Highly Site Selective Formal [5+2] and [4+2] Annulations of Isoxazoles with Heterosubstituted Alkynes by Platinum Catalysis: Rapid Access to Functionalized 1,3-Oxazepines and 2,5-Dihydropyridines

Article abstract of DOI:10.1002/anie.201610042

Platinum-catalyzed formal [5+2] and [4+2] annulations of isoxazoles with heterosubstituted alkynes enabled the atom-economical synthesis of valuable 1,3-oxazepines and 2,5-dihydropyridines, respectively. Importantly, this Pt catalysis not only led to unique reactivity dramatically divergent from that observed under Au catalysis, but also proceeded via unprecedented α-imino platinum carbene intermediates.

Full text of DOI:10.1002/anie.201610042

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International Edition: DOI: 10.1002/anie.201610042
German Edition: DOI: 10.1002/ange.201610042
Heterocycles
Highly Site Selective Formal [5+2] and [4+2] Annulations of
Isoxazoles with Heterosubstituted Alkynes by Platinum Catalysis:
Rapid Access to Functionalized 1,3-Oxazepines and
2,5-Dihydropyridines
Wen-Bo Shen+, Xin-Yu Xiao+, Qing Sun, Bo Zhou, Xin-Qi Zhu, Juan-Zhu Yan, Xin Lu,* and
Long-Wu Ye*
À
Abstract: Platinum-catalyzed formal [5+2] and [4+2] annu-
lations of isoxazoles with heterosubstituted alkynes enabled the
atom-economical synthesis of valuable 1,3-oxazepines and 2,5-
dihydropyridines, respectively. Importantly, this Pt catalysis
not only led to unique reactivity dramatically divergent from
that observed under Au catalysis, but also proceeded via
unprecedented a-imino platinum carbene intermediates.
indoles through the gold-catalyzed C H annulation of
anthranils with ynamides by a similar strategy (Scheme 1b).[9]
Notably, nonpolarized alkynes also underwent this trans-
formation when MsOH (10 mol%) was used as an additive.
This chemistry has also been aptly exploited in the synthesis
of 3-aminopyrroles through the rhodium-catalyzed formal
[3+2] annulation of 1,2,3-triazoles with isoxazoles by Tang
and co-workers.[10]
C
atalytic transformations involving metal carbenes are
Herein, we report an unprecedented platinum-catalyzed
formal [5+2] annulation between ynamides and isoxazoles
through pathway presumably involving an a-imino Pt carbene
(Scheme 1c), in sharp contrast to the above-reported [3+2]
annulations. This Pt catalysis led to the unexpected formation
of various polysubstituted 1,3-oxazepines, which are struc-
tural motifs commonly found in natural products and
bioactive molecules.[11] This chemistry could also be extended
to the site-selective synthesis of 2,5-dihydropyridines through
among the most important aspects of homogeneous transi-
tion-metal catalysis. Recently, the generation of metal car-
benes directly from readily available alkynes has attracted
much attention, and various synthetic methods have been
developed.[1] However, the generation of Pt carbenes has
been explored relatively seldom as compared with the related
Au carbenes,[1] and most studies have focused on vinyl Pt
carbenes.[2] To the best of our knowledge, the generation of a-
oxo or a-imino Pt carbenes has been unsucessful to date.[3,4]
Hence, access to novel Pt carbenes is highly desirable, not
only for the enrichment of platinum chemistry, but also
because it may result in a selectivity switch for the con-
struction of diverse intricate scaffolds.[5]
a
platinum-catalyzed formal [4+2] annulation between
alkynyl ethers and isoxazoles. Furthermore, our proposed
mechanistic rationale for this novel cascade reaction is
strongly supported by theoretical calculations.
Considering that the formation of a bulky a-imino metal
carbene intermediate may increase the chance of 1,7-cycliza-
tion, ynamide 1a and fully substituted isoxazole 2a were
chosen as model substrates for our initial study. Typical gold
catalysts, such as [IPrAuNTf2] and [Ph3PAuNTf2], only
afforded the 1,5-cyclization product 3aa, as in our previously
reported study (Table 1, entries 1–3).[8b] However, the desired
1,7-cyclization product was produced in 30% yield with
[BrettPhosAuNTf2] as the catalyst, and importantly, no
formation of 3aa was observed (entry 5). Interesting, the
structure of this cyclized product was assigned by X-ray
diffraction[12] as 1,3-oxazepine 3a rather than the expected
1,4-oxazepine. Compounds 3a and 3aa could not be con-
verted into one another under the relevant reaction con-
ditions.[13] Product 3a was formed exclusively with Pt
catalysts, but with low efficiency even when the catalyst
loading was increased to 10 mol% (entries 7–9). Gratifyingly,
further studies revealed that the efficiency of the above PtCl2-
catalyzed reaction was substantially improved in toluene
under a CO (1 atm) atmosphere,[14] under which conditions 3a
was formed in 86% yield (Table 1, entry 11). Brønsted acids
and other (non-noble) metals did not catalyze this reaction.[13]
We explored the scope of the reaction under the
optimized reaction conditions. Ynamides with different N-
protecting groups were first investigated, and it was found
During the course of our recent studies on transition-
metal-catalyzed tandem reactions based on ynamides,[6,7] we
disclosed a novel and atom-economical route to the gener-
ation of a-imino Au carbenes through a gold-catalyzed formal
[3+2] annulation between ynamides and isoxazoles, thus
providing ready access to various 2-aminopyrroles (Sche-
me 1a).[8] Very recently, Hashmi and co-workers reported an
elegant protocol for the synthesis of unprotected 7-acyl
[*] W.-B. Shen,[+] X.-Y. Xiao,[+] Q. Sun, B. Zhou, X.-Q. Zhu, J.-Z. Yan,
Prof. Dr. X. Lu, Prof. Dr. L.-W. Ye
Collaborative Innovation Center of Chemistry for Energy Materials
State Key Laboratory of Physical Chemistry of Solid Surfaces
Key Laboratory for Chemical Biology of Fujian Province
College of Chemistry and Chemical Engineering, Xiamen University
Xiamen 361005 (China)
E-mail: xinlu@xmu.edu.cn
longwuye@xmu.edu.cn
Prof. Dr. L.-W. Ye
State Key Laboratory of Organometallic Chemistry, Shanghai
Institute of Organic Chemistry, Chinese Academy of Sciences
Shanghai 200032 (China)
[+] These authors contributed equally.
Supporting information for this article can be found under:
http://dx.doi.org/10.1002/anie.201610042.
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into the corresponding product 3l in 74% yield
(Table 2, entry 12). Attempts to extend the reaction
to alkyl-substituted or terminal ynamides only gave
a complex mixture of products.[13] To test the practi-
cality of the current catalytic system, the reaction was
carried out on a gram scale (4.0 mmol, 1.26 g) in the
presence of PtCl2 (5 mol%), and the desired product
3a was obtained in 80% yield (1.56 g), thus high-
lighting the synthetic utility of this transformation
(Table 2, entry 1).
We next extended the reaction to a variety of fully
substituted isoxazoles 2 (Table 3). To our satisfaction,
various aryl-substituted isoxazoles (R2 = Ar) were
compatible with this transformation, which gave the
corresponding 1,3-oxazepines 3m–t in 72–87% yield
(entries 1–8). Interestingly, the reaction proceeded
well to convert the corresponding styryl-substituted
isoxazole into the desired product 3u in 65% yield
(entry 9). Finally, it was found that isoxazoles with
other R1 or R3 substituents also reacted smoothly, thus
allowing the assembly of the corresponding products
3v–y in good yields (Table 3, entries 10–13). Thus, this
Scheme 1. Formal [3+2] versus [5+2] annulation via a-imino metal carbenes.
PG=protecting group.
Table 1: Optimization of the reaction conditions.[a]
Table 2: Reaction scope with different ynamides 1.[a]
Entry Metal catalyst
Reaction conditions
Yield [%][b]
3a 3aa 1a
[c]
1
2
3
4
5
6
7
8
9
[(ArO)3PAu]NTf2
[IPrAu]NTf2
[Ph3PAu]NTf2
DCE, 808C, 14 h
DCE, 808C, 14 h
DCE, 808C, 14 h
<1 51 <1
<1 73 <1
<1 59 <1
10 54 <1
30 <1 13
36 <1 10
22 <1 71
11 <1 <1
26 <1 <1
45 <1 47
[(CyJohnPhos)Au]NTf2 DCE, 808C, 14 h
[BrettPhosAu]NTf2
[BrettPhosAu]NTf2
PtCl2
DCE, 808C, 14 h
DCE, 608C, 48 h
DCE, 608C, 48 h
DCE, 608C, 48 h
DCE, 608C, 48 h
toluene, 608C, 48 h
[Pt(C2H4)2Cl2]
[Pt(MeCN)2Cl2]
PtCl2
10
11
PtCl2
toluene, CO, 608C, 48 h 86 <1 <1
[a] [1a]=0.05m. [b] The yield was determined by 1H NMR spectroscopy
with diethyl phthalate as the internal standard. [c] Ar=2,4-di-tert-
butylphenyl. BrettPhos=2-(dicyclohexylphosphanyl)-3,6-dimethoxy-
2’,4’,6’-triisopropyl-1,1’-biphenyl, CyJohnPhos=2-(dicyclohexylphospha-
nyl)biphenyl, DCE=1,2-dichloroethane, IPr=1,3-bis(2,6-diisopropyl-
phenyl)imidazol-2-ylidene, Ms=methanesulfonyl, PMB=p-methoxy-
benzyl, Tf=trifluoromethanesulfonyl.
[a] Reactions were carried out in vials under a CO atmosphere (1 atm);
[1]=0.05m; reported yields are for the isolated product. [b] The reaction
was carried out on a 4.0 mmol scale with 5 mol% PtCl2; [1a]=0.10m.
Bn=benzyl, Bs=4-bromobenzenesulfonyl.
that the methanesulfonyl-protected ynamide 1a gave the best
yield (Table 2, entries 1–4). Ynamides bearing different R1
groups were also suitable substrates and were converted into
the corresponding fully substituted 1,3-oxazepines 3e–g in
62–67% yield (entries 5–7). Various aryl-substituted yna-
mides (R2 = Ar) were screened, and the reaction furnished
the desired products 3h–k in moderate to good yields
(entries 8–11). This new reaction was also extended to
a heteroaryl-substituted ynamide, which was transformed
protocol provides a general and efficient way to prepare
synthetically important 1,3-oxazepines, which are not readily
accessible by known methods.[11,15] Our attempts to extend the
platinum-catalyzed reaction to anthranil substrates only
resulted in the formation of 7-formylindoles.[9a,13]
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Table 3: Reaction scope with different isoxazoles 2.[a]
Table 4: Formal [4+2] annulation of alkynyl ethers and isoxazoles to give
2,5-dihydropyridines.[a]
[a] Reactions were carried out in vials under a CO atmosphere (1 atm);
[4]=0.05m; reported yields are for the isolated product.
instead of the previous 1,3-oxazepines is attributed to
thermodynamic factors.[13] Once again, only the 1,5-cycliza-
tion product was obtained when an isoxazole reacted with an
alkynyl ether under gold catalysis.[13] Attempts to extend the
reaction to nonpolarized alkynes, such as 1-octyne and
phenylacetylene, only gave a complex mixture of products,
and no desired seven-membered heterocycles were
obtained.[13]
[a] Reactions were carried out in vials under a CO atmosphere (1 atm);
[1a]=0.05m; reported yields are for the isolated product.
The further synthetic transformation of the as-synthesized
products was also explored (Scheme 2).[13] Interestingly, the
treatment of 1,3-oxazepine 3a with trifluoroacetic acid (TFA)
led to the formation of 6a in 71% yield, whereas carbamate 7
was obtained in 62% yield by treatment with p-toluenesul-
fonic acid (p-TsOH). Furthermore, 2,5-dihydropyridines 5
could be converted into the corresponding 2-ethoxypyridines
8 in good yields. Notably, the reaction of 5 with tetracyano-
ethylene resulted in the formation of 9 in 73–78% yield. The
molecular structures of 6b and 9b were confirmed by X-ray
diffraction.[12]
When the scope of this Pt catalysis was extended to 3,5-
disubstituted isoxazoles, the formation of 2-aminopyrroles
was observed to a significant extent. As shown in Equa-
tion (1), the treatment of ynamide 1a with isoxazole 2o in the
presence of PtCl2 (5 mol%) under CO (1 atm) afforded the
corresponding 1,3-oxazepine 3z in 77% yield along with 2-
aminopyrrole 3za in 21% yield. We speculate that the side
1,5-cyclization may arise from the decreased steric hindrance
of the generated enone partner.
On the basis of the above experimental observations and
density functional theory (DFT) computations,[13] we propose
that the platinum- and gold-catalyzed annulations between
isoxazoles and ynamides proceed by the following mechanism
(Scheme 3): Initially, nucleophilic attack of isoxazole 2a on
the [M]-ligated ynamide A forms a vinyl metal intermediate
B,[13,14] which upon cleavage of the isoxazole N O bond can
À
isomerize to an a-imino metal carbene intermediate C. In the
case of Pt catalysis, the platinum(II) carbene C favors
kinetically 1,7-cyclization (via TSD) to afford eventually the
formal [5+2] annulation product, that is, 1,3-oxazepine 3a,
through electrocyclization[16] and ring rearrangements.[17,18]
On the contrary, in the case of Au catalysis,[8] the AuI carbene
C prefers 1,5-cyclization (via TSD’), which leads eventually to
the formal [3+2] annulation product. Note that in the key
metal carbene C, the carbenoid carbon atom bound to the
tetracoordinated PtII center is more positively charged[13] (i.e.,
less selective in terms of the nucleophilicity of attacking sites),
Besides ynamides, the reaction also proceeded well with
alkynyl ethers to furnish unexpected 2,5-dihydropyridines
through a formal [4+2] annulation. Thus, the treatment of
isoxazoles 2 with alkynyl ethers 4 in the presence of PtCl2
(5 mol%) under CO (1 atm) afforded the corresponding 2,5-
dihydropyridines 5a–m in 68–85% yield (Table 4). The
reaction presumably involves a platinum-catalyzed amina-
tion-initiated 1,7-cyclization/6p electrocyclization/epoxide-
opening cascade, and the formation of 2,5-dihydropyridines
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idines through the platinum-catalyzed formal [4+2]
annulation of alkynyl ethers with isoxazoles.
Acknowledgements
We are grateful for financial support from the
NNSFC (21272191, 21273177, 21572186, 91545105,
and 21622204), the NSFFJ for Distinguished Young
Scholars (2015J06003) and NFFTBS (No.
J1310024).
Scheme 2. Transformation of the products. DCM=dichloromethane.
Conflict of interest
The authors declare no conflict of interest.
Keywords: annulation · heterocycles · homogeneous catalysis ·
platinum · ynamides
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Scheme 3. Plausible mechanism accounting for the different chemo-
selectivity of platinum- and gold-catalyzed annulations of isoxazoles
with ynamides. Relative free energies of key intermediates and
transition states were computed at the SMD-M06/6-31G(d,p)/SDD
level of theory in a solvent (toluene for Pt catalysis and DCE for Au
catalysis) at 298 K. Data for Au catalysis are given in parentheses.
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aligned dicoordinated AuI center. Thus, the regioselectivity of
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the sterically less hindered carbonyl oxygen atom) in the case
of Pt catalysis, but depends mostly on the relative nucleophi-
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In summary, we have developed a novel platinum-
catalyzed formal [5+2] annulation of ynamides with isoxa-
zoles. Besides the efficient and atom-economical formation of
valuable 1,3-oxazepine frameworks, the reactivity is dramat-
ically divergent from that observed under Au catalysis.
Moreover, a computational study provided further evidence
for the feasibility of the proposed mechanism. Importantly,
this protocol provides the first example of the generation of a-
imino platinum carbenes. Furthermore, this Pt catalysis is also
applicable to the site-selective synthesis of 2,5-dihydropyr-
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À
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Manuscript received: October 13, 2016
Final Article published: && &&, &&&&
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
5
These are not the final page numbers!

Angewandte
Communications
Chemie
Communications
Heterocycles
W.-B. Shen, X.-Y. Xiao, Q. Sun, B. Zhou,
X.-Q. Zhu, J.-Z. Yan, X. Lu,*
L.-W. Ye*
&&&& — &&&&
Highly Site Selective Formal [5+2] and
[4+2] Annulations of Isoxazoles with
Heterosubstituted Alkynes by Platinum
Catalysis: Rapid Access to Functionalized
1,3-Oxazepines and 2,5-Dihydropyridines
Gold’s deviant relative: Platinum-cata-
lyzed formal [5+2] and [4+2] annulations
of isoxazoles and heterosubstituted
alkynes provided valuable 1,3-oxazepines
and 2,5-dihydropyridines (see scheme).
This reactivity deviates dramatically from
that observed under gold catalysis and
involves the generation of an a-imino
platinum carbene. A computational study
provided evidence for the proposed
mechanism of this unusual tandem
sequence.
6
www.angewandte.org
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2016, 55, 1 – 6
These are not the final page numbers!