protected alkenylamines,[13] a plausi-
TfOH to TFA. A substrate bearing a bulky naphthyl ble mechanism was proposed as shown in Scheme 3.
group also cyclized to the corresponding product 2i Reversible protonation on the urea moiety in 1 leads
under both conditions in lower yield. Next, we turned to intermediate A.[14] Intramolecular proton transfer
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Brønsted Acid-Promoted Sequential Hydroarylation–Hydroamidation
Table 2. Scope of the cascade hydroarylation–hydroamidation.
Entry Substrate 1
Product 2
Yield [%] from Condi-
tionsA[a]
Yield [%] from Condi-
tions B[b]
1
2
3
4
5
6
R=H
R=Et
R=F
R=Cl
R=Br
R=OMe
1a R=H
1b R=Et
1c R=F
1d R=Cl
1e R=Br
1f R=OMe
2a 87
93
96
88
88
94
68
2b 77
2c 85
2d 74
2e 65
[c]
2f
–
7
8
1g
1h
2g 74
94
2h 61 (4:1)[d]
87 (2:1)[d]
9
1i
2i 34
42
10
11
1j
2j 96
2k 78
[c]
93
33
1k
12
1l
2l
–
59[e]
[a]
[b]
[c]
[d]
[e]
1 (0.5 mmol), TfOH (0.75 mmol), DCE (2 mL), reflux, 0.5–5 h, isolated yield.
1 (0.5 mmol), TFA (1 mL), DCE (2 mL), reflux, 8–13 h, isolated yield.
Substrate decomposed.
Isomer ratio, determined by 1H NMR.
TFA: DCE=2:1, 3 mL, reflux.
ꢀ
from the protonated urea to the C C triple bond gen- fer via intermediate E, gives a stabilized dibenzylic
erates intermediate B, which is attacked by the teth- carbonium F. The following C N bond formation af-
À
ered phenyl ring quickly. The following deprotona- fords the protonated final product 2.
tion–aromatization yields the cyclized hydroarylation
In summary, we have developed a concise method
intermediate D. Further protonation of the resulting for the synthesis of 4,4-spiro-3,4-dihydro-2-(1H)-qui-
alkene, through another intramolecular proton trans- nazolinones through a TfOH- or TFA-promoted cas-
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Table 3. Intermolecular hydroarylation–hydroamidation.
Entry
1
Substrate 3
Solvent
toluene
Product 4
Time [h]
Yield [%][a]
3a
4a
12
77
2
3
3a
3a
benzene
4b
4c
15
3
49
51
p-xylene
4
5
3a
3b
3c
m-xylene
toluene
toluene
4d
4e
4f
5
3
3
51
60
58
6
[a]
3 (0.5 mmol), TfOH (0.75 mmol), arene (1 mL), reflux, 3–15 h, isolated yield.
cade intramolecular hydroarylation–hydroamidation
reaction of arene-tethered 1-(2-alkynylphenyl)ureas.
In addition to the merit of using a Brønsted acid in-
stead of expensive Au and Pt catalysts, the reaction
exhibits good functional group and tethering atom
tolerance, providing structurally diversified analogues
of spiroquinazolinones. The results of mechanistic
ꢀ
studies suggest that initial hydroarylation of the C C
triple bond, assisted by intramolecular proton transfer
from the protonated urea, is highly likely. The inter-
molecular variant of this cascade reaction works well
too in arenes as solvent under the more forcing TfOH
conditions, generating 4,4-disubstituted-3,4-dihydro-2-
(1H)-quinazolinones in moderate to good yields.
Scheme 2. Mechanistic study.
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Brønsted Acid-Promoted Sequential Hydroarylation–Hydroamidation
Scheme 3. Plausible reaction mechanism.
General Procedure for the Synthesis of 4
Experimental Section
Following the general procedure of Method A, except for
1
using arene (1 mL) as solvent. H NMR (400 MHz, CDCl3):
General Procedure for the Synthesis of 2
d=7.96 (s, 1H), 7.28 (d, J=8.4 Hz, 2H), 7.14–7.10 (m, 3H),
6.96 (d, J=6.4 Hz, 1H), 6.93–6.89 (m, 1H), 6.72 (d, J=
8.0 Hz, 1H), 5.35 (s, 1H), 2.35–2.18 (m, 1H), 2.34 (s, 3H),
2.09–2.03 (m, 1H), 1.51–1.38 (m, 1H), 1.30–1.26 (m, 5H),
0.86–0.83 (m, 3H); 13C NMR (125 MHz, CDCl3): d=154.5,
143.1, 137.0, 135.8, 129.2, 128.0, 126.1, 126.0, 124.9, 122.3,
114.4, 63.2, 41.8, 31.9, 23.4, 22.5, 20.9, 14.0; HR-MS:
m/z=309.1961, calcd. for C20H25N2O [M+H]+: 309.1961.
Method A: To a solution of 1 (0.5 mmol) in DCE (2 mL),
was added TfOH (0.75 mmol). The resulting mixture was
stirred and heated at reflux under air for 0.5 to 5 h until all
of the starting material was consumed. Saturated aqueous
NaHCO3 (10 mL), and EtOAc (10 mL) were added to the
cooled reaction mixture successively. The organic phase was
separated, and the aqueous phase was further extracted with
EtOAc (2ꢂ10 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated. The residue was
purified by flash chromatography to provide the desired
product 2.
Acknowledgements
Method B: A solution of 1a (0.5 mmol) in TFA (1 mL)
and DCE (2 mL) was stirred and heated at reflux under air
for 8 to 13 h. After completion of the reaction, most of the
solvents were removed under vacuum. Saturated aqueous
NaHCO3 (10 mL), and EtOAc (10 mL) were added to the
reaction mixture successively. The organic phase was sepa-
rated, and the aqueous phase was further extracted with
EtOAc (2ꢂ10 mL). The combined organic layers were dried
over anhydrous Na2SO4 and concentrated. The residue was
We are grateful for the support of this work by a Start-up
Grant from Guangzhou Institutes of Biomedicine and Health
(GIBH), the National Basic Research Program of China
(973 Program 2011CB504004 and 2010CB945500) and
Guangzhou Municipal Foundation for Science and Technolo-
gy (2010Y1-C241).
purified by flash chromatography to provide the desired References
product 2a. 1H NMR (400 MHz, CDCl3): d=9.31 (s, 1H),
7.29–7.26 (m, 1H), 7.22–7.12 (m, 2H), 6.91–6.84 (m, 4H),
6.67 (d, J=7.2 Hz, 1H), 5.93 (s, 1H), 4.27–4.15 (m, 2H),
2.38–2.21 (m, 2H); 13C NMR (100 MHz, CDCl3): d=155.3,
154.7, 136.0, 129.8, 129.7, 128.5, 127.0, 126.1, 124.6, 122.2,
121.2, 117.1, 114.6, 62.0, 55.8, 38.5; HR-MS (ESI): m/z=
267.1132, calcd. for C16H15N2O2 [M+H]+: 267.1128.
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Adv. Synth. Catal. 2011, 353, 2653 – 2658