Gold-catalyzed formal [4π + 2π]-cycloadditions of propiolate derivatives with unactivated nitriles

Article abstract of DOI:10.1039/c5sc01950h

Gold-catalyzed hetero-[4π + 2π]-cycloadditions of tert-butyl propiolates with unactivated nitriles are described; the resulting 6H-1,3-oxazin-6-ones are not easily accessible via conventional methods. This new finding enables a one-pot gold-catalyzed synthesis of highly substituted pyridines through sequential gold-catalyzed reactions of tert-butyl propiolates with nitriles, and then with electron-deficient alkynes in the same solvent. The utility of these [4 + 2]-cycloadditions is further expanded with various aldehydes, ketones and 2-phenyloxetane, yielding satisfactory yields of cycloadducts.

Full text of DOI:10.1039/c5sc01950h

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Gold-catalyzed formal [4p + 2p]-cycloadditions of
propiolate derivatives with unactivated nitriles†
Cite this: DOI: 10.1039/c5sc01950h
*
Somnath Narayan Karad, Wei-Kang Chung and Rai-Shung Liu
Gold-catalyzed hetero-[4p + 2p]-cycloadditions of tert-butyl propiolates with unactivated nitriles are
described; the resulting 6H-1,3-oxazin-6-ones are not easily accessible via conventional methods. This
Received 1st June 2015
Accepted 17th July 2015
new finding enables
a one-pot gold-catalyzed synthesis of highly substituted pyridines through
sequential gold-catalyzed reactions of tert-butyl propiolates with nitriles, and then with electron-
deficient alkynes in the same solvent. The utility of these [4 + 2]-cycloadditions is further expanded with
various aldehydes, ketones and 2-phenyloxetane, yielding satisfactory yields of cycloadducts.
DOI: 10.1039/c5sc01950h
www.rsc.org/chemicalscience
are important structural cores commonly found in many
bioactive molecules (see ESI Fig. S1†);9,10 their availability from
Introduction
convenient t-butyl propiolates increases the synthetic utility of
this gold catalysis.
Metal-catalyzed [4p + 2p]-cycloadditions are powerful tools
for the construction of carbo- or heterocyclic frameworks.1,2
Although common nitriles and alkynes represent common
triple bond motifs, nitriles are generally less reactive than
alkynes in catalytic [4p + 2p]-cycloadditions; the chemical
stability of nitriles is reected by their bond energy (854 kJ
molꢀ1), being larger than that of alkynes (835 kJ molꢀ1).3 For
instance, thermal [4p + 2p]-cycloadditions of dienes with
unactivated nitriles required 600 ꢁC (2 min) to give pyridine
derivatives in 0.1–0.5% yields.4a In the context of catalytic [4p +
2p]-cycloadditions, not surprisingly, only one literature report
documents both nitrile/1,3-diene and nitrile/1,3-enyne systems
(eqn (1) and (2)).4b,c Ogoshi reported the rst formal [4 + 2]-
cycloadditions of common nitriles with dienes using Ni(0)
catalysts (eqn (1)).4b Although Barluenga and Aguilar reported
formal [4p + 2p]-cycloadditions of some 3-en-1-ynes with
unactivated nitriles,4c such highly functionalized 3-en-1-ynes (X
¼ cis-unsaturated ester, Z ¼ alkoxy) are too specialized to reect
the reaction generality (eqn (2)). The [4p + 2p]-nitrile cycload-
ditions still remain an unsolved task for O- and N-substituted
analogues of 1,3-dienes and 1,3-enynes (X ¼ O, NR0, eqn (1) and
(2)).5 In a signicant advance, we here report the gold-catalyzed
formal hetero-[4p + 2p]-cycloadditions6,7 of various propiolates
with nitriles to afford 6H-1,3-oxazin-6-ones efficiently (eqn (3)).8
These ndings enable the development of new cascade cyclo-
additions using three p-motifs including propiolates, nitriles
and alkynes, yielding highly substituted pyridine derivatives.
Notably, 6H-1,3-oxazin-6-ones are useful intermediates in
various organic reactions whereas highly substituted pyridines
(1)
(2)
(3)
(4)
Results and discussion
Department of Chemistry, National Tsing Hua University 101, Sec. 2, Kuang-Fu Rd.,
Hsinchu, 30013, Taiwan. E-mail: rsliu@mx.nthu.edu.tw
We envisage that direct [4p + 2p]-cycloadditions of propiolate
derivatives with nitriles provide the most convenient
synthesis of 6H-1,3-oxazin-6-ones such as 3; the current
procedures rely mainly on thermal rearrangement of N-acyl b-
† Electronic supplementary information (ESI) available. CCDC 1062512, 1062513
and 1062772. For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c5sc01950h
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lactams.8a–d To test the feasibility, as shown in Table 1, tert- propiolate species 1c–1e (R ¼ isopropyl, cyclopropyl and
butyl hept-2-ynoate (1a, 1 equiv.) was treated with benzonitrile cyclohexyl), yielding the desired products 3c–3e in satisfactory
2a (3 equiv.) and AuCl3 (5 mol%) in hot DCE (70 ꢁC, 16 h), yields (77–85%, entries 2–4). This formal cycloaddition is also
affording the desired product 3a in only a small yield (5%) applicable to alkenyl-substituted propiolate 1f to afford the
together with the initial 1a in 45% recovery (entry 1). The corresponding product 3f in 68% yield (entry 5). We tested the
use of PPh3AuCl/AgSbF6 signicantly increased the yield of reactions on various phenyl-substituted propiolate species
the desired 3a to 51% (entry 2). We also examined other 1g–1j bearing various para-substituents (X ¼ H, OMe, F and
cationic gold catalysts (5 mol%) including IPrAuCl/AgSbF6 Cl); their resulting cycloadducts 3g–3j were obtained in
and P(t-Bu)2(o-biphenyl)AuCl/AgSbF6, yielding compound satisfactory yields (65–72%, entries 6–9). We performed an X-
3a in 64% and 85% yields, respectively (see entries 3 and 4). ray diffraction study of product 3g to conrm its molecular
With the alteration of the silver salts as in P(t-Bu)2- structure.11 We also prepared 2- and 3-thienyl-substituted
(o-biphenyl)AuCl/AgX (X ¼ NTf2 and OTf), the product yields propiolate derivatives 1k and 1l; their reactions with benzo-
slightly decreased to 77% and 72%, respectively (entries 5 and nitrile afforded cycloadducts 3k and 3l in reasonable yields
ꢁ
6). AgSbF6 (70 C, 24 h) and Zn(OTf)2 (19 h) were found to be (entries 10 and 11, 55–58%). Entries 12–15 show the tests of
inactive in DCE, leading to a recovery of the starting tert-butyl hept-2-ynoate 1a with benzonitriles 2b–2e bearing
compound 1a in 72–75% yield (entries 7 and 8). The use of various para-substituents (X ¼ OMe, Me, CO2Me, Cl) that
In(OTf)3, Sc(OTf)3 and TfOH in DCE gave hept-2-ynoic acid afforded the desired cycloadducts 3m–3p in satisfactory yields
1a0 in 65–72% yield and amide species 2a-H (25–35% yield) (62–76%). These catalytic cycloadditions were compatible
along with unreacted starting compound 1a (5–15% yield, with disparate nitriles including cyclohexyl nitrile (2f), cin-
entries 9–11). The yields of compound 3a varied with the namonitrile (2g) and 3-thienyl nitrile (2h), affording the
solvents (70 ꢁC), with 65% in toluene (22 h), 82% in C6H5Cl (18 expected products 3q–3s in satisfactory yields (66–78%,
h) and 56% in 1,4-dioxane (19 h, entries 12–14).
entries 16–18).
Table 2 assesses the reaction generality using various
As inferred from the chemistry of 2H-pyran-2-ones,12,13
propiolate derivatives with varied nitriles. We rst examined one representative compound 3a (1 equiv.) was treated with
the reactions with unsubstituted propiolate species 1b; its diethyl but-2-ynedioate (4 equiv.) in hot p-xylene (150 ꢁC,
cycloaddition with benzonitrile 2a proceeded smoothly to 10 h) to afford tetrasubstituted pyridine 5a in 96% yield;
form the formal cycloadduct 3b in 65% yield (entry 1). The this reaction sequence presumably proceeds with interme-
reaction scope is extensible to aliphatically substituted diate I that is prone to a loss of CO2 (eqn (5)). As chloro-
benzene is also an effective solvent for such a nitrile/
propiolate cycloaddition (Table 1, entry 9), we developed a
Table 1 Tests of propiolate derivatives with gold catalysts
Table 2 Formal cycloadditions of various propiolates with nitriles
Yieldsa,b (%)
Entries Catalyst
Solvent
DCE
Time (h) 1a 3a 1a0 2a-H
1
AuCl3
16
12
19
18
20
22
24
19
18
22
15
22
18
45
—
—
—
—
—
75
72
15
10
5
5
51
64
85
77
72
—
—
—
—
—
65
82
56
—
—
—
—
—
—
—
—
—
—
—
—
2
Ph3PAuCl/AgSbF6 DCE
3
4
5
6
IPrAuCl/AgSbF6
LAuCl/AgSbF6
LAuCl/AgNTf2
LAuCl/AgOTf
AgSbF6
DCE
DCE
DCE
DCE
DCE
DCE
DCE
DCE
7
c
8
Zn(OTf)2
—
—
c
9
In(OTf)3
72 35
65 32
67 25
—
—
—
c
10
11
12
13
14
Sc(OTf)3
HOTfc
DCE
Toluene
C6H5Cl
LAuCl/AgSbF6
LAuCl/AgSbF6
LAuCl/AgSbF6
—
—
—
—
—
—
1,4-Dioxane 19
a
b
[1a] ¼ 0.18 M. Product yields are reported aer purication using a
silica column. IPr ¼ 1,3-bis(diisopropyl phenyl)-imidazol-2-ylidene, L ¼
c
a
b
P(t-Bu)2(o-biphenyl), Tf
¼
triuoromethansesulfonyl.
Reactions
2 (3 equiv.), [1] ¼ 0.18 M. Product yields are reported aer
carried out at room temperature.
purication using a silica column. L ¼ P(t-Bu)2(o-biphenyl).
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one-pot reaction involving the prior heating of a chloroben- ynones 4e and 4f (EWG ¼ COPh), their reactions afforded 5n
zene solution of propiolate derivative 1a, benzonitrile (3 and 5o with excellent regioselectivity and satisfactory yields
equiv.) and P(t-Bu)2(o-biphenyl) AuCl/AgSbF6 (5 mol%) at 70 (81–84%) (entries 13–14). The structures of representative
ꢁC (18 h) in a sealed tube to ensure a complete consumption compounds 5m and 5n were conrmed by proton NOE effects
of starting compound 1a; to this solution was added diethyl whereas the structure of cycloadduct 5o was elucidated with an
ꢁ
but-2-ynedioate (4 equiv.) with further heating at 150 C for HMBC experiment (see ESI†).
20 h. This one-pot process delivered the desired pyridine 5a
As nitriles are weakly nucleophilic, we envisage that alde-
in 80% yield (eqn (6)). If the three reactants in the same hydes and ketones might be applicable substrates. To our
proportions were heated together with a gold catalyst in hot pleasure, gold-catalyzed reactions of 3-phenylpropiolate 1g with
chlorobenzene (150 ꢁC, 20 h), the yield of 5a was decreased to benzaldehyde, phenyl methyl ketone and acetone in hot
38% yield.
dichloroethane (DCE) proceeded smoothly to afford formal
cycloadducts 6a–6c in high yields (86–89%, eqn (7)). The
structure of compound 6a was determined by X-ray diffraction.11
These carbonyl cycloadditions were also applicable to alkyl-
substituted propiolates (1a) and (1e), yielding the desired
compounds 6d and 6e in 87% and 77% yield, respectively (eqn
(8)). Such a reaction was, notably, accessible to an eight-
membered oxacyclic compound 6f with 2.5 mol% 1,3-bis(dii-
sopropyl phenyl)-imidazol-2-ylidene AuSbF6; it was isolated as a
single regioisomer with 67% yield with 2-phenyloxetane (3
equiv.) and its molecular structure has been conrmed by X-ray
diffraction.11 The compatibility of this gold catalysis with alde-
hydes, ketones and oxetanes truly reects a broad applicability
of these cycloadditions.
(5)
(6)
The easy operation of this one-pot reaction inspires us to
examine the scope of the reaction using various propiolates,
nitriles and alkynes; the results are summarized in Table 3.
The procedures follow exactly that described in eqn (6). In the
second stage ꢁof heating, the temperature is 150 C for entries
Table 3 One-pot operations with nitriles, propiolates and alkynes
ꢁ
1–7 and 180 C for entries 8–12. Entry 1 shows the compati-
bility of these cycloadditions with unsubstituted propiolate
derivative 1b (R ¼ H) that reacted sequentially with benzoni-
trile (2a) and diethyl but-2-ynedioate (4a) to yield the desired
pyridine 5b in 45% yield. We also tested the reactions on
various alkyl-substituted propiolates 1c–1e (R ¼ isopropyl,
cyclopropyl and cyclohexyl) that reacted with the same alkyne
and benzonitrile to afford the desired pyridine species 5c–5e in
73–76% yields (entries 2–4). The reaction is further applicable
to aryl-substituted propiolates 1g and 1l (R ¼ Ph, 3-thienyl) to
deliver the desired pyridines 5f and 5g in 61% and 51% yield,
respectively (entries 5 and 6). We tested the reactions of model
propiolate (1a) and diethyl but-2-ynedioate (4a) with various
nitriles (R1 ¼ cyclohexyl, 3-thienyl and trans-styryl), affording
the expected pyridine products 5h–5j in satisfactory yields (68–
75%, entries 7–9). The reactions were extensible to various
unsymmetric alkynes 4b–4f that reacted with propiolate (1a)
and benzonitrile (2a) with excellent or high regioselectivity
(entries 11–15). The reactions worked well for terminal alkynes
4b (EWG ¼ COOMe) and 4c (EWG ¼ COPh) to afford the
desired pyridines 5k and 5l as single regioisomers, with
respective yields of 83% and 76% (entries 10 and 11). For n-
butyl propiolate 4d, this one-pot sequence gave two insepa-
rable isomeric products 5m/5m0 ¼ 4/1, in a combined 82%
yield (entry 12). For the other n-butyl and phenyl-substituted
a
5 mol% gold catalyst, L ¼ P(t-Bu)2(o-biphenyl), R1CN (3 equiv.), R2CC–
EWG (4 equiv.), 150 ꢁC for entries 1–9 and 180 ꢁC for entries 10–14.
b
These data correspond to the reaction time t1/t2.
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(10)
The control experiments in eqn (10) indicate a mechanism
involving a prior formation of nitrilium species B via a p-alkyne
activation, proceeding with an attack of nitrile at the gold-p-
alkyne species A. As shown in Scheme 1, we postulate that the
tert-butyoxy group of species B increases the nucleophilicity of a
carbonyl group to attack this nitrilium moiety efficiently. This
process releases a tert-butyl cation to induce a demetalation to
form the observed cycloadduct 3g. Beside nitriles, various
aldehydes, ketones and oxetanes are more reactive than alkenes
upon comparison of their applicable propiolates. We postulate
that these nucleophiles generate intermediates B, E and F
bearing a large positive charge on the reacting Ca-carbons
because of their adjacent oxonium and ammonium centers. We
envisage that the propiolate cycloadditions match well with
those nucleophiles that can develop highly polarized carboca-
tions through p-alkyne activations.
Scheme 1 A postulated reaction mechanism.
(7)
(8)
(9)
Conclusions
Unactivated nitriles are known to be stable triple-bond species,
and their [4 + 2]-cycloadditions with 4p-bond motifs and other
small molecules have few successful examples.15 This work
reports the hetero-[4p + 2p]-cycloadditions of tert-butyl pro-
piolates and nitriles catalyzed by gold catalysts. Such formal
cycloadditions are applicable to diverse tert-butyl propiolates
and nitriles, yielding useful 6H-1,3-oxazin-6-ones, which are not
readily prepared with current methods.8 This new nding
enables a one-pot gold-catalyzed synthesis of highly substituted
pyridines through sequential reactions of tert-butyl propiolates
with nitriles, and then with electron-decient alkynes in the
same solvent. The utility of these [4 + 2]-cycloadditions is
further expanded with various aldehydes, ketones and 2-phe-
nyloxetane, yielding satisfactory yields of cycloadducts. This
work provides a new version of tert-butyl propiolates that
feature useful four-atom building blocks with polar p-bond
motifs such as nitriles, aldehydes and ketones, although their
reactions with alkenes were reported to be restrictive.8
Prior to this work, Shin reported gold-catalyzed [4 + 2]-
cycloadditions of alkenes with propiolic acid, which was,
however, the only applicable substrate.6a Here, we employ
diverse propiolate substrates to comply with not only nitriles
but also aldehydes, ketones and oxetanes. To understand this
discrepancy, we performed the reaction of 3-phenylpropiolic
acid (1g0) with benzonitrile with the same gold catalyst in
DCE, but the yield of the desired compound 1g was only 8%,
much smaller than that (68%) of its tert-butoxy derivative 1g
(Table 2, entry 5). Clearly, prior transformations of t-butoxy
propiolates to the propiolate acids do not occur in the course
of the reactions. For ethyl propiolate 1g00, its corresponding
reaction with benzonitrile gave the amide-addition product
3g0 in 68% yield (eqn (10)); under this condition, benzonitrile
was not effectively transformed into benzamide with this gold
catalyst.14
Acknowledgements
We thank the National Science Council, Taiwan, for nancial
support of this work.
Notes and references
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alkenes or alkynes were reported, the mechanisms were 14 In the absence of ethyl propiolate 1g00, treatment of
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benzonitrile with P(t-Bu)2(o-biphenyl)AuCl/AgSbF6 (5
mol%) in hot DCE (70 ꢁC, 15 h) gave benzamide in 34%
yield with 1g0 recovered in 60% yield. A prior hydrolysis of
benzonitrile could not be completed for the reaction in
eqn (10).
7 For gold-catalyzed cycloadditions of common nitriles with 15 Only one paper was noted for the [4 + 2]-cycloadditions of
other small molecules, see: (a) S. N. Karad and R. S. Liu,
Angew. Chem., Int. Ed., 2014, 53, 9072–9076; (b) W. He,
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