Silver-Catalyzed Selective Multicomponent Coupling Reactions of Arynes with Nitriles and Isonitriles

Article abstract of DOI:10.1021/acs.orglett.9b04416

Pathway selective aryne-based novel multicomponent coupling reactions with isonitriles and nitriles are described. Crucial to these reactions is the formation of a silver-aryne complex, which shows differential reactivity toward isonitriles and nitriles to form two different forms of ortho-nitrilium organosilver arene species. Interception of the nitrilium of an aryne-isonitrile adduct with another isonitrile leads to the formation of benzocyclobutene-1,2-diimines, whereas the nitrilium of an aryne-nitrile adduct renders selective formation of 3H-indol-3-imines or 3-iminoindolin-2-ol depending on the structure of the nitrile employed.

Full text of DOI:10.1021/acs.orglett.9b04416

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Silver-Catalyzed Selective Multicomponent Coupling Reactions of
Arynes with Nitriles and Isonitriles
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: Pathway selective aryne-based novel multicomponent coupling reactions with isonitriles and nitriles are
described. Crucial to these reactions is the formation of a silver−aryne complex, which shows differential reactivity toward
isonitriles and nitriles to form two different forms of ortho-nitrilium organosilver arene species. Interception of the nitrilium of
an aryne−isonitrile adduct with another isonitrile leads to the formation of benzocyclobutene-1,2-diimines, whereas the
nitrilium of an aryne−nitrile adduct renders selective formation of 3H-indol-3-imines or 3-iminoindolin-2-ol depending on the
structure of the nitrile employed.
ryne is a versatile intermediate whereby numerous
transformations have been developed to generate
of the isonitrile adduct of benzyne with esters,8e aldehydes,8b,c
cyanoformates,8k and imines8b to generate benzannulated
heterocycles. Biju further extended the reaction with CO2 to
synthesize N-substituted phthalimides.8j,l In this regard, we
consider the HDDA reaction of multiynes will be a versatile
platform that can broaden the scope of aryne-based MCR,
which can be further expanded by employing transition metal
complexes that can modulate the reactivity of arynes (Scheme
1).9
A
functionalized aromatic compounds.1 Base-mediated 1,2-
elimination of aryl halide,2a fluoride-promoted 1,2-elimination
of aryl silyl triflate,2b or thermal decomposition of
arenediazonium-2-carboxylate2c are common methods to
generate aryne species among many others. These 1,2-
elimination protocols, albeit a powerful synthetic tool in
their own right, require the preparation of prefunctionalized
aromatic precursors, which often limits the structural and
functional diversity of the products. On the other hand, direct
cyclization of tri- and tetraynes to form arynes, named as a
hexadehydro Diels−Alder (HDDA) reaction by Hoye,3 allows
for the construction of structurally more complex and diverse
arene products. The temperature range for the aromatization
subtly depends on the structure of the linker and the nature of
their substituents.4 The HDDA reaction of tri- and tetraynes
pioneered by Johnson and Ueda,5 subsequently rediscovered
by Hoye, Lee, and others,6 has resulted in a significant
expansion of the scope of aryne chemistry. Being formed under
neutral reaction conditions at a varying range of temperature,
the HDDA-derived arynes have displayed reactivity profiles
different from those generated via base- or fluoride-mediated
1,2-elimination protocols.
Scheme 1. Different Reactivity of Aryne with and without
Ag+
Exploitation of the prowess of silver-catalyzed MCR has
shown that the reaction of the putative silver-complexed aryne
2 with nitriles provided amides or imides in the presence of
water or carboxylic acid,10 whereas, in the absence of these
extra nucleophiles, quinazoline 3 was generated through path
A.11 Based on this result, we envision a new MCR of 2 with
isonitriles, which is expected to generate 4 (n = 0 or 1) via path
Multicomponent coupling reaction (MCR) is a powerful
synthetic tool to merge three or more reactants in a single-step
operation to generate relatively complex molecular structures
with high atom economy.7 Aryne-based MCRs involving
isonitrile8 have been explored over the last 20 years mainly
with simple benzynes generated from the fluoride-promoted
1,2-elimination of aryl silyl triflates. The research groups of
Yoshida, Stoltz, and Nishihara independently reported trapping
Received: December 9, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b04416
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Organic Letters
Letter
B.12 For the development of new isonitrile-based MCRs, we
wonder about the possibility of hetero-MCR to generate
products 5 and 6. Depending on the stoichiometry and
inherent reactivity of isonitrile and nitrile, aryne intermediate 2
might take path C or path D. Herein, we report on the
discovery of new silver-catalyzed MCRs of arynes with
isonitriles and nitriles to generate 4 (n = 0) and 5 devoid of
its constitutional isomer 6.
Scheme 3. [A+2B] MCR Reaction for Benzocyclobutene-1,2
Diimines
a
Our investigation commenced with screening of various
metal catalysts for maximum yield of [A+2B] or [A+3B] type
MCR products. Several catalysts displaying a good catalytic
activity have been identified among which AgSbF6 provided
the highest yield of benzocyclobutene-1,2-diimine 4aa (Table
1). The product 4 (n = 1) incorporating three isonitriles was
Table 1. Optimization for Metal Catalyst
a
a
entry
catalyst
AgSbF6
AgOTf
AgOAc
Ag2CO3
yield (%) entry
catalyst
yield (%)
1
2
3
4
5
6
62
61
5
7
55
59
7
8
9
10
11
12
Sc(OTf)3
Mg(OTf)2
Zn(OTf)2
AuCl
InCl3
none
13
32
15
10
trace
trace
a
AgSbF6 (10 mol %), PhNC (5 equiv), toluene, 150 °C, 0.5−5 h.
Sm(Otf)3
(CuOTf)2·C6H6
as 2-isocyanonaphthalene and 3-isocyanoquinoline provided
products 4ah (70%) and 4ai (68%) in increased yield.
Compared to the broad scope of aromatic isonitriles, aliphatic
isonitriles14 did not afford benzocyclobutene-1,2-diimine
products. The MCR reactions of different aryne precursors
were also examined. The reaction of tetrayne tethered with a
fluorenyl moiety afforded product 4be in 70% yield, while that
with ketoarene-tethered triyne provided 4ce in 71% yield.
Tetraynes with an N-Ts and an ether linker participated in the
reaction smoothly to generate 4da and 4ee in 61 and 48%
yield. An N-Ts-tethered tetrayne provided product 4de, the X-
ray diffraction analysis of which provided additional con-
firmation for these benzocyclobutene-1,2-diimine structures.
Also, an amide-tethered triyne afforded product 4fe in slightly
lower yield (42%).
Once formation of homocoupled benzocyclobutene-1,2-
diimine 4 was realized efficiently (path B in Scheme 2), we
pursued the possibility of generating a heterocoupled aryne−
nitrile−isonitrile adduct 5 (path C in Scheme 2). We
hypothesized that, by controlling the stoichiometry of nitrile
and isonitrile under the optimized conditions, appropriate
kinetic and thermodynamic parameters could be found to favor
reaction path C, leading to selective formation of adduct 5.
Because of the higher reactivity of isonitrile as a nucleophile,15
the incorporation of less reactive nitrile could be feasible either
with its significantly higher concentration compared to that of
isonitrile or activating aryne toward nitrile.
a
Measured by NMR with an internal standard (CH2Br2).
not detected. AgOTf also displayed a good catalytic activity in
promoting this transformation (entry 2); however, AgOAc and
Ag2CO3 were almost inactive (entries 3−4), indicating an
important counterion effect. Other catalysts such as Sm(OTf)3
and (CuOTf)2·C6H6 also generated product 4aa (55 and 59%,
entries 5 and 6). However, Sc(OTf)3, Mg(OTf)2, Zn(OTf)2,
AuCl, and InCl3 were less effective (entries 7−11). In the
absence of a catalyst under otherwise identical conditions,
product 4aa was not observed (entry 12).
Employing the optimized conditions, we next explored the
generality of [A+2B] type MCR with isonitriles and tetrayne13
1a−1f (Scheme 3). Aromatic isonitriles containing either an
electron-donating methyl (4ab), methoxy (4ac), or para-N,N-
dimethyl (4ad) or an electron-withdrawing carbomethoxy
(4ae), nitro (4af), or bromo (4ag) substituent participated in
the reaction, delivering desired benzocyclobutene-1,2-diimines
in moderate to good (43−76%) yield. Bulkier isonitriles such
Scheme 2. Silver-Catalyzed MCR Reactions of Arynes with
Isonitriles and Nitriles
To verify these hypotheses, we first examined the impact of
the stoichiometry of nitrile and isonitrile on the product
distribution and yield (Table 2). With less than 5 equiv of
nitrile, a heterocoupled product 5ag and a homocoupled
product 4aa were obtained in low yield and selectivity (entries
1−4). When 5 equiv of nitrile and isonitrile were employed, a
good total yield of products 4aa and 5ag was observed with a
10:1 ratio (entry 5). Ultimately, by running the reaction in
B
DOI: 10.1021/acs.orglett.9b04416
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Organic Letters
Letter
Table 2. Influence of Nitrile and Isonitrile Stoichiometry on
the Yield and Product Distribution
Scheme 4. Aryne−Nitrile−Isonitrile Heterocoupling to
Generate 3H-Indol-3-imine and 3-Iminoindolin-2-ol
b
b
entry
PhCN:PhNC (equiv)
3aa + 4aa + 5ag (%)
3aa:4aa:5ag
1
2
3
4
5
1:1
2:2
2:1
3:1
5:5
300:3
300:5
30
43
48
52
63
85
83
0:0.45:1
0:1.2:1
0:0.8:1
0:0.7:1
0:10:1
c
6
c
0.1:0:1
0.1:0.1:1
7
a
b
AgSbF6 (10 mol %), PhCN, PhNC, toluene, 150 °C, 2 h. Measured
c
by NMR with an internal standard (CH2Br2). Toluene is replaced
with PhCN.
nitrile as the solvent with 3−5 equiv of isonitrile, excellent
yield and selectivity for the aryne−nitrile−isonitrile coupled
product 5ag was realized (entries 6 and 7). With a large excess
of nitrile, the small difference in isonitrile stoichiometry (3
equiv vs 5 equiv) did not cause a significant difference for yield
and selectivity. Surprisingly, even in nitrile solvent, the
formation of nitrile homocoupled quinazoline 3aa was
observed only to a very minor extent.
With the optimized conditions in hand, we next explored the
aryne−nitrile−isonitrile cross condensation with different
combinations of substrates, nitriles, and isonitriles to generate
3-iminoindolin-2-ol and 3H-indol-3-imine16 depending on the
structure of the nitrile (Scheme 4). When sterically unhindered
nitriles such as acetonitrile or propionitrile were used, the
expected products 3H-indol-3-imines were not obtained.
Instead, 3-iminoindolin-2-ols 5aa−5ae and 5fd were obtained
in moderate yields (36−55%). Based on extensive exper-
imentations, we conclude that these products are derived from
3H-indol-3-imines via hydration by adventitious water in the
reaction medium. On the contrary, sterically more hindered
isobutyronitrile provided 3H-indol-3-imine 5af (48%). This
difference between methyl/ethyl versus isopropyl is due to the
increased steric bulkiness of the isopropyl group, which
disfavors the conversion the sp2-hybridized imine to the sp3-
hybridized hemiaminal moiety. We suspect that other
substituents that can electronically stabilize an imine17 should
also provide 3H-indol-3-imine products without hydration.
Indeed, the reactions with benzonitrile provided 3H-indol-3-
imines 5ag−5ak with improved yield. The reaction of N-Ts-
tethered tetrayne with benzoisonitrile and para-toluene
isonitrile provided 3H-indol-3-imines 5dg and 5dh in 40 and
36% yield, respectively. Triyne containing a phenyl amide
tether provided 3-iminoindolin-2-ol 5fd in 43% yield in
propionitrile, whereas 3H-indol-3-imine 5fg was obtained in
benzonitrile in 42% yield.
a
AgSbF6 (10 mol %), ArNC (3 equiv), RCN (solvent), 150 °C, 0.5−
2 h.
of the E-configuration, the N-phenyl group on these 3H-indol-
3-imines is perpendicular to the mainframe of the molecule to
avoid the steric clash.
Next, we explored conversion of benzocyclobutene-1,2-
diimine to other functional groups (Scheme 5). Under acidic
conditions, the 1,2-diimine moiety in 4da was readily
hydrolyzed to generate 1,2-diketone 9a.18 Treating 9a with
m-CPBA induced Baeyer−Villiger oxidation to generate
phthalic anhydride 10a in excellent yield,19 whereas treating
with H2O2 in a basic medium formed phthalic acid 11a.20
Reaction with NaBH4 afforded a mixture of cis/trans-diols
12a/a′ in 82% yield.21 Interestingly, treating 1,2-diketone 9a
with sodium alkoxide in alcoholic solvent provided 3-
alkoxyphthalides 13a,b22 in excellent yield, whereas sodium
thiolate afforded 13c in low yield.23
To gain further insight into the mechanism and selectivity
for the formation of benzocyclobutene-1,2-diimine, we carried
out DFT calculations.24 Starting from IN1, the cyclization of
bis-isonitrile adduct IN4 prefers to form benzocyclobutene-
1,2-diimine IN5 (path B) via TS3 (Figure 1). The barrier for
isonitrile addition to IN4 (path B′) to form adduct IN6 is 9.3
kcal/mol higher, and the formation of a product of a triple
The structural identity of 3H-indol-3-imine was ensured by
X-ray crystallographic analysis of 5aj, and that of 3-
iminoindolin-2-ol was confirmed by extensive NOE experi-
ments. It is worth mentioning that the stereochemistry of the
3-imino moiety in 3H-indol-3-imines (5af−5ak, 5dg−5dh,
5fg) is in the E-configuration, which is opposite to the Z-
configuration of 3-iminoindolin-2-ols (5aa−5ae, 5fd). Because
C
DOI: 10.1021/acs.orglett.9b04416
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Organic Letters
Letter
with the actual reaction that occurred to generate 3H-indol-3-
imines or 3-iminoindolin-2-ols.
Scheme 5. Transformations of a Benzocyclobutene-1,2-
diimine
a
In conclusion, we developed pathway-selective silver-
catalyzed [A+2B], [A+B+C], and [A+B+C+D] type MCRs
of arynes with isonitriles and nitriles. In the presence of
isonitrile, a silver-complexed aryne undergoes double addition
to provide benzocyclobutene-1,2-diimines as the sole product.
DFT calculations revealed that the intramolecular ring closure
of the bis-isonitrile adduct (IN4) to form benzocyclobutene-
1,2-diimines is the consequence of both the kinetic and
thermodynamic preference over triple isonitrile adduct
formation. MCR with both nitrile and isonitrile produced
3H-indol-3-imines and 3-iminoindolin-2-ols via the incorpo-
ration of each molecule of nitrile and isonitrile rather than
generating quinazolines via double nitrile addition. This
intriguing pathway selectivity can be justified by DFT
calculations, which show that in the first committed step the
aryne−nitrile adduct IN8 is kinetically favored over the aryne−
isonitrile adduct IN3. The reversal of the common reactivity
trend of nitrile and isonitrile in this step is due to the presence
of a silver catalyst, which forms the isonitrile complex IN2
which is more stable than the nitrile complex IN7. In the
second selectivity-determining step, the predominant forma-
tion of isonitrile complex IN12 from IN8 steers the overall
reaction to proceed toward the formation of 3H-indol-3-imines
and 3-iminoindolin-2-ols. The different types of aryne-based
MCRs render a broad substrate scope for all three components
and show excellent regioselectivity and pathway selectivity to
generate novel molecular structures.25
a
Conditions: (a) 12 N HCl (10 equiv), THF:H2O (4:1), 0 °C, 30
min. (b) m-CPBA (5 equiv), CH2Cl2, 0 °C, 6 h. (c) H2O2 (4 equiv),
Na2CO3 (4 equiv), THF:H2O (4:1), 10 min. (d) NaBH4 (5 equiv),
THF/MeOH, rt, 5 h. (e) RONa (3 equiv), ROH, THF:H2O (4:1), rt,
1 h. (f) PhSH (2 equiv), NaHCO3 (2 equiv), THF:H2O (4:1), rt, 5 h.
isonitrile adduct via TS4 is unfavorable and thus was not
observed.
For selective formation of 3H-indol-3-imines, the calculated
reaction profiles show that the partitioning of path B and path
C is dictated by the lower activation barrier of IN7 to form
nitrile adduct IN8 via TS5 (15.1 kcal/mol) compared to that
of IN2 to form IN3 via TS1 (22.8 kcal/mol). Once
intermediate IN8 is generated, it reacts with isonitrile or
nitrile in the subsequent step. In path A, IN8 reacts with nitrile
to generate IN9, which proceeds to generate intermediate
IN10 via TS6, and the final ring closure of IN10 through low
barrier TS7 yields IN11. On the other hand, in path C, IN8
forms isonitrile complex IN12, which leads to the next
intermediate IN13 via transition state TS8. Subsequently,
IN13 proceeds through a low barrier TS9 to provide a silver
complexed 3H-indol-3-imine IN14. The reaction profile in
path C, calculated to be the most favorable one, is consistent
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.9b04416.
The experimental procedures and spectroscopic data for
all new compounds (PDF)
Figure 1. Calculated potential energy profiles for the formation of benzocyclobutene-1,2-diimine (in red) and 3H-indol-3-imine (in blue); all
substituents on the phenyl moiety from the HDDA reaction are omitted for clarity, and full computational models are given in the Supporting
Information.
D
DOI: 10.1021/acs.orglett.9b04416
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Accession Codes
Letter
Hoye, T. R. Nat. Chem. 2018, 10, 838. (q) Karmakar, R.; Le, A.; Xie,
P.; Xia, Y.; Lee, D. Org. Lett. 2018, 20, 4168. (r) Gupta, S.; Lin, Y.;
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CCDC 1911066 and 1911067 contain the supplementary
crystallographic data for this paper. These data can be obtained
free of charge via www.ccdc.cam.ac.uk/data_request/cif, or by
emailing data_request@ccdc.cam.ac.uk, or by contacting The
Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge CB2 1EZ, UK; fax: +44 1223 336033.
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AUTHOR INFORMATION
Corresponding Authors
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■
*E-mail: dsunglee@uic.edu.
*E-mail: 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
■
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Tetrahedron 2015, 71, 2768. (m) Gesu, A.; Pozzoli, C.; Torre, E.;
The authors thank the NSF (CHE-1764141, D.L.) and NSFC
(21572163 and 21873074, Y.X.) for financial support. The
Mass Spectrometry Laboratory at UIUC is also acknowledged.
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(23) The mechanism of these transformations is under investigation
by DFT calculations.
E
DOI: 10.1021/acs.orglett.9b04416
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Organic Letters
Letter
(24) DFT studies were done at the SMD/M06/6-311++G(d,p)/
SDD//B3LYP/6-31G*/Lanl2dz level of theory. All reported energy
values are relative free energies including salvation corrections and are
relative to the energy of the silver coordinated aryne complex.
Computational details and full models for all transition states and
intermediates are provided in the Supporting Information.
(25) Based on a reviewer’s suggestion, we carried out the following
experiments to compare the reaction profiles of arynes generated via a
hexadehydro Diels−Alder reaction and fluoride-induced 1,2-elimi-
nation of 2-(trimethylsilyl)phenyl trifluoromethanesulfonate.
F
DOI: 10.1021/acs.orglett.9b04416
Org. Lett. XXXX, XXX, XXX−XXX