Silver-Catalyzed Annulation of Arynes with Nitriles for Synthesis of Structurally Diverse Quinazolines

Article abstract of DOI:10.1021/acs.orglett.9b04395

An efficient silver catalyzed annulation reaction of aryne with nitriles to generate quinazolines is described. Arynes generated from triynes or tetraynes through a hexadehydro Diels-Alder reaction readily participated in an [A + 2B] mode of annulation with nitriles in the presence of AgSbF₆ catalyst. The mechanism was explored by DFT calculations, which supports the silver-catalyzed formation of nitrilium ion as a key intermediate. This annulation generates an array of polysubstituted novel quinazoline derivatives with excellent regioselectivity.

Full text of DOI:10.1021/acs.orglett.9b04395

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver-Catalyzed Annulation of Arynes with Nitriles for Synthesis of
Structurally Diverse Quinazolines
Sourav Ghorai,† Yongjia Lin,‡ Yuanzhi Xia,‡,* Donald J. Wink,† and Daesung Lee*,†
†Department of Chemistry, University of Illinois at Chicago, 845 West Taylor Street, Chicago, Illinois 60607, United States
‡College of Chemistry and Materials Engineering, Wenzhou University, Wenzhou, Zhejiang Province 325035, P.R. China
S
* Supporting Information
ABSTRACT: An efficient silver catalyzed annulation reaction
of aryne with nitriles to generate quinazolines is described.
Arynes generated from triynes or tetraynes through a
hexadehydro Diels−Alder reaction readily participated in an
[A + 2B] mode of annulation with nitriles in the presence of
AgSbF6 catalyst. The mechanism was explored by DFT
calculations, which supports the silver-catalyzed formation of
nitrilium ion as a key intermediate. This annulation generates an array of polysubstituted novel quinazoline derivatives with
excellent regioselectivity.
eterocyclic compounds draw significant attention from
synthetic chemists because of their immense importance
alkyne or its functional equivalent and two molecules of
nitrile6a−e,h−m under thermal or acid-catalyzed conditions. Hua
realized a TfOH-catalyzed [2 + 2 + 2] cycloaddition reaction
of 1,4-diaryl-1,3-butadiyne with nitriles to form quinazolines
(Scheme 1).6b Cu(OTf)2-mediated and thermal annulations
H
in human life.1 Quinazoline, a family of nitrogen-based bicyclic
aromatic compounds, constitutes the core of numerous
biologically active molecules that show anticancer,2a anti-
bacterial,2b antifungal,2c antiviral,2d antitubercular,2e anti-
inflammatory,2f antimutagenic,2g anticoccidial,2h antimalarial,2i
antileishmanial,2j antioxidant,2k neuroprotective,2l antiobesi-
ty,2m and antihypertensive activities.2n Prazosin,3a erlotinib,3b
trimetrexate,3c and vandetanib3d are representative marketed
drugs (Figure 1).3e,f In addition, the unique photochromic
Scheme 1. [2 + 2 + 2] Annulation Strategies for Quinazoline
Synthesis
Figure 1. Representative quinazoline-based drugs.
behavior of quinazoline molecules4 was exploited to elucidate
cellular signaling processes of epidermal growth factor receptor
(EGFR)4c,d and α1-adrenergic receptors.4e,f Recently, quinazo-
lines have been recognized as light-emitting materials for
electronic devices.5
Many protocols for quinazoline synthesis via a nitrilium
intermediate are reported in the literature;6a−g however, the
generality of these methods is often limited by the requirement
of prefunctionalized arene moieties. In theory, quinazolines can
be generated via a formal [2 + 2 + 2] cycloaddition between
are also developed to generate quinazolines by employing
diaryliodonium6c or aryldiazonium salts.6e Although Romero-
Ortega employed [4 + 2] cycloaddition of benzyne with 1,3-
diazabutadiene derivatives to generate quinazolines,7 however,
direct annulation of benzynes with nitriles to form quinazolines
has not been reported. In this regard, we envisaged a new
Received: December 7, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04395
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Letter
double-annulation strategy whereby tri- and tetrayne 1 are
annulated to generate quinazolines 2 via in situ formation of an
aryne followed by addition of two nitrile molecules catalyzed
by a silver ion. A caveat in this approach is that the 1,3-diyne
moiety in 1 should preferentially participate in a hexadehydro
Diels−Alder reaction8 to generate an aryne intermediate before
its engagement in other process. Herein, we report successful
implementation of an aryne-based [A + 2B]-type double-
annulation reaction for the synthesis of structurally diverse
quinazoline derivatives.
Silver catalysts are known to confer a profound impact on
the reactivity of arynes.9 By employing certain silver complexes
as a catalyst, we have developed many aryne-based trans-
formations including C−H insertion,10 nucleophilic trapping,11
hydroarylation,12 hydrofluorination,13 hydride transfer reac-
tion,14 and so forth.15 It was shown that the reactivity
preference of arynes toward different nucleophiles could be
switched in the absence and presence of a silver catalyst. For
example, the reaction of an aryne to generate aryl ester A from
carboxylic acid in acetonitrile16 could be completely redirected
to provide N-arylimide B in the presence of a silver complex
(Scheme 2).11b We surmised that A is derived from a direct
Table 1. Optimization of Reaction Conditions
b
b
entry
catalyst
yield (%) entry
catalyst
yield (%)
1
2
3
4
5
6
AgOAc
Ag2CO3
AgOTf
AgSbF6
AgSbF6
Zn(OTf)2
5
38
47
97
92
93
7
8
9
10
11
12
Mg(OTf)2
ln(OTf)3
Sm(OTf)3
AuCl
Cu(OTf)2·C6H6
none
91
2
74
23
34
26
c
d
a
b
Used as solvent. NMR yields using an internal standard (1,5-
c
d
difluoro-2,4-dinitrobenzene). 92% yield at 120 °C after 12 h. With 5
equiv of PhCN.
Scheme 3. Quinazoline Formation from Arynes Derived
from Structurally Different Tetraynes and Triynes
Scheme 2. Differential Reactivity of Arynes in the Absence
and Presence of Silver Catalyst
interaction of a more nucleophilic carboxylic acid with the
aryne via C, whereas imide B results from the initial interaction
of a silver-complexed aryne species with nitriles to form D
followed by formation of a nitriliam intermediate E,17 which is
then trapped by a carboxylic acid.
Based on these observations, we hypothesized that without a
carboxylic acid the putative intermediate E would be trapped
with another molecule of nitrile, which will set for a favorable
6-endo-dig cyclization18 of an organosilver moiety with the
resulting nitrilium species to form the quinazoline skeleton.
With this hypothesis, we commenced our exploration with
symmetric tetrayne 1a and benzonitrile and optimized the
reaction conditions in terms of catalyst and temperature
(Table 1). Among silver, AgSbF6 was found to be the most
effective catalyst, while other metal triflates such as Zn(OTf)3,
Mg(OTf)2, and Sm(OTf)3 were also effective. With AgSbF6
(10 mol %, 150 °C, 2 h) in benzonitrile as solvent, quinazoline
2aa was obtained in 97% yield (entry 4). When the reaction
was carried out in toluene with 5 equiv of benzonitrile a
slightly lower yield (92%) was observed. It is noteworthy that a
single isomer of 2aa was generated from the reaction, which
was unambiguously assigned by NOE experiments.
a
20 wt % 4 Å MS was added into reaction mixture.
afford a somewhat low yield of the quinazolines.20 There seems
to be an inverse correlation between the rate of aryne
formation and the yield of quinazoline. The aryne precursors
forming arynes slowly (2 h) result in high yields of 2ba−2fa in
the range of 69−95%, except for 2ga (5 h, 53%). On the other
hand, the nitrogen- and oxygen-tethered tetraynes consumed
quickly (0.5 h) tend to decompose to a larger extent, resulting
in relatively lower yield of quinazolines 2ha−2ja (36−58%).
An ester-tethered triyne provided quinazoline 2ka in 70% yield
With the optimized conditions in hand, we next explored
quinazoline formation from the aryne species derived from
structurally different tetraynes (1b−1d and 1f−1j)19 and
triynes (1e, 1k, 1l) (Scheme 3). While all carbon-tethered
tetraynes are generally good substrates to generate quinazo-
lines in high yield, nitrogen- and oxygen-tethered tetraynes
B
DOI: 10.1021/acs.orglett.9b04395
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(5 h) while the corresponding amide-tethered triyne afforded
2la in 76% yield (5 h). Substituents on aryne intermediates
played a pivotal role for the regioselectivity of the first nitrile
addition. Thus, tert-butyl group dictates the initial nitrile
addition at the meta position from it (2ba and 2b′a),21
whereas with trimethylsilyl (SiMe3) substituent22 nitrile
addition selectively occurred at the ortho position (2ea). In
the case of aryl substituents, formation of a mixture of two
isomers was observed with a slight meta preference (2ca and
2fa).23 The identity of these isomers was unambiguously
confirmed by X-ray diffraction analysis of 2ca and 2ka.
Scheme 5. Quinazoline Formation with Structurally
Differentiated Triynes and Tetraynes with Various Nitriles*
Next, we examined annulation reactions of tetrayne 1a with
different nitriles (Scheme 4). In these reactions, the fluctuating
Scheme 4. Efficiency of Quinazoline Formation with
Tetrayne 1a and Different Nitriles*
*
a
Conditions: AgSbF6 (10 mol %), RCN (5 equiv), 150 °C. With 20
b
c
wt % 4 Å MS. Nitrile as a solvent instead. With 10 equiv of nitrile.
substituted quinazolines 2ke (5 h, 59%) and 2le (2 h, 65%).
Also, quinazolines 2kc (5 h, 51%), 2kd (5 h, 42%), and 2kl (5
h, 57%) were generated in slightly lower yields. In general,
electro-neutral or electron-rich aliphatic and aromatic nitriles
can participate in the reaction with arynes to furnish 2,4-
disubstituted quinazoline derivatives in moderate to high yield.
On the other hand, the reaction with electron-deficient nitriles
or nitriles containing a sensitive functional group (see in the
legend of Scheme 5) provided no or low yield of quinazoline
products.
*
a
Conditions: AgSbF6 (10 mol %), toluene, 150 °C, 2 h. With 5 equiv
b
c
of nitrile. Nitriles as solvent. With 10 equiv of nitrile.
To gain further insight into the reaction mechanism and
regioselectivity, we carried out DFT calculations26 (SMD/
M06/6-311++G(d,p)/SDD//B3LYP/631G*/Lanl2dz level of
theory)27 (Figure 2: Calculations employed an NTs-tethered
tetrayne (1h) that leads to product 2ha). These calculated
reaction profiles26 indicate that silver-complexed aryne (IN1)
interacts with benzonitrile to form a more stable complex IN2
from which nitrilium species IN3 could be formed via TS1. In
the next step, intermediate IN3 could undergo ring closure to
generate azabicyclo IN428 in path A, but it requires a high
barrier (31 kcal/mol). On the other hand, IN3 interacts with
another benzonitrile to generate IN5 exergonically in path B.
Due to a highly stabilized nature of an ionic complex IN5, its
conversion to bis-nitrile adduct IN6 via TS3 requires an
activation barrier of 28.5 kcal/mol, being 2.5 kcal/mol lower
than the highest barrier in path A.
Once intermediate IN6 is generated in path B, it can take
two different reaction paths leading to ring closure or triple
nitrile adduct formation (Figure 2B). The barrier for ring
closure of IN6 via TS4 is only 1.1 kcal/mol (path C), affording
silver-complexed quinazoline IN7. On the other hand, the
stabilized nitrile complex IN8 formed from IN6 in path D
should overcome a much higher barrier of 28.9 kcal/mol to
proceed to the next intermediate IN9. Thus, the thermody-
namically and kinetically favorable formation of IN7 in path C
provides the observed quinazoline product 2ha.
yields with different substrates, most likely caused by
adventitious water, became more consistent and improved by
adding molecular sieve (4 Å, 20 wt %)24 to the reaction
medium. While the reaction with benzonitrile provided 2aa in
excellent yield (92%), with more electron-rich benzonitriles
containing 4-OMe and 4-NMe2 substituent, 2ab and 2ac were
obtained in significantly lower yield (48%) and with 4-
fluorobenzonitrile 2ad was obtained in 65% yield. On the other
hand, reactions with electron-rich aminonitriles such as
piperidinecarbonitrile and 4-morpholinecarbonitrile afforded
2,4-diaminoquinazolines25 2ae and 2af in 83 and 70% yield,
respectively. Reactions of cinnamyl- and vinyl-substituted
quinazolines cinnamylcarbonitrile and acrylonitrile (used as
solvent) provided 2ag and 2ah in 40 and 54% yield. Aliphatic
nitriles such as acetonitrile, propionitrile, isobutyronitrile, and
cyclopropane−carbonitrile provided quinazolines 2ai−2al in
good yield (66−87%) when employed as a solvent. Sterically
more hindered naphthalene-2-carbonitrile (5 equiv) also
provided quinazoline 2am in moderate yield (46%).
Subsequently, different combinations of aryne precursors and
nitriles were employed to broaden the structural space of the
quinazolines (Scheme 5). The reaction of ketoarene-tethered
triyne generated 2ee and 2ej in 67 and 63% yield within 2 h,
while a fluorene-tethered tetrayne generated 2gj in 75% yield
after 5 h. A heteroatom-tethered tetrayne provided 2hl within
0.5 h in marginal yield (35%) regardless of the molecular sieve
additive or an increased amount of nitrile. On the other hand,
an ester- or an amide-tethered triyne provided 2,4-diamino-
In summary, we have developed an efficient [A + 2B]
annulation of arynes with nitriles to form quinazolines under
silver-catalyzed conditions. Structurally diverse and noble
C
DOI: 10.1021/acs.orglett.9b04395
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
AUTHOR INFORMATION
Corresponding Authors
■
*Email: dsunglee@uic.edu.
*Email: xiayz04@mails.ucas.ac.cn.
ORCID
Yuanzhi Xia: 0000-0003-2459-3296
Donald J. Wink: 0000-0002-2475-2392
Daesung Lee: 0000-0003-3958-5475
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the NSF (CHE-1764141, D.L.) and NSFC
(21572163 and 21873074, Y.X.) for financial support. The
Mass Spectrometry Laboratory at UIUC is acknowledged.
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DOI: 10.1021/acs.orglett.9b04395
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